Proposals for Post-Market Randomized Childhood Vaccine Trials with Ethical Designs

Proposals for Post-Market Randomized Childhood Vaccine Trials with Ethical Designs | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Method Article Proposals for Post-Market Randomized Childhood Vaccine Trials with Ethical Designs Christine S Benn, Martin Kulldorff This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7202535/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract While we know that vaccines can both save lives and cause harm, there are many things about vaccines that we do not know. What is the optimal timing and order of different vaccines? To what extent do vaccines have non-specific effects on other infectious diseases than the targeted one? Are there any harms from aluminum adjuvants? May there be adverse outcomes due to cumulative negative effects from different vaccines in the vaccine schedule even if individual vaccines are fine? The gold standard of medical research is the double-blind placebo controlled randomized trial, but there has been few of those for vaccines. We propose a set of such trials for childhood vaccines. By using factorial trial designs, and by linking trial data to electronic health records, one can answer multiple questions about multiple vaccines within the framework of two large, randomized trials, one for infants and toddlers ages 0–5 years, and another for older children ages 9–16 years. Epidemiology Childhood vaccines Safety evaluation Randomized trials Ethics 1. Introduction Vaccines are one of the most important health interventions, together with antibiotics, anesthesia and sanitation. The smallpox vaccine alone has saved millions of lives. Despite this, confidence in vaccines took a dive during the pandemic. To ensure effective and safe vaccines, ethical and well-designed randomized vaccine trials are needed. The randomized COVID-19 vaccine trials were poorly designed 1 . While proving that the vaccines had good short-term efficacy against symptomatic COVID-19 disease, they did not evaluate any of the three important outcomes: death, hospitalization and transmission. Terminated early, neither did they evaluate long-term efficacy or safety. Despite this lack of evidence, governments claimed that vaccines would both prevent infection and transmission, while instituting mandates for young people at miniscule risk from severe COVID-19 infection as well as for people with infection-acquired immunity. As it became clear that the vaccines were not able to fulfill these expectations, public trust in vaccine recommendations declined, followed by decreasing coverage of some routine childhood vaccines 2 . The designs of some earlier randomized vaccine trials have also been flawed. For example, in the randomized trial of the four-valent Gardasil vaccine against the human papilloma virus (HPV), the adjuvant containing vaccine was compared against the adjuvant rather than a saline placebo. That was unethical. In a randomized clinical trial, participating patients are generously allowing scientists to experiment on them by randomizing them into different treatment arms, and there must be a genuine uncertainty about the benefit-risk balance in each arm. The Gardasil-4 vaccine arm could potentially generate some harm, just as for any other drug or vaccine, but the hope was that the vaccine would provide benefits that outweigh any potential harms. So, that was ethical. A placebo arm would also have been ethical, since we know that it’s not harmful. For the adjuvant-only control group, we know that there is no benefit against the targeted disease, since there is no active vaccine ingredient. At the same time, there may be some harm from the adjuvant. That is, the girls in this arm were given something that could potentially be harmful without any chance of benefit. The design was also flawed in terms of safety evaluation. Since the adjuvant is in both the vaccine and control groups, it was impossible to evaluate whether there was an increased risk of any adverse reactions due to the adjuvant ingredient of the vaccine 3 . It is increasingly clear that vaccines can affect the immune system much more broadly than it was previously imagined 4 . Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines such as measles-containing vaccines and the Bacille Calmette-Guérin (BCG) vaccine against tuberculosis, have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines such as the diphtheria-tetanus-whole-cell-pertussis (DTwP) vaccine and the inactivated influenza vaccine (IIV), have in certain contexts been associated with increases in all-cause mortality and morbidity 4 , 5 . The non-specific effects are often greater for female than male individuals 4 . Immunological studies have provided several mechanisms that may explain how vaccines could modulate the immune response to unrelated pathogens, such as through trained innate immunity 6 , emergency granulopoiesis 7 , and heterologous T-cell immunity 8 . None of the currently used vaccines were assessed for their effect on other diseases and on overall health before being introduced 9 . This leaves us with gaps in our knowledge about these vaccines’ potential non-specific effects. More importantly, it leaves gaps in our knowledge about their effects on overall health, which should be seen as the sum of their specific effects, their non-specific effects and their adverse reactions. The effect on overall health is what people care about. To properly evaluate the overall health effects of vaccines, and to restore confidence in safe and important vaccines, it is necessary to conduct well-designed double-blind placebo-controlled randomized trials with sufficiently long follow-up. Equally important, there are open questions about the optimal vaccine schedule. The measles-mumps-rubella (MMR) vaccine is critically important, but what is the optimal age for the first dose? Should it be given before, together with or after the non-live diphtheria-tetanus-acelluar pertussis (DTaP) vaccine? Is it necessary to give the first dose of the hepatitis B vaccine on the day of birth? Is it better to give the HPV vaccine at age 9 or 14 years? While important vaccines like MMR are recommended in most countries, some vaccines are only recommended by some countries. There has never been a randomized trial to determine the pros and cons of different recommended schedules. The fact that quite similar countries have very different vaccination schedules is a testament to the fact that there are considerable uncertainties about the optimal schedule. In this article we propose eight double-blind placebo controlled randomized trials to evaluate various parts of the CDC recommended childhood vaccine schedule for which there is equipoise, showing how they can be done in both a scientific and ethical manner. For example, by randomizing vaccines to be given at different ages, it is possible to evaluate vaccine safety during the time between the two vaccination ages, as well as the comparative efficacy after both arms have received the vaccines. Five of the proposed trials are for the infant and toddler vaccination schedule up to 24 months of age, two are for older children, and one is for both groups. An overview of the proposed trials is provided in Table 1 . Table 1 Potential randomized trials to test the overall health effects of vaccines in the US vaccination schedule. All trials in infants/toddlers and in older children can be conducted as stand-alone trials or as part of a factorial trial. Intervention Control Design Follow-up Main Outcomes Day-of-birth vs 2 months vs 9 years for first Hep B vaccine for children of Hepatitis B negative women Arm 1: Hep B at age 2, 4 and 15 months Arm 2: Hep B at 9 years, + 1 month and + 6 months Three Hep B vaccines on day of birth, 2 months and 15 months (CDC schedule) Double-blind placebo-controlled RCT To age 2 months and 9 years respectively, with interim analyses All-cause hospitalization, non-targeted infectious disease hospitalization, neurodevelopmental disorders, asthma, allergy, autoimmune diseases MMR at 12 vs 15 vs. 24 months, before or after DTaP and other non-live vaccines Arm 1: MMR at 15 months after non-live vaccines Arm 2: MMR at 24 months MMR at 12 months, before non-live vaccines (CDC schedule) Double-blind placebo-controlled RCT To age 15 months and 4 years with interim analyses All-cause hospitalization, non-targeted infectious disease hospitalization, neurodevelopmental disorders, asthma, allergy, autoimmune diseases High vs low aluminum content of infant vaccines Low aluminum content vaccines from Sanofi Pasteur (CDC schedule) High aluminum content vaccines from GSK (CDC schedule) Double-blind placebo-controlled RCT To age 5 years with interim analyses All-cause hospitalization, neurodevelopmental disorders, asthma, allergy, autoimmune diseases Non-live influenza vs no influenza vaccine for infants No influenza vaccine from 6 months to 2 years Non-live influenza vaccines from 6 months to 2 years (CDC schedule) Double-blind placebo-controlled RCT To first influenza dose after age 2 All-cause hospitalization, non-targeted infectious disease hospitalization, influenza hospitalization, influenza infection, asthma, allergy, autoimmune diseases Live vs non-live influenza vaccine among children ages 2–4 and 9–15 respectively Annual live influenza vaccine (CDC schedule) Annual non-live influenza vaccine (CDC schedule) Double-blind placebo-controlled RCT To age 5 and 16 years respectively All-cause hospitalization, non-targeted infectious disease hospitalization, influenza hospitalization, influenza infection, asthma, allergy, autoimmune diseases US vs Danish vaccine schedule for infants and toddlers Danish schedule CDC schedule Double-blind placebo-controlled RCT To age 5 years with annual interim analyses All-cause hospitalization, non-targeted infectious disease hospitalization, autism, asthma, allergy, autoimmune diseases, neurodevelopmental disorders, obesity HPV vaccines at 9/10 vs 14/15 years HPV vaccines at 14 and 15 years HPV vaccines at 9 and 10 years (CDC schedule) Double-blind placebo-controlled RCT To age 14 years for placebo-controlled analyses. To age 25 for time of vaccination analyses All-cause hospitalization, non-targeted infectious disease hospitalization, autoimmune diseases (POTS, POI, CRPS, CFS), cervical dysplasia, condyloma First meningococcal vaccine at 11 vs 13 years Meningococcal vaccines at 13 and 16 years of age Meningococcal vaccines at 11 and 16 years of age (CDC schedule) Double-blind placebo-controlled RCT To age 13 years for placebo-controlled analyses. To age 25 for time of vaccination analyses All-cause hospitalization, non-targeted infectious disease hospitalization Table 2 Proposed trial design to study the effect of hepatitis B vaccine Age Arm 1 Arm 2 Arm 3 0 days Hep B placebo placebo 2 months Hep B Hep B placebo 4 months placebo Hep B placebo 15 months Hep B Hep B placebo 9 years 3 doses of Hep B Schedule CDC Modified CDC Danish for infants Table 3 Proposed trial design to study the effect of the timing of MMR vaccine Age Arm 1 Arm 2 Arm 3 12 months MMR + Varicella + PCV + Hib PCV + Hib + DTaP PCV + Hib 15 months DTaP MMR + Varicella DTaP 24 months placebo placebo MMR + Varicella Schedule CDC Danish plus Varicella CDC with MMR and Varicella delayed until 24 months Double-blind randomized trials are the gold standard of medical research. People, who are convinced that vaccines are safe and effective, should welcome these trials as they will prove them right if they are right. People, who are sceptic about vaccines, should also welcome these trials as they will help answer their questions, revealing problems if there are problems with the vaccines while ensuring them that they are safe if they are safe. If there turns out to be some difference between the evaluated trial arms, the CDC recommended vaccine schedule can be fine-tuned accordingly. Below, we outline the eight vaccine trials, describing the current US vaccination schedule for the vaccine(s), the knowledge gaps, and the design of the suggested trial. 2. Eight vaccine trials 2.1. Hepatitis B Vaccine Current policy The CDC recommends all infants to be vaccinated against hepatitis B, with the first dose within 24 hours of delivery, a second dose at 1–2 months plus a third dose at 6–18 months. The first dose at birth is to prevent the few percent of mothers, who are hepatitis B positive, from transmitting the virus to their children. Most other countries only recommend hepatitis B vaccine at birth to children of women who are hepatitis B positive. In Western Europe, only Portugal recommends universal hepatitis B vaccination at birth. The US has a well-functioning screening program for hepatitis B in pregnancy, and it should not be necessary to vaccinate children of hepatitis B negative women at birth. Knowledge gaps The overall health effects of hepatitis B vaccine have never been studied before they were introduced. The only post-licensure studies were done in West Africa. In two studies, receiving hepatitis B vaccine was associated with a higher female-to-male all-cause mortality ratio, which is contrary to what was expected, and which is suggestive of negative non-specific effects on the risk of other infections in females. 10 , 11 This is a pattern that has been seen for other non-live vaccines 4 . Concerns have been raised regarding providing an aluminum containing vaccine within 24 hours after birth 12 . Aluminum is known to be a neurotoxin. 13 – 15 This is particularly relevant in infancy 16 and aluminum adjuvants have been speculated to be associated with neurodevelopment disorders 17 , 18 . Suggested trial : In a randomized trial the control arm would receive the currently CDC-recommended schedule with the first dose within 24 hours of delivery, with two subsequent doses at 2 and 15 months. The second arm, with slightly delayed hepatitis B vaccination, would receive the first dose at 2 months, together with the first DTaP dose, and then subsequent doses at 4 and 15 months. A third arm would receive placebo as an infant and a delayed hepatitis B vaccine at the age of 9 years around the time of the first HPV vaccine, + 1 month, + 6 months. Overall health outcomes including all-cause infections and all-cause infectious hospitalizations should be assessed at the age of 2 months, before other vaccines were given, as well by e.g. 5 years and again by 9 years, by which time outcomes related to neurodevelopment disorders and other chronic diseases should also be assessed. In a three-armed study, there would be a 1:2 ratio of those vaccinated at birth and still unvaccinated at 2 months. Beyond 2 months there would be a 1:2 ratio of those vaccinated at birth or not, while there would be a 2:1 ratio of those who received or did not receive hepatitis B vaccine at all, with follow-up to age 9 years. 2.2. Timing of the First MMR Vaccine Current policy In the US, the live MMR vaccine, together with the live Varicella vaccine, is recommended at 12–15 months of age. Around the same time, children are due to receive the last dose of pneumococcal vaccine (PCV) and the vaccine against H. Influenzae type b (Hib) at age 12–15 months, as well as the fourth DTaP dose at age 15–18 months. Thus, most children will receive their MMR co-administered with non-live vaccines. Globally, the age of MMR vaccination varies considerably, with several European countries recommending MMR at a later age, without coadministration with other vaccines 19 . Knowledge gaps : In a WHO review of non-specific effects of vaccines 20 , based on studies from low-income settings, receiving a non-live DTP vaccine with or after a measles containing vaccine was associated with higher all-cause mortality than having the measles vaccine as the most recent vaccine. In a US observational study, between 16 and 24 months of age, children who had a live vaccine (mostly MMR) as their most recent vaccine had a 50% (95% CI: 43–57%) lower risk of non-targeted infectious hospitalizations than children having a non-live vaccine as their most recent vaccine 21 , while children who had received a combination of live and non-live vaccines had 22% (95%CI: 9–33%) lower risk than those having non-live vaccines as their most recent vaccine. This all suggests that receiving MMR after the non-live vaccines would be more optimal than receiving the non-live vaccines with or after MMR. Since small UK studies linked MMR to autism spectrum disorders, fear of autism has been an often-cited reason for MMR hesitancy 22 . Large Danish observational studies have tested the effect of MMR given as a single vaccine at age 15 months, as per Danish recommendations, and consistently reported no association 23 , 24 . It is noteworthy, though, that many of the casuistic reports of MMR-linked autism come from the UK and US, where MMR is recommended at age 12–15 months and given together with non-live vaccines. It remains to be studied whether this combination could potentially in rare circumstances be linked with neurodevelopment disorders. Suggested trial A randomized trial could allocate children to two or three arms. The control arm would receive one option within the current CDC recommended schedule in the US, with MMR, Varicella, PCV and Hib at 12 months followed by DTaP at 15 months. The second arm would receive the non-live PCV, Hib and DTaP vaccines at 12 months, followed by the live MMR and Varicella vaccines at age 15 months. This second arm is also within the recommended CDC schedule except for the fourth dose of DTaP which is given at 12 months instead of 15 to 18 months. A third arm with a more delayed MMR would receive the MMR and Varicella vaccines at 24 months, with the other vaccines according to the control arm. Outcomes should be assessed at the age of 15 months for overall health outcomes including all-cause infections and neurodevelopment disorders, and at the age of 4 years before booster vaccines are given for the same outcomes. During rare community outbreaks, children as young as 6 months may be vaccinated against measles, but they still need their subsequent regular doses. Such public health measures should be maintained during the randomized trial, so that all unvaccinated children receive the measles vaccine if there is a measles outbreak in their community. 2.3. Aluminum Containing Vaccines Current policy Some vaccines have aluminum containing adjuvants to enhance the immune response. Knowledge gap A recent study from the Vaccine Safety Datalink showed that children receiving more aluminum in their vaccine during the first two years had more asthma, with the author suggesting that further studies are warranted 25 . While this observational study adjusted for many factors, it did not adjust for all potential confounding variables 26 . A randomized study is needed to convincingly resolve the issue, as well as evaluate other health outcomes that have been speculated associated with the use of aluminum containing adjuvants, such as allergies, seizures, neurological disorders, gastrointestinal diseases, auto-immune diseases, non-specific infectious diseases, all-cause morbidity and all-cause hospitalization. Suggested trial The primary source of aluminum is the DTaP vaccines, but there is also aluminum in the Hepatitis A and B vaccines and PCV. While standalone vaccines against Hib and polio do not contain aluminum, they are part of multi-valent DTaP-containing vaccines that do. To properly evaluate the aluminum hypothesis in a randomized trial, the two arms should be identical in terms of the number and type of vaccines received. For PCV and Hepatitis A, the alternative vaccines have almost identical aluminum content, at 0.125 mg for PCV and either 0.225 or 0.250 mg for Hepatitis A. Hence, it is necessary to compare different versions of the multivalent DTaP-containing vaccines, Hepatitis B and PCV, where the two trial arms have significantly different amounts of aluminum. Using vaccines from GlaxoSmithKlein (GSK) the standard vaccination schedule for DTaP, Hepatitis B, Hib and polio, shown as Schedule A in Table 4 , can be achieved with two doses each of Pediarix (0.700 mg aluminum/dose) and Infanrix (0.500 mg), one dose of Engerix-B (0.250 mg) and four doses of Hiberix (0 mg), for a total of 2.650 mg of aluminum. By substituting everything except Engerix-B with vaccines from Sanofi Pasteur, a much lower aluminum exposure can be achieved with two doses of Vaxelis (0.319 mg), and one dose each of Pentacel (0.330 mg), Deptacel (0.330 mg), Engerix-B (0.250 mg) and ActHIB (0 mg), for a total of 1.548 mg of aluminum. Table 4 Total aluminum content for different vaccine combinations. Age Schedule A Sanofi GSK Schedule B Sanofi GSK 0 Days HepB Engerix-B Engerix-B .. .. .. 2 Months DTaP, Hib, HepB, Polio Vaxelis Pediarix + Hiberix DTaP, Hib, HepB, Polio Vaxelis Pediarix + Hiberix 4 Months DTaP, Hib, Polio Pentacel Infanrix + Ipol + Hiberix DTaP, Hib, HepB, Polio Vaxelis Pediarix + Hiberix 6 Months DTaP, Hib Deptacel + ActHIB Infanrix + Hiberix DTaP, Hib Deptacel + ActHIB Infanrix + Hiberix 15 Months DTaP, Hib, HepB, Polio Vaxelis Pediarix + Hiberix DTaP, Hib, HepB, Polio Vaxelis Pediarix + Hiberix Total Aluminum (mg) : 1.548 2.650 1.287 2.600 Since all these vaccines are already approved by FDA and since Schedule A is recommended by CDC, both trial arms would fall within existing approvals and current recommendations. If the randomized trial does not find any difference in outcomes between the two arms, that is evidence that the amount of aluminum content does not matter. If there are fewer adverse reactions in the lower aluminum arm, then that is very important knowledge that should lead to a change in vaccine recommendations. Such a result would be consistent with the concerns that aluminum containing adjuvants may cause adverse reactions. The result could also be due to other differences between the Sanofi Pasteur and GSK vaccines, such as the use of Aluminum Phosphate (Sanofi) versus Aluminum Hydroxide (GSK). An even lower aluminum exposure can be obtained if the Hepatitis B vaccinations are given at 2, 4 and 15 months as part of multivalent vaccines, instead of giving the first dose on the day of birth. Using vaccines from Sanofi Pasteur, the total aluminum content would be only 1.287 mg from three doses of Vaxelis at ages 2, 4 and 15 months and Deptacel and ActHIB and 6 months. For this alternative vaccine schedule, shown as Schedule B in Table 4 , the GSK vaccines would consist of three doses of Pediarix, one dose of Infanrix and four doses of Hiberix, with a total aluminum content of 2,600 mg; twice as much the low aluminum alternative. Children should be followed to the age of 5 for all health outcomes indicated in Table 1 . 2.4. Infant and Toddler Influenza Vaccines Current policy The CDC schedule starts with the annual non-live influenza vaccines (IIV) from age 6 months. After 2 years of age, the live attenuated influenza vaccine (LAIV) can be used instead. Infants, who receive IIV for the first time, should receive a second dose 4 weeks after the first. Once they have received two doses, the next season they are only recommended one dose. Most European countries do not recommend influenza vaccine before age 2, and several do not recommend it to children of any age 27 . Knowledge gaps The overall health effects of IIV in infants have not been studied prior to their introduction. A randomized trial from Hong Kong suggested that IIV vs placebo was associated with a 4-times increased risk of non-influenza illness (RR = 4.40 (1.31–14.8)) and concluded that IIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses 28 . In a study from Guinea-Bissau, comparing individual risk time prior to and after a national H1N1 vaccination campaign, mortality was 86% (2-242%) higher after the campaign 29 . In contrast, an observational study from Australia suggested a protective effect of IIV against RSV 30 . Suggested trial Since young children rarely get severely ill from influenza, and given the detected safety signals, a randomized trial studying the overall health effect of IIV is justified. Children could be randomly allocated to following the recommendations for IIV during the first 2 years of life, vs. not receiving IIV. By 2 years of age, the outcomes in terms of overall health can be assessed, as well as specific adverse events. 2.5. Live Versus Non-Live Influenza Vaccines for Children Current policy From the age of 2 years, CDC recommends yearly influenza vaccine, which can be of either the inactivated type (IIV) or the live attenuated intra-nasal influenza vaccine (LAIV). In Europe, countries have different recommendations with regards to vaccinating children or not and with regards to which vaccine is recommended. In Denmark, for example, influenza vaccines are not recommended for children, unless they have a chronic illness and only after an individual medical assessment. Knowledge gaps The two vaccine types have been compared for their specific effects against influenza, with LAIV seemingly more efficient in children 31 , 32 , but t he two vaccines have not been compared head-to-head for their overall health effects. Few studies have assessed the broader effects of IIV and LAIV, respectively. As indicated above, results regarding IIV have been mixed. For LAIV, a US trial indirect protective effects of LAIV against medically attended acute respiratory illness were detected in children 33 . Suggested trial It will be important to assess which vaccine has the best effects on overall health. Children could be randomly allocated to receive IIV or LAIV each year, the same vaccine each year, from 2 years of age. The outcomes in terms of overall health, influenza specific and non-influenza specific infectious diseases can be assessed yearly and cumulatively by e.g. 12 years of age. Ideally, there should be two separate trials for younger and older children of for example, age 2 to 4 years and age 9 to 15 years, respectively. 2.6. CDCs versus Danish Infant Vaccine Schedule Current policy With rational reasoning, different countries have made different conclusions on what they believe is the optimal childhood vaccine schedule. During the first 18 months of life, the CDC recommends 34? vaccination doses against 14 different diseases, while for example Denmark recommends 21 vaccination doses against 9 different diseases. Both countries recommend vaccination against measles, mumps, rubella, polio, diphtheria, tetanus, pertussis, Hib and pneumococcal infections. CDC also recommends that we vaccinate toddlers against hepatitis A, hepatitis B, varicella, rotavirus, and influenza, while childhood COVID-19 vaccines were recently stopped. There is also a difference that Denmark only recommends three doses against diphtheria, tetanus and pertussis for toddlers while CDC recommends four doses (both recommend an additional booster at age 4 to 6 years). Knowledge gap Danish children are, by international standards, very healthy. It is therefore reasonable to ask whether the CDC or Danish vaccine schedule is superior. Suggested trial That question can best be answered through a double-blind randomized trial. Two arms for such a randomized trial are shown in Table 5 . Table 5 Proposed vaccine schedules randomized according to the CDC versus Danish recommendations. DTaP and MMR counts as three vaccines each. Age CDC Denmark 0 days HepB .. 2 months DTaP,Hib,Polio,PCV,HepB,RV DTaP,Hib,Polio,PCV 4 months DTaP,Hib,Polio,PCV,RV DTaP,Hib,Polio,PCV 6 months DTaP,Hib,PCV,RV .. 12 months MMR,Varicella,Hib,Polio,PCV,HepA DTaP,Hib,Polio,PCV 15 months DTaP,HepB MMR 18 months HepA .. annual Influenza .. Total from birth to 18m 36 21 The CDC schedule allows for some flexibility in the exact timing for some vaccines. For example, MMR is recommended at age 12 to 15 months while the fourth dose of DTaP is recommended at 15 to 18 months. For the randomized trial, it is better to be more specific by defining the exact pediatrician visit for each vaccine, although there will always be some delays and catch-up. The proposed Danish scheduled has been slightly altered to coincide with the typical pediatrician visits in the United States, at 2, 4 and 12 months after birth. In Denmark, the DTaP, Hib, polio and PCV vaccines are normally given at age 3, 5 and 12 months. If a difference is found, it could either be because of the schedule as a whole or because of one or more of the individual vaccines. This would have to be investigated subsequently, after the trial completion, using either observational data or another randomized trial. 2.7. Human Papilloma Virus Vaccines Current policy The Gardasil vaccine is provided to protect against cervical cancer and a few other cancers caused by the human papilloma virus (HPV). It has been approved for both males and females, ages 9 to 26 years. CDC recommends that the first dose be given to both girls and boys sometime between the age of 9 and 12 years, with the second dose 6 to 12 months after the first. In 2022, WHO stated that one dose offers sufficient protection against cervical cancer when given to the primary target of girls ages 9 to 14 34 . Knowledge gap Gardasil has never been evaluated against a true placebo. As explained in the introduction, the Gardasil-4 trial was both unethical and unable to properly evaluate the safety of the vaccine. The subsequent nine-valent Gardasil-9 vaccine was evaluated using a saline placebo in a very small trial, but all participants had prior exposure to Gardasil-4, so none were truly unexposed to HPV vaccines. It is unknown at what age it is overall better to give the HPV vaccine, but there are some indications that antibody responses are improved the earlier the vaccine is given 35 . Suggested trial We propose a double-blind randomized trial where half the children receive the two dose Gardasil-9 vaccine at age 9 and 10 years, with the other half receiving saline placebo. The latter group will receive the two dose Garadsil-9 vaccine at age 14 and 15 years, with the first group receiving a saline placebo at those times. This provides a five-year follow-up period to evaluate the safety of the HPV vaccine against placebo. By continuing the trial beyond age 14, it also allows for the evaluation of the efficacy and safety of the two-dose regiment at age 14 and 15 years, which could be either better or worse than after age 9 and 10. Some of the primary safety concerns are postural orthostatic tachycardia syndrome (POTS), primary ovarian insufficiency (POI), complex regional pain syndrome (CRPS) and chronic fatigue syndrome (CFS) 36 . Given the low incidence of these events, a trial should be of a considerable size. 2.8. Meningococcal vaccine Current policy CDC recommends the first dose of meningococcal vaccine at age 11 or 12 years and a second dose at age 16 years. Many European countries do not use meningococcal vaccine 37 . Knowledge gap There has never been a placebo controlled randomized trial to determine whether the meningococcal vaccine affects overall health. Suggested trial We propose a double-blind randomized trial where half the children receive the two meningococcal vaccines at age 11 and 16 years, with the other half receiving them at ages 13 and 16. This provides a two-year follow-up period to evaluate the health effects of the meningococcal vaccine against placebo. 3. Methodologies 3.1. Study Outcomes For each vaccine listed above there are some health outcomes that are of specific interest, but the trials should not be limited to those outcomes. If the trials are conducted either within integrated health care systems or within a set of health insurance plans, almost any outcome can be evaluated without having to do extra clinical assessment in addition to regular patient care. That means that once the individuals have been randomized, follow-up can be performed in an efficient manner using electronic health data. For example, if the trials are performed within the Vaccine Safety Datalink partners, there is already an efficient set-up to collect outcome data, either with or without chart review. This also means that subsequently arising concerns can be evaluated using historical data long after the trial has been completed. In such a setting, it is also possible to use datamining methods to discover unsuspected adverse reactions, using the tree-based scan statistic. The Vaccine Safety Datalink has successfully used such data mining for observational data, and the same methods can be applied within a randomized trial 38 – 40 . In addition to disease specific outcomes, all trials could evaluate a set of general outcomes using electronic health data. This would include all-case morbidity, all-cause hospitalization, all non-targeted infectious diseases hospitalizations, all non-targeted infectious diseases antibiotics prescriptions, and the total number of pediatrician visits. 3.2. Randomization Randomization should ideally be done at the patient level. As non-specific effects of vaccines have been sex-differential, trials should include approximately equal numbers of boys and girls, Stratified and interaction term analysis by sex should be an integrated part of the statistical analysis plan. An alternative option is to do a cluster randomized trial, where different pediatric clinics or even different regions? are randomized to different vaccine schedules. This has some logistical advantages for rare outcomes, increasing statistical power through a larger patient population, but without double blinding and placebo injections, the design is not as methodologically strong. 3.3. Sample Size For the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial, the National Cancer Institute randomized 155,000 men and women at the patient level 41 . For the two mRNA COVID vaccines, Pfizer and Moderna randomized a combined 73,000 patients 42 , 43 . For the approval of the RotaTeq vaccine against rotavirus infections, Merck conducted a randomized trial with around 70,000 children, to properly evaluate both efficacy and safety 44 . Similar size trials are warranted for other childhood vaccines. 3.4. Factorial Designs It is both unrealistic and unnecessary to conduct separate trials with over 100,000 children for each of the eight childhood vaccine questions listed above. With factorial designs, one only needs to conduct two large trials: one for infant/toddlers and another one for the 9-15-year age group. By using a factorial design, a randomized trial can efficiently evaluate multiple vaccine questions, where the same sample size is used to simultaneously answer multiple different research questions, without losing statistical power. A second advantage is that one can evaluate interaction effects between, for example, the HPV and influenza vaccines. Factorial Design for Ages 9 to 16 As proposed in Table 6 , a randomized trial to determine whether it is better to give the Gardasil HPV vaccine at age 9 or 14 years can be combined with a randomized trial of giving the first dose of the meningococcal vaccine at age 11 or 13 years, as well as a trial of annual IIV versus LAIV versus no influenza vaccines, using a 2x2x3 factorial design. In such a design, the children are randomized so that one twelves of the children receive each of the possible twelve combinations of the timing of Gardasil, the timing of the first dose of the meningococcal vaccine, and the IIV versus LAIV versus no influenza vaccine, as shown in Table 6 . With a total sample size of for example 72,000; 6,000 children would be randomized to each of the twelve combinations, with 36,000 in each of the two arms for Gardasil and meningococcal vaccines and 24,000 in each of the three influenza arms. Table 6 Proposed 2x2x3 factorial trial design to simultaneously study the effect of HPV, meningococcal and influenza vaccines. HPV Meningococcal Influenza 2 arms 2 arms 3 arms Sample size 9 and 10 years 11 years live 6,000 9 and 10 years 11 years non-live 6,000 9 and 10 years 11 years no 6,000 9 and 10 years 13 years live 6,000 9 and 10 years 13 years non-live 6,000 9 and 10 years 13 years no 6,000 14 and 15 years 11 years live 6,000 14 and 15 years 11 years non-live 6,000 14 and 15 years 11 years no 6,000 14 and 15 years 13 years live 6,000 14 and 15 years 13 years non-live 6,000 14 and 15 years 13 years no 6,000 When Gardasil at age 9 is compared to placebo after five-years follow-up, it uses everyone in the trial, adjusting for the two meningococcal arms and the three influenza arms. The primary analysis will estimate an overall Gardasil versus placebo effect that incorporates both meningococcal arms and all three influenza arms. In secondary interaction analyses, effect modifications will be evaluated to determine if, for example, the Gardasil versus placebo effect is different among those receiving annual IIV versus LAIV influenza vaccinations. Factorial Design for Infants/Toddlers In a large randomized trial concerning the infant/toddler vaccine schedule, a 2x2x2 factorial design can be used to simultaneously evaluate the CDC versus Danish schedules, the timing of the MMR vaccine and the high versus low aluminum content. Nested within the CDC arm, one can simultaneously evaluate the timing of the first dose of the hepatitis B vaccine and the type of influenza vaccine. In a trial of complete vaccine schedules, the CDC arm has many more vaccines than the Danish arm, but some vaccines are the same and those can be evaluated together with the schedules using a factorial design. We propose a 2x2x3 factorial design that also randomize children to high versus low aluminum content vaccines, whether they are randomized to the CDC or Danish schedules, and that also randomize the timing of the MMR vaccine to 12, 15 or 24 months in accordance with the MMR specific proposal above (Table 7 ). Table 7 A 2x2x3 factorial design to evaluate the CDC versus Danish infant and toddler vaccine schedules, simultaneously with aluminum content and the timing of the MMR vaccine. Schedule Aluminum MMR 2 arms 2 arms 3 arms Sample size CDC high 12 months 12,000 CDC high 15 months 12,000 CDC high 24 months 12,000 CDC low 12 months 12,000 CDC low 15 months 12,000 CDC low 24 months 12,000 Danish high 12 months 6,000 Danish high 15 months 6,000 Danish high 24 months 6,000 Danish low 12 months 6,000 Danish low 15 months 6,000 Danish low 24 months 6,000 We propose a 2:1 randomization ratio, with twice as many children randomized to the CDC arm compared to the Danish arm, for reasons explained below. With a sample size of for example 108,000 children, we would compare 72,000 children on the CDC schedule with 36,000 children on the Danish schedule. For aluminum, the comparison would be between 54,000 children receiving the low content Sanofi Pasteur vaccines versus 54,000 receiving the higher content GSK vaccines. For the timing of the MMR vaccine, the comparison would be between 36,000 children receiving the MMR vaccine at 12 months and before the DTaP vaccine, 36,000 children receiving the MMR vaccine at 15 months and after the DTaP vaccine, and 36,000 children receiving the MMR vaccine at 24 months. Nested within the CDC arm, we would add two more arms concerning the timing of the hepatitis B vaccine and the IIV versus LAIV. This makes it a 2x2x2x3 factorial design as illustrated in Table 8 . Table 8 A 2x2x2x3 factorial design nested within the CDC arm of the CDC versus Dabish vaccine schedules. Schedule Hep B Influenza Aluminum MMR 2 arms 2 arms 2 arms 2 arms 3 arms Sample size CDC 0,2,15 live high 12 months 3,000 CDC 0,2,15 live high 15 months 3,000 CDC 0,2,15 live high 24 months 3,000 CDC 0,2,15 live low 12 months 3,000 CDC 0,2,15 live low 15 months 3,000 CDC 0,2,15 live low 24 months 3,000 CDC 0,2,15 non-live high 12 months 3,000 CDC 0,2,15 non-live high 15 months 3,000 CDC 0,2,15 non-live high 24 months 3,000 CDC 0,2,15 non-live low 12 months 3,000 CDC 0,2,15 non-live low 15 months 3,000 CDC 0,2,15 non-live low 24 months 3,000 CDC 2,4,15 live high 12 months 3,000 CDC 2,4,15 live high 15 months 3,000 CDC 2,4,15 live high 24 months 3,000 CDC 2,4,15 live low 12 months 3,000 CDC 2,4,15 live low 15 months 3,000 CDC 2,4,15 live low 24 months 3,000 CDC 2,4,15 non-live high 12 months 3,000 CDC 2,4,15 non-live high 15 months 3,000 CDC 2,4,15 non-live high 24 months 3,000 CDC 2,4,15 non-live low 12 months 3,000 CDC 2,4,15 non-live low 15 months 3,000 CDC 2,4,15 non-live low 24 months 3,000 Within the CDC arm, children could be randomized to receive the Hep B vaccine at either the standard schedule on day of birth, 2 months and 15 months, or at a slightly revised schedule of 2, 4 and 15 months. Moreover, half the children could be randomized to receive the annual IIV starting at age 6 month and the other half to receive the annual LAIV starting at age 2 years with placebo instead of the IIV vaccine before that. With a sample size 72,000 for the CDC arm, the timing of Hepatitis B vaccine would be evaluated with 36,000 children in each arm. The evaluation of the live versus non-live influenza vaccines would also have 36,000 children in each arm. Increasing the sample size for these two vaccine questions is the reason for using a 2:1 randomization ratio for the CDC versus the Danish schedule. 4. Discussion This article shows how double-blind placebo controlled randomized trials can be used in an ethical and efficient way to answer important questions about the childhood vaccine schedule for which there is equipoise. For each proposed trial, a detailed study protocol is needed, determining for example the study population, sample size, randomization, outcome definitions, data collection, sequential monitoring, and statistical analysis. Such details will very between the proposed trials and is the responsibility of the principal investigators of each randomized vaccine trial. Since the focus of the proposed trials is on the timing and safety of long standing and approved vaccines, one can argue that the trials should be funded by a government agency. There is precedence for that. In the 1980s, NIH funded the Cardiac Arrhythmia Suppression Trial, an important study to evaluate if the cardiovascular drug Tambocor reduced mortality. Approved by FDA in 1985 to prevent heart attacks, it had been shown in a randomized clinical trial to reduce cardiac dysrhythmias, a known risk factor for heart attacks. NIH was criticized for funding unethical research by randomizing patients to placebo rather than giving them the FDA approved drug to reduce their risk of heart attacks, but NIH prevailed. The trial was terminated early though. It turned out that Tambocor increased the risk of fatal heart attacks rather than reduce it. NIH was hence right to insist on evaluating an FDA approved drug using important clinical outcomes rather than a surrogate endpoint 45 . NIH could fund these proposed vaccine trials, either through a request for proposal (RFP), or internally as with the Tambocor trial. Other options are CDC or FDA. CDC runs the world’s best vaccine safety surveillance system in the form of the Vaccine Safety Datalink, in collaboration with several integrated managed care systems. By conducting the randomized vaccine trials with such a system, the electronic health records can be used to record a wide variety of health outcomes. Another option is to conduct the trials within FDA’s BEST vaccine safety surveillance system. BEST uses health insurance claims data in a similar way to VSD’s electronic health records. We have proposed randomized vaccine trials for what we think are some of the most important unanswered questions regarding non-specific vaccine outcomes, potential adverse reactions, and the optimal timing of vaccines. These also coincide with vaccine safety concern expressed by parents and other members of the public. There are several other vaccine trials that could be proposed. Around the age of five years, CDC recommends booster doses of the MMR, DTaP, varicella and polio vaccines. Similarly to what we have proposed for one-year old children, it would be interesting to randomize these older children to different ordering and timing of these vaccines. Randomized trials are also warranted for adult vaccines, such as vaccines during pregnancy or the mRNA COVID booster for older Americans, but that is outside the scope of this article. Vaccines are important for public health, but there are important unresolved questions about efficacy, safety, and overall health, that are best answered using double-blind placebo-controlled randomized vaccine trials. Conducting high quality vaccine research is also critically important to determine the efficacy and safety of vaccines and to address concerns that many parents have, and addressing such concern is the only way to ensure high confidence and coverage in the long run. When there are widely divergent views on an important medical issue, as there currently is with childhood vaccines, the only way to resolve it is through large double-blind placebo controlled randomized trials, the gold standard of medical research. Declarations Conflict of Interest The authors have no conflicts of interest that are directly relevant to the content of this article. The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of their institutions. Funding No funding was available for the work. Ethical Approval Not applicable; no data was analyzed. Consent to participate and consent for publication No patient contact or data were involved. Availability of data and materials N/A Code availability N/A Author contributions. Both authors (mentioned in alphabetical order) wrote, read and commented on the paper and approved the final version of the manuscript. References Bhattacharya J, Kulldorff M (2025) The Covid Vaccine Trials: Failures in Design and Interpretation. 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N Engl J Med 336(22):1557–1561 Angrand L, Masson JD, Rubio-Casillas A, Nosten-Bertrand M, Crépeaux G (2022) Inflammation and Autophagy: A Convergent Point between Autism Spectrum Disorder (ASD)-Related Genetic and Environmental Factors: Focus on Aluminum Adjuvants. Toxics ; 10(9) Tomljenovic L, Shaw CA (2011) Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? J Inorg Biochem 105(11):1489–1499 ECDC Vaccine Scheduler. Measles: Recommended vaccinations. https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=8&SelectedCountryIdByDisease=-1 Higgins JP, Soares-Weiser K, Lopez-Lopez JA et al (2016) Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 355:i5170 Bardenheier BH, McNeil MM, Wodi AP, McNicholl JM, DeStefano F (2017) Risk of Nontargeted Infectious Disease Hospitalizations Among US Children Following Inactivated and Live Vaccines, 2005–2014. Clin Infect Dis 65(5):729–737 Novilla MLB, Goates MC, Redelfs AH et al (2023) Why Parents Say No to Having Their Children Vaccinated against Measles: A Systematic Review of the Social Determinants of Parental Perceptions on MMR Vaccine Hesitancy. Vaccines (Basel) ; 11(5) Hviid A, Hansen JV, Frisch M, Melbye M, Measles (2019) Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study. Ann Intern Med 170(8):513–520 Madsen KM, Hviid A, Vestergaard M et al (2002) A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 347(19):1477–1482 Daley MF, Reifler LM, Glanz JM et al (2023) Association Between Aluminum Exposure From Vaccines Before Age 24 Months and Persistent Asthma at Age 24 to 59 Months. Acad Pediatr 23(1):37–46 Kulldorff M (2025) Open Peer Review of: Association Between Aluminum Exposure from Vaccines Before Age 24 Months and Persistent Asthma at Age 24 to 59 Months. J Acad Public Health ECDC Vaccine Scheduler. Influenza: Recommended vaccinations. https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=15&SelectedCountryIdByDisease=-1 Cowling BJ, Fang VJ, Nishiura H et al (2012) Increased risk of noninfluenza respiratory virus infections associated with receipt of inactivated influenza vaccine. Clin Infect Dis 54(12):1778–1783 Andersen A, Fisker AB, Rodrigues A et al (2018) National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials. Front Public Health 6:13 Le H, de Klerk N, Blyth CC, Gidding H, Fathima P, Moore HC (2023) Non-specific benefit of seasonal influenza vaccine on respiratory syncytial virus-hospitalisations in children: An instrumental variable approach using population-based data. Vaccine 41(34):5029–5036 Garai R, Jánosi Á, Krivácsy P et al (2024) Head-to-head comparison of influenza vaccines in children: a systematic review and meta-analysis. J Transl Med 22(1):903 Minozzi S, Lytras T, Gianola S et al (2022) Comparative efficacy and safety of vaccines to prevent seasonal influenza: A systematic review and network meta-analysis. eClinicalMedicine ; 46 Piedra PA, Gaglani MJ, Kozinetz CA et al (2007) Trivalent live attenuated intranasal influenza vaccine administered during the 2003–2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children. Pediatrics 120(3):e553–e564 World Health Organization. One-dose Human Papillomavirus (HPV) vaccine offers solid protection against cervical cancer (2022) https://www.who.int/news/item/11-04-2022-one-dose-human-papillomavirus-(hpv)-vaccine-offers-solid-protection-against-cervical-cancer Petäjä T, Pedersen C, Poder A et al (2011) Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women. Int J Cancer 129(9):2147–2157 Chandler RE, Juhlin K, Fransson J, Caster O, Edwards IR, Norén GN (2017) Current Safety Concerns with Human Papillomavirus Vaccine: A Cluster Analysis of Reports in VigiBase(®). Drug Saf 40(1):81–90 ECDC Vaccine Scheduler. Meningococcal Disease: Recommended vaccinations. https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=48&SelectedCountryIdByDisease=-1 Li R, Weintraub E, McNeil MM et al (2018) Meningococcal conjugate vaccine safety surveillance in the Vaccine Safety Datalink using a tree-temporal scan data mining method. Pharmacoepidemiol Drug Saf 27(4):391–397 Yih WK, Daley MF, Duffy J et al (2023) A broad assessment of covid-19 vaccine safety using tree-based data-mining in the vaccine safety datalink. Vaccine 41(3):826–835 Yih WK, Kulldorff M, Dashevsky I, Maro JC (2023) Sequential Data-Mining for Adverse Events After Recombinant Herpes Zoster Vaccination Using the Tree-Based Scan Statistic. Am J Epidemiol 192(2):276–282 Gren L, Broski K, Childs J et al (2009) Recruitment methods employed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Clin Trials 6(1):52–59 Polack FP, Thomas SJ, Kitchin N et al (2020) Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383(27):2603–2615 Baden LR, El Sahly HM, Essink B et al (2021) Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 384(5):403–416 Heyse JF, Kuter BJ, Dallas MJ, Heaton P (2008) Evaluating the safety of a rotavirus vaccine: the REST of the story. Clin Trials 5(2):131–139 Moore T, Deadly, Medicine (1995) Why Tens of Thousands of Heart Patients Died in America's Worst. Simon & Schuster, Drug Disaster Additional Declarations The authors declare no competing interests. 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Introduction","content":"\u003cp\u003eVaccines are one of the most important health interventions, together with antibiotics, anesthesia and sanitation. The smallpox vaccine alone has saved millions of lives. Despite this, confidence in vaccines took a dive during the pandemic. To ensure effective and safe vaccines, ethical and well-designed randomized vaccine trials are needed.\u003c/p\u003e\u003cp\u003eThe randomized COVID-19 vaccine trials were poorly designed\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. While proving that the vaccines had good short-term efficacy against symptomatic COVID-19 disease, they did not evaluate any of the three important outcomes: death, hospitalization and transmission. Terminated early, neither did they evaluate long-term efficacy or safety. Despite this lack of evidence, governments claimed that vaccines would both prevent infection and transmission, while instituting mandates for young people at miniscule risk from severe COVID-19 infection as well as for people with infection-acquired immunity. As it became clear that the vaccines were not able to fulfill these expectations, public trust in vaccine recommendations declined, followed by decreasing coverage of some routine childhood vaccines\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe designs of some earlier randomized vaccine trials have also been flawed. For example, in the randomized trial of the four-valent Gardasil vaccine against the human papilloma virus (HPV), the adjuvant containing vaccine was compared against the adjuvant rather than a saline placebo. That was unethical. In a randomized clinical trial, participating patients are generously allowing scientists to experiment on them by randomizing them into different treatment arms, and there must be a genuine uncertainty about the benefit-risk balance in each arm. The Gardasil-4 vaccine arm could potentially generate some harm, just as for any other drug or vaccine, but the hope was that the vaccine would provide benefits that outweigh any potential harms. So, that was ethical. A placebo arm would also have been ethical, since we know that it\u0026rsquo;s not harmful. For the adjuvant-only control group, we know that there is no benefit against the targeted disease, since there is no active vaccine ingredient. At the same time, there may be some harm from the adjuvant. That is, the girls in this arm were given something that could potentially be harmful without any chance of benefit. The design was also flawed in terms of safety evaluation. Since the adjuvant is in both the vaccine and control groups, it was impossible to evaluate whether there was an increased risk of any adverse reactions due to the adjuvant ingredient of the vaccine\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIt is increasingly clear that vaccines can affect the immune system much more broadly than it was previously imagined\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines such as measles-containing vaccines and the Bacille Calmette-Gu\u0026eacute;rin (BCG) vaccine against tuberculosis, have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines such as the diphtheria-tetanus-whole-cell-pertussis (DTwP) vaccine and the inactivated influenza vaccine (IIV), have in certain contexts been associated with increases in all-cause mortality and morbidity\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The non-specific effects are often greater for female than male individuals\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Immunological studies have provided several mechanisms that may explain how vaccines could modulate the immune response to unrelated pathogens, such as through trained innate immunity\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, emergency granulopoiesis\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, and heterologous T-cell immunity\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. None of the currently used vaccines were assessed for their effect on other diseases and on overall health before being introduced\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. This leaves us with gaps in our knowledge about these vaccines\u0026rsquo; potential non-specific effects. More importantly, it leaves gaps in our knowledge about their effects on \u003cem\u003eoverall\u003c/em\u003e health, which should be seen as the sum of their specific effects, their non-specific effects and their adverse reactions. The effect on overall health is what people care about.\u003c/p\u003e\u003cp\u003eTo properly evaluate the overall health effects of vaccines, and to restore confidence in safe and important vaccines, it is necessary to conduct well-designed double-blind placebo-controlled randomized trials with sufficiently long follow-up. Equally important, there are open questions about the optimal vaccine schedule. The measles-mumps-rubella (MMR) vaccine is critically important, but what is the optimal age for the first dose? Should it be given before, together with or after the non-live diphtheria-tetanus-acelluar pertussis (DTaP) vaccine? Is it necessary to give the first dose of the hepatitis B vaccine on the day of birth? Is it better to give the HPV vaccine at age 9 or 14 years? While important vaccines like MMR are recommended in most countries, some vaccines are only recommended by some countries. There has never been a randomized trial to determine the pros and cons of different recommended schedules. The fact that quite similar countries have very different vaccination schedules is a testament to the fact that there are considerable uncertainties about the optimal schedule.\u003c/p\u003e\u003cp\u003eIn this article we propose eight double-blind placebo controlled randomized trials to evaluate various parts of the CDC recommended childhood vaccine schedule for which there is equipoise, showing how they can be done in both a scientific and ethical manner. For example, by randomizing vaccines to be given at different ages, it is possible to evaluate vaccine safety during the time between the two vaccination ages, as well as the comparative efficacy after both arms have received the vaccines.\u003c/p\u003e\u003cp\u003eFive of the proposed trials are for the infant and toddler vaccination schedule up to 24 months of age, two are for older children, and one is for both groups. An overview of the proposed trials is provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePotential randomized trials to test the overall health effects of vaccines in the US vaccination schedule. All trials in infants/toddlers and in older children can be conducted as stand-alone trials or as part of a factorial trial.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDesign\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMain Outcomes\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDay-of-birth vs 2 months vs 9 years for first Hep B vaccine for children of Hepatitis B negative women\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArm 1: Hep B at age 2, 4 and 15 months\u003c/p\u003e\u003cp\u003eArm 2: Hep B at 9 years, +\u0026thinsp;1 month and +\u0026thinsp;6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThree Hep B vaccines on day of birth, 2 months and 15 months (CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo age 2 months and 9 years respectively, with interim analyses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, non-targeted infectious disease hospitalization, neurodevelopmental disorders, asthma, allergy, autoimmune diseases\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMMR at 12 vs 15 vs. 24 months, before or after DTaP and other non-live vaccines\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArm 1: MMR at 15 months after non-live vaccines\u003c/p\u003e\u003cp\u003eArm 2: MMR at 24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMMR at 12 months, before non-live vaccines\u003c/p\u003e\u003cp\u003e(CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo age 15 months and 4 years with interim analyses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, non-targeted infectious disease hospitalization, neurodevelopmental disorders, asthma, allergy, autoimmune diseases\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHigh vs low aluminum content of infant vaccines\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow aluminum content vaccines from Sanofi Pasteur (CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh aluminum content vaccines from GSK (CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo age 5 years with interim analyses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, neurodevelopmental disorders, asthma, allergy, autoimmune diseases\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNon-live influenza vs no influenza vaccine for infants\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo influenza vaccine from 6 months to 2 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNon-live influenza vaccines from 6 months to 2 years (CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo first influenza dose after age 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, non-targeted infectious disease hospitalization, influenza hospitalization, influenza infection, asthma, allergy, autoimmune diseases\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLive vs non-live influenza vaccine among children ages 2\u0026ndash;4 and 9\u0026ndash;15 respectively\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnnual live influenza vaccine\u003c/p\u003e\u003cp\u003e(CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAnnual non-live influenza vaccine\u003c/p\u003e\u003cp\u003e(CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo age 5 and 16 years respectively\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, non-targeted infectious disease hospitalization, influenza hospitalization, influenza infection, asthma, allergy, autoimmune diseases\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUS vs Danish vaccine schedule for infants and toddlers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDanish schedule\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCDC schedule\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo age 5 years with annual interim analyses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, non-targeted infectious disease hospitalization, autism, asthma, allergy, autoimmune diseases, neurodevelopmental disorders, obesity\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHPV vaccines at 9/10 vs 14/15 years\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHPV vaccines at 14 and 15 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHPV vaccines at 9 and 10 years (CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo age 14 years for placebo-controlled analyses. To age 25 for time of vaccination analyses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, non-targeted infectious disease hospitalization, autoimmune diseases (POTS, POI, CRPS, CFS), cervical dysplasia, condyloma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFirst meningococcal vaccine at 11 vs 13 years\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeningococcal vaccines at 13 and 16 years of age\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningococcal vaccines at 11 and 16 years of age (CDC schedule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDouble-blind placebo-controlled RCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTo age 13 years for placebo-controlled analyses. To age 25 for time of vaccination analyses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAll-cause hospitalization, non-targeted infectious disease hospitalization\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eProposed trial design to study the effect of hepatitis B vaccine\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eArm 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eArm 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArm 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHep B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHep B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHep B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHep B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHep B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHep B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 doses of Hep B\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSchedule\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eModified CDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDanish for infants\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eProposed trial design to study the effect of the timing of MMR vaccine\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArm 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eArm 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eArm 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMMR\u0026thinsp;+\u0026thinsp;Varicella\u0026thinsp;+\u0026thinsp;PCV\u0026thinsp;+\u0026thinsp;Hib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePCV\u0026thinsp;+\u0026thinsp;Hib\u0026thinsp;+\u0026thinsp;DTaP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePCV\u0026thinsp;+\u0026thinsp;Hib\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMMR\u0026thinsp;+\u0026thinsp;Varicella\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDTaP\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMMR\u0026thinsp;+\u0026thinsp;Varicella\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSchedule\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDanish plus Varicella\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCDC with MMR and Varicella delayed until 24 months\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eDouble-blind randomized trials are the gold standard of medical research. People, who are convinced that vaccines are safe and effective, should welcome these trials as they will prove them right if they are right. People, who are sceptic about vaccines, should also welcome these trials as they will help answer their questions, revealing problems if there are problems with the vaccines while ensuring them that they are safe if they are safe. If there turns out to be some difference between the evaluated trial arms, the CDC recommended vaccine schedule can be fine-tuned accordingly.\u003c/p\u003e\u003cp\u003eBelow, we outline the eight vaccine trials, describing the current US vaccination schedule for the vaccine(s), the knowledge gaps, and the design of the suggested trial.\u003c/p\u003e"},{"header":"2. Eight vaccine trials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Hepatitis B Vaccine\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eThe CDC recommends all infants to be vaccinated against hepatitis B, with the first dose within 24 hours of delivery, a second dose at 1\u0026ndash;2 months plus a third dose at 6\u0026ndash;18 months. The first dose at birth is to prevent the few percent of mothers, who are hepatitis B positive, from transmitting the virus to their children. Most other countries only recommend hepatitis B vaccine at birth to children of women who are hepatitis B positive. In Western Europe, only Portugal recommends universal hepatitis B vaccination at birth. The US has a well-functioning screening program for hepatitis B in pregnancy, and it should not be necessary to vaccinate children of hepatitis B negative women at birth.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eKnowledge gaps\u003c/strong\u003e\u003cp\u003eThe overall health effects of hepatitis B vaccine have never been studied before they were introduced. The only post-licensure studies were done in West Africa. In two studies, receiving hepatitis B vaccine was associated with a higher female-to-male all-cause mortality ratio, which is contrary to what was expected, and which is suggestive of negative non-specific effects on the risk of other infections in females. \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e This is a pattern that has been seen for other non-live vaccines\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eConcerns have been raised regarding providing an aluminum containing vaccine within 24 hours after birth\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Aluminum is known to be a neurotoxin.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e This is particularly relevant in infancy\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e and aluminum adjuvants have been speculated to be associated with neurodevelopment disorders\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSuggested trial\u003c/em\u003e: In a randomized trial the control arm would receive the currently CDC-recommended schedule with the first dose within 24 hours of delivery, with two subsequent doses at 2 and 15 months. The second arm, with slightly delayed hepatitis B vaccination, would receive the first dose at 2 months, together with the first DTaP dose, and then subsequent doses at 4 and 15 months. A third arm would receive placebo as an infant and a delayed hepatitis B vaccine at the age of 9 years around the time of the first HPV vaccine, + 1 month, + 6 months. Overall health outcomes including all-cause infections and all-cause infectious hospitalizations should be assessed at the age of 2 months, before other vaccines were given, as well by e.g. 5 years and again by 9 years, by which time outcomes related to neurodevelopment disorders and other chronic diseases should also be assessed. In a three-armed study, there would be a 1:2 ratio of those vaccinated at birth and still unvaccinated at 2 months. Beyond 2 months there would be a 1:2 ratio of those vaccinated at birth or not, while there would be a 2:1 ratio of those who received or did not receive hepatitis B vaccine at all, with follow-up to age 9 years.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Timing of the First MMR Vaccine\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eIn the US, the live MMR vaccine, together with the live Varicella vaccine, is recommended at 12\u0026ndash;15 months of age. Around the same time, children are due to receive the last dose of pneumococcal vaccine (PCV) and the vaccine against H. Influenzae type b (Hib) at age 12\u0026ndash;15 months, as well as the fourth DTaP dose at age 15\u0026ndash;18 months. Thus, most children will receive their MMR co-administered with non-live vaccines. Globally, the age of MMR vaccination varies considerably, with several European countries recommending MMR at a later age, without coadministration with other vaccines\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eKnowledge gaps\u003c/em\u003e: In a WHO review of non-specific effects of vaccines\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, based on studies from low-income settings, receiving a non-live DTP vaccine with or after a measles containing vaccine was associated with higher all-cause mortality than having the measles vaccine as the most recent vaccine. In a US observational study, between 16 and 24 months of age, children who had a live vaccine (mostly MMR) as their most recent vaccine had a 50% (95% CI: 43\u0026ndash;57%) lower risk of non-targeted infectious hospitalizations than children having a non-live vaccine as their most recent vaccine\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, while children who had received a combination of live and non-live vaccines had 22% (95%CI: 9\u0026ndash;33%) lower risk than those having non-live vaccines as their most recent vaccine. This all suggests that receiving MMR after the non-live vaccines would be more optimal than receiving the non-live vaccines with or after MMR.\u003c/p\u003e\u003cp\u003eSince small UK studies linked MMR to autism spectrum disorders, fear of autism has been an often-cited reason for MMR hesitancy\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Large Danish observational studies have tested the effect of MMR given as a single vaccine at age 15 months, as per Danish recommendations, and consistently reported no association\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. It is noteworthy, though, that many of the casuistic reports of MMR-linked autism come from the UK and US, where MMR is recommended at age 12\u0026ndash;15 months and given together with non-live vaccines. It remains to be studied whether this combination could potentially in rare circumstances be linked with neurodevelopment disorders.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSuggested trial\u003c/strong\u003e\u003cp\u003eA randomized trial could allocate children to two or three arms. The control arm would receive one option within the current CDC recommended schedule in the US, with MMR, Varicella, PCV and Hib at 12 months followed by DTaP at 15 months. The second arm would receive the non-live PCV, Hib and DTaP vaccines at 12 months, followed by the live MMR and Varicella vaccines at age 15 months. This second arm is also within the recommended CDC schedule except for the fourth dose of DTaP which is given at 12 months instead of 15 to 18 months. A third arm with a more delayed MMR would receive the MMR and Varicella vaccines at 24 months, with the other vaccines according to the control arm. Outcomes should be assessed at the age of 15 months for overall health outcomes including all-cause infections and neurodevelopment disorders, and at the age of 4 years before booster vaccines are given for the same outcomes.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eDuring rare community outbreaks, children as young as 6 months may be vaccinated against measles, but they still need their subsequent regular doses. Such public health measures should be maintained during the randomized trial, so that all unvaccinated children receive the measles vaccine if there is a measles outbreak in their community.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Aluminum Containing Vaccines\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eSome vaccines have aluminum containing adjuvants to enhance the immune response.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eKnowledge gap\u003c/strong\u003e\u003cp\u003eA recent study from the Vaccine Safety Datalink showed that children receiving more aluminum in their vaccine during the first two years had more asthma, with the author suggesting that further studies are warranted\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. While this observational study adjusted for many factors, it did not adjust for all potential confounding variables\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. A randomized study is needed to convincingly resolve the issue, as well as evaluate other health outcomes that have been speculated associated with the use of aluminum containing adjuvants, such as allergies, seizures, neurological disorders, gastrointestinal diseases, auto-immune diseases, non-specific infectious diseases, all-cause morbidity and all-cause hospitalization.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSuggested trial\u003c/strong\u003e\u003cp\u003eThe primary source of aluminum is the DTaP vaccines, but there is also aluminum in the Hepatitis A and B vaccines and PCV. While standalone vaccines against Hib and polio do not contain aluminum, they are part of multi-valent DTaP-containing vaccines that do. To properly evaluate the aluminum hypothesis in a randomized trial, the two arms should be identical in terms of the number and type of vaccines received. For PCV and Hepatitis A, the alternative vaccines have almost identical aluminum content, at 0.125 mg for PCV and either 0.225 or 0.250 mg for Hepatitis A. Hence, it is necessary to compare different versions of the multivalent DTaP-containing vaccines, Hepatitis B and PCV, where the two trial arms have significantly different amounts of aluminum.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eUsing vaccines from GlaxoSmithKlein (GSK) the standard vaccination schedule for DTaP, Hepatitis B, Hib and polio, shown as Schedule A in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, can be achieved with two doses each of Pediarix (0.700 mg aluminum/dose) and Infanrix (0.500 mg), one dose of Engerix-B (0.250 mg) and four doses of Hiberix (0 mg), for a total of 2.650 mg of aluminum. By substituting everything except Engerix-B with vaccines from Sanofi Pasteur, a much lower aluminum exposure can be achieved with two doses of Vaxelis (0.319 mg), and one dose each of Pentacel (0.330 mg), Deptacel (0.330 mg), Engerix-B (0.250 mg) and ActHIB (0 mg), for a total of 1.548 mg of aluminum.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTotal aluminum content for different vaccine combinations.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSchedule A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSanofi\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGSK\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSchedule B\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSanofi\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGSK\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0 Days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEngerix-B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEngerix-B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e..\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e..\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e..\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP, Hib, HepB, Polio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVaxelis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePediarix\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDTaP, Hib, HepB, Polio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVaxelis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePediarix\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP, Hib, Polio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePentacel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInfanrix\u0026thinsp;+\u0026thinsp;Ipol\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDTaP, Hib, HepB, Polio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVaxelis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePediarix\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP, Hib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDeptacel\u0026thinsp;+\u0026thinsp;ActHIB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInfanrix\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDTaP, Hib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDeptacel\u0026thinsp;+\u0026thinsp;ActHIB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eInfanrix\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 Months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP, Hib, HepB, Polio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVaxelis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePediarix\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDTaP, Hib, HepB, Polio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVaxelis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePediarix\u0026thinsp;+\u0026thinsp;Hiberix\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTotal Aluminum (mg)\u003c/b\u003e:\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e1.548\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e2.650\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e1.287\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e2.600\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSince all these vaccines are already approved by FDA and since Schedule A is recommended by CDC, both trial arms would fall within existing approvals and current recommendations. If the randomized trial does not find any difference in outcomes between the two arms, that is evidence that the amount of aluminum content does not matter. If there are fewer adverse reactions in the lower aluminum arm, then that is very important knowledge that should lead to a change in vaccine recommendations. Such a result would be consistent with the concerns that aluminum containing adjuvants may cause adverse reactions. The result could also be due to other differences between the Sanofi Pasteur and GSK vaccines, such as the use of Aluminum Phosphate (Sanofi) versus Aluminum Hydroxide (GSK).\u003c/p\u003e\u003cp\u003eAn even lower aluminum exposure can be obtained if the Hepatitis B vaccinations are given at 2, 4 and 15 months as part of multivalent vaccines, instead of giving the first dose on the day of birth. Using vaccines from Sanofi Pasteur, the total aluminum content would be only 1.287 mg from three doses of Vaxelis at ages 2, 4 and 15 months and Deptacel and ActHIB and 6 months. For this alternative vaccine schedule, shown as Schedule B in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the GSK vaccines would consist of three doses of Pediarix, one dose of Infanrix and four doses of Hiberix, with a total aluminum content of 2,600 mg; twice as much the low aluminum alternative.\u003c/p\u003e\u003cp\u003eChildren should be followed to the age of 5 for all health outcomes indicated in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Infant and Toddler Influenza Vaccines\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eThe CDC schedule starts with the annual non-live influenza vaccines (IIV) from age 6 months. After 2 years of age, the live attenuated influenza vaccine (LAIV) can be used instead. Infants, who receive IIV for the first time, should receive a second dose 4 weeks after the first. Once they have received two doses, the next season they are only recommended one dose. Most European countries do not recommend influenza vaccine before age 2, and several do not recommend it to children of any age\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eKnowledge gaps\u003c/strong\u003e\u003cp\u003eThe overall health effects of IIV in infants have not been studied prior to their introduction. A randomized trial from Hong Kong suggested that IIV vs placebo was associated with a 4-times increased risk of non-influenza illness (RR\u0026thinsp;=\u0026thinsp;4.40 (1.31\u0026ndash;14.8)) and concluded that IIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In a study from Guinea-Bissau, comparing individual risk time prior to and after a national H1N1 vaccination campaign, mortality was 86% (2-242%) higher after the campaign\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. In contrast, an observational study from Australia suggested a protective effect of IIV against RSV\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSuggested trial\u003c/strong\u003e\u003cp\u003eSince young children rarely get severely ill from influenza, and given the detected safety signals, a randomized trial studying the overall health effect of IIV is justified. Children could be randomly allocated to following the recommendations for IIV during the first 2 years of life, vs. not receiving IIV. By 2 years of age, the outcomes in terms of overall health can be assessed, as well as specific adverse events.\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Live Versus Non-Live Influenza Vaccines for Children\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eFrom the age of 2 years, CDC recommends yearly influenza vaccine, which can be of either the inactivated type (IIV) or the live attenuated intra-nasal influenza vaccine (LAIV). In Europe, countries have different recommendations with regards to vaccinating children or not and with regards to which vaccine is recommended. In Denmark, for example, influenza vaccines are not recommended for children, unless they have a chronic illness and only after an individual medical assessment.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eKnowledge gaps\u003c/strong\u003e\u003cp\u003eThe two vaccine types have been compared for their specific effects against influenza, with LAIV seemingly more efficient in children\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, \u003cem\u003ebut t\u003c/em\u003ehe two vaccines have not been compared head-to-head for their overall health effects. Few studies have assessed the broader effects of IIV and LAIV, respectively. As indicated above, results regarding IIV have been mixed. For LAIV, a US trial indirect protective effects of LAIV against medically attended acute respiratory illness were detected in children\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSuggested trial\u003c/strong\u003e\u003cp\u003eIt will be important to assess which vaccine has the best effects on overall health. Children could be randomly allocated to receive IIV or LAIV each year, the same vaccine each year, from 2 years of age. The outcomes in terms of overall health, influenza specific and non-influenza specific infectious diseases can be assessed yearly and cumulatively by e.g. 12 years of age. Ideally, there should be two separate trials for younger and older children of for example, age 2 to 4 years and age 9 to 15 years, respectively.\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6. CDCs versus Danish Infant Vaccine Schedule\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eWith rational reasoning, different countries have made different conclusions on what they believe is the optimal childhood vaccine schedule. During the first 18 months of life, the CDC recommends 34? vaccination doses against 14 different diseases, while for example Denmark recommends 21 vaccination doses against 9 different diseases. Both countries recommend vaccination against measles, mumps, rubella, polio, diphtheria, tetanus, pertussis, Hib and pneumococcal infections. CDC also recommends that we vaccinate toddlers against hepatitis A, hepatitis B, varicella, rotavirus, and influenza, while childhood COVID-19 vaccines were recently stopped. There is also a difference that Denmark only recommends three doses against diphtheria, tetanus and pertussis for toddlers while CDC recommends four doses (both recommend an additional booster at age 4 to 6 years).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eKnowledge gap\u003c/strong\u003e\u003cp\u003eDanish children are, by international standards, very healthy. It is therefore reasonable to ask whether the CDC or Danish vaccine schedule is superior.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSuggested trial\u003c/strong\u003e\u003cp\u003eThat question can best be answered through a double-blind randomized trial. Two arms for such a randomized trial are shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eProposed vaccine schedules randomized according to the CDC versus Danish recommendations. DTaP and MMR counts as three vaccines each.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDenmark\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e..\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP,Hib,Polio,PCV,HepB,RV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDTaP,Hib,Polio,PCV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP,Hib,Polio,PCV,RV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDTaP,Hib,Polio,PCV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP,Hib,PCV,RV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e..\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMMR,Varicella,Hib,Polio,PCV,HepA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDTaP,Hib,Polio,PCV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDTaP,HepB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMMR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e..\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eannual\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInfluenza\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e..\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal from birth to 18m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/p\u003e\u003cp\u003eThe CDC schedule allows for some flexibility in the exact timing for some vaccines. For example, MMR is recommended at age 12 to 15 months while the fourth dose of DTaP is recommended at 15 to 18 months. For the randomized trial, it is better to be more specific by defining the exact pediatrician visit for each vaccine, although there will always be some delays and catch-up.\u003c/p\u003e\u003cp\u003eThe proposed Danish scheduled has been slightly altered to coincide with the typical pediatrician visits in the United States, at 2, 4 and 12 months after birth. In Denmark, the DTaP, Hib, polio and PCV vaccines are normally given at age 3, 5 and 12 months.\u003c/p\u003e\u003cp\u003eIf a difference is found, it could either be because of the schedule as a whole or because of one or more of the individual vaccines. This would have to be investigated subsequently, after the trial completion, using either observational data or another randomized trial.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.7. Human Papilloma Virus Vaccines\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eThe Gardasil vaccine is provided to protect against cervical cancer and a few other cancers caused by the human papilloma virus (HPV). It has been approved for both males and females, ages 9 to 26 years. CDC recommends that the first dose be given to both girls and boys sometime between the age of 9 and 12 years, with the second dose 6 to 12 months after the first. In 2022, WHO stated that one dose offers sufficient protection against cervical cancer when given to the primary target of girls ages 9 to 14\u003csup\u003e34\u003c/sup\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eKnowledge gap\u003c/strong\u003e\u003cp\u003eGardasil has never been evaluated against a true placebo. As explained in the introduction, the Gardasil-4 trial was both unethical and unable to properly evaluate the safety of the vaccine. The subsequent nine-valent Gardasil-9 vaccine was evaluated using a saline placebo in a very small trial, but all participants had prior exposure to Gardasil-4, so none were truly unexposed to HPV vaccines.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eIt is unknown at what age it is overall better to give the HPV vaccine, but there are some indications that antibody responses are improved the earlier the vaccine is given\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSuggested trial\u003c/strong\u003e\u003cp\u003eWe propose a double-blind randomized trial where half the children receive the two dose Gardasil-9 vaccine at age 9 and 10 years, with the other half receiving saline placebo. The latter group will receive the two dose Garadsil-9 vaccine at age 14 and 15 years, with the first group receiving a saline placebo at those times.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eThis provides a five-year follow-up period to evaluate the safety of the HPV vaccine against placebo. By continuing the trial beyond age 14, it also allows for the evaluation of the efficacy and safety of the two-dose regiment at age 14 and 15 years, which could be either better or worse than after age 9 and 10.\u003c/p\u003e\u003cp\u003eSome of the primary safety concerns are postural orthostatic tachycardia syndrome (POTS), primary ovarian insufficiency (POI), complex regional pain syndrome (CRPS) and chronic fatigue syndrome (CFS)\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Given the low incidence of these events, a trial should be of a considerable size.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e2.8. Meningococcal vaccine\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eCurrent policy\u003c/strong\u003e\u003cp\u003eCDC recommends the first dose of meningococcal vaccine at age 11 or 12 years and a second dose at age 16 years. Many European countries do not use meningococcal vaccine\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eKnowledge gap\u003c/strong\u003e\u003cp\u003eThere has never been a placebo controlled randomized trial to determine whether the meningococcal vaccine affects overall health.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSuggested trial\u003c/strong\u003e\u003cp\u003eWe propose a double-blind randomized trial where half the children receive the two meningococcal vaccines at age 11 and 16 years, with the other half receiving them at ages 13 and 16. This provides a two-year follow-up period to evaluate the health effects of the meningococcal vaccine against placebo.\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Methodologies","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Study Outcomes\u003c/h2\u003e\u003cp\u003eFor each vaccine listed above there are some health outcomes that are of specific interest, but the trials should not be limited to those outcomes.\u003c/p\u003e\u003cp\u003eIf the trials are conducted either within integrated health care systems or within a set of health insurance plans, almost any outcome can be evaluated without having to do extra clinical assessment in addition to regular patient care. That means that once the individuals have been randomized, follow-up can be performed in an efficient manner using electronic health data. For example, if the trials are performed within the Vaccine Safety Datalink partners, there is already an efficient set-up to collect outcome data, either with or without chart review. This also means that subsequently arising concerns can be evaluated using historical data long after the trial has been completed.\u003c/p\u003e\u003cp\u003eIn such a setting, it is also possible to use datamining methods to discover unsuspected adverse reactions, using the tree-based scan statistic. The Vaccine Safety Datalink has successfully used such data mining for observational data, and the same methods can be applied within a randomized trial\u003csup\u003e\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn addition to disease specific outcomes, all trials could evaluate a set of general outcomes using electronic health data. This would include all-case morbidity, all-cause hospitalization, all non-targeted infectious diseases hospitalizations, all non-targeted infectious diseases antibiotics prescriptions, and the total number of pediatrician visits.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Randomization\u003c/h2\u003e\u003cp\u003eRandomization should ideally be done at the patient level. As non-specific effects of vaccines have been sex-differential, trials should include approximately equal numbers of boys and girls, Stratified and interaction term analysis by sex should be an integrated part of the statistical analysis plan. An alternative option is to do a cluster randomized trial, where different pediatric clinics or even different regions? are randomized to different vaccine schedules. This has some logistical advantages for rare outcomes, increasing statistical power through a larger patient population, but without double blinding and placebo injections, the design is not as methodologically strong.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Sample Size\u003c/h2\u003e\u003cp\u003eFor the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial, the National Cancer Institute randomized 155,000 men and women at the patient level\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. For the two mRNA COVID vaccines, Pfizer and Moderna randomized a combined 73,000 patients\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. For the approval of the RotaTeq vaccine against rotavirus infections, Merck conducted a randomized trial with around 70,000 children, to properly evaluate both efficacy and safety\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Similar size trials are warranted for other childhood vaccines.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.4. Factorial Designs\u003c/h2\u003e\u003cp\u003eIt is both unrealistic and unnecessary to conduct separate trials with over 100,000 children for each of the eight childhood vaccine questions listed above. With factorial designs, one only needs to conduct two large trials: one for infant/toddlers and another one for the 9-15-year age group.\u003c/p\u003e\u003cp\u003eBy using a factorial design, a randomized trial can efficiently evaluate multiple vaccine questions, where the same sample size is used to simultaneously answer multiple different research questions, without losing statistical power. A second advantage is that one can evaluate interaction effects between, for example, the HPV and influenza vaccines.\u003c/p\u003e\u003cp\u003e\u003cem\u003eFactorial Design for Ages 9 to 16\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAs proposed in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, a randomized trial to determine whether it is better to give the Gardasil HPV vaccine at age 9 or 14 years can be combined with a randomized trial of giving the first dose of the meningococcal vaccine at age 11 or 13 years, as well as a trial of annual IIV versus LAIV versus no influenza vaccines, using a 2x2x3 factorial design. In such a design, the children are randomized so that one twelves of the children receive each of the possible twelve combinations of the timing of Gardasil, the timing of the first dose of the meningococcal vaccine, and the IIV versus LAIV versus no influenza vaccine, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. With a total sample size of for example 72,000; 6,000 children would be randomized to each of the twelve combinations, with 36,000 in each of the two arms for Gardasil and meningococcal vaccines and 24,000 in each of the three influenza arms.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eProposed 2x2x3 factorial trial design to simultaneously study the effect of HPV, meningococcal and influenza vaccines.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHPV\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeningococcal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eInfluenza\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9 and 10 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9 and 10 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9 and 10 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9 and 10 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9 and 10 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9 and 10 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14 and 15 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14 and 15 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14 and 15 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14 and 15 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14 and 15 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14 and 15 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eno\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWhen Gardasil at age 9 is compared to placebo after five-years follow-up, it uses everyone in the trial, adjusting for the two meningococcal arms and the three influenza arms. The primary analysis will estimate an overall Gardasil versus placebo effect that incorporates both meningococcal arms and all three influenza arms. In secondary interaction analyses, effect modifications will be evaluated to determine if, for example, the Gardasil versus placebo effect is different among those receiving annual IIV versus LAIV influenza vaccinations.\u003c/p\u003e\u003cp\u003e\u003cem\u003eFactorial Design for Infants/Toddlers\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn a large randomized trial concerning the infant/toddler vaccine schedule, a 2x2x2 factorial design can be used to simultaneously evaluate the CDC versus Danish schedules, the timing of the MMR vaccine and the high versus low aluminum content. Nested within the CDC arm, one can simultaneously evaluate the timing of the first dose of the hepatitis B vaccine and the type of influenza vaccine.\u003c/p\u003e\u003cp\u003eIn a trial of complete vaccine schedules, the CDC arm has many more vaccines than the Danish arm, but some vaccines are the same and those can be evaluated together with the schedules using a factorial design. We propose a 2x2x3 factorial design that also randomize children to high versus low aluminum content vaccines, whether they are randomized to the CDC or Danish schedules, and that also randomize the timing of the MMR vaccine to 12, 15 or 24 months in accordance with the MMR specific proposal above (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eA 2x2x3 factorial design to evaluate the CDC versus Danish infant and toddler vaccine schedules, simultaneously with aluminum content and the timing of the MMR vaccine.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSchedule\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAluminum\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMMR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDanish\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDanish\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDanish\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDanish\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDanish\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDanish\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWe propose a 2:1 randomization ratio, with twice as many children randomized to the CDC arm compared to the Danish arm, for reasons explained below. With a sample size of for example 108,000 children, we would compare 72,000 children on the CDC schedule with 36,000 children on the Danish schedule. For aluminum, the comparison would be between 54,000 children receiving the low content Sanofi Pasteur vaccines versus 54,000 receiving the higher content GSK vaccines. For the timing of the MMR vaccine, the comparison would be between 36,000 children receiving the MMR vaccine at 12 months and before the DTaP vaccine, 36,000 children receiving the MMR vaccine at 15 months and after the DTaP vaccine, and 36,000 children receiving the MMR vaccine at 24 months.\u003c/p\u003e\u003cp\u003eNested within the CDC arm, we would add two more arms concerning the timing of the hepatitis B vaccine and the IIV versus LAIV. This makes it a 2x2x2x3 factorial design as illustrated in Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eA 2x2x2x3 factorial design nested within the CDC arm of the CDC versus Dabish vaccine schedules.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSchedule\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHep B\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eInfluenza\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAluminum\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMMR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 arms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSample size\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,2,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ehigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-live\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWithin the CDC arm, children could be randomized to receive the Hep B vaccine at either the standard schedule on day of birth, 2 months and 15 months, or at a slightly revised schedule of 2, 4 and 15 months. Moreover, half the children could be randomized to receive the annual IIV starting at age 6 month and the other half to receive the annual LAIV starting at age 2 years with placebo instead of the IIV vaccine before that.\u003c/p\u003e\u003cp\u003eWith a sample size 72,000 for the CDC arm, the timing of Hepatitis B vaccine would be evaluated with 36,000 children in each arm. The evaluation of the live versus non-live influenza vaccines would also have 36,000 children in each arm. Increasing the sample size for these two vaccine questions is the reason for using a 2:1 randomization ratio for the CDC versus the Danish schedule.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis article shows how double-blind placebo controlled randomized trials can be used in an ethical and efficient way to answer important questions about the childhood vaccine schedule for which there is equipoise.\u003c/p\u003e\u003cp\u003eFor each proposed trial, a detailed study protocol is needed, determining for example the study population, sample size, randomization, outcome definitions, data collection, sequential monitoring, and statistical analysis. Such details will very between the proposed trials and is the responsibility of the principal investigators of each randomized vaccine trial.\u003c/p\u003e\u003cp\u003eSince the focus of the proposed trials is on the timing and safety of long standing and approved vaccines, one can argue that the trials should be funded by a government agency. There is precedence for that.\u003c/p\u003e\u003cp\u003eIn the 1980s, NIH funded the Cardiac Arrhythmia Suppression Trial, an important study to evaluate if the cardiovascular drug Tambocor reduced mortality. Approved by FDA in 1985 to prevent heart attacks, it had been shown in a randomized clinical trial to reduce cardiac dysrhythmias, a known risk factor for heart attacks. NIH was criticized for funding unethical research by randomizing patients to placebo rather than giving them the FDA approved drug to reduce their risk of heart attacks, but NIH prevailed. The trial was terminated early though. It turned out that Tambocor increased the risk of fatal heart attacks rather than reduce it. NIH was hence right to insist on evaluating an FDA approved drug using important clinical outcomes rather than a surrogate endpoint\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNIH could fund these proposed vaccine trials, either through a request for proposal (RFP), or internally as with the Tambocor trial. Other options are CDC or FDA. CDC runs the world\u0026rsquo;s best vaccine safety surveillance system in the form of the Vaccine Safety Datalink, in collaboration with several integrated managed care systems. By conducting the randomized vaccine trials with such a system, the electronic health records can be used to record a wide variety of health outcomes. Another option is to conduct the trials within FDA\u0026rsquo;s BEST vaccine safety surveillance system. BEST uses health insurance claims data in a similar way to VSD\u0026rsquo;s electronic health records.\u003c/p\u003e\u003cp\u003eWe have proposed randomized vaccine trials for what we think are some of the most important unanswered questions regarding non-specific vaccine outcomes, potential adverse reactions, and the optimal timing of vaccines. These also coincide with vaccine safety concern expressed by parents and other members of the public.\u003c/p\u003e\u003cp\u003eThere are several other vaccine trials that could be proposed. Around the age of five years, CDC recommends booster doses of the MMR, DTaP, varicella and polio vaccines. Similarly to what we have proposed for one-year old children, it would be interesting to randomize these older children to different ordering and timing of these vaccines. Randomized trials are also warranted for adult vaccines, such as vaccines during pregnancy or the mRNA COVID booster for older Americans, but that is outside the scope of this article.\u003c/p\u003e\u003cp\u003eVaccines are important for public health, but there are important unresolved questions about efficacy, safety, and overall health, that are best answered using double-blind placebo-controlled randomized vaccine trials. Conducting high quality vaccine research is also critically important to determine the efficacy and safety of vaccines and to address concerns that many parents have, and addressing such concern is the only way to ensure high confidence and coverage in the long run.\u003c/p\u003e\u003cp\u003eWhen there are widely divergent views on an important medical issue, as there currently is with childhood vaccines, the only way to resolve it is through large double-blind placebo controlled randomized trials, the gold standard of medical research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest that are directly relevant to the content of this article. The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of their institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was available for the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable; no data was analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate and consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo patient contact or data were involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth authors (mentioned in alphabetical order) wrote, read and commented on the paper and approved the final version of the manuscript. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBhattacharya J, Kulldorff M (2025) The Covid Vaccine Trials: Failures in Design and Interpretation. 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Simon \u0026amp; Schuster, Drug Disaster\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Childhood vaccines, Safety evaluation, Randomized trials, Ethics","lastPublishedDoi":"10.21203/rs.3.rs-7202535/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7202535/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile we know that vaccines can both save lives and cause harm, there are many things about vaccines that we do not know. What is the optimal timing and order of different vaccines? To what extent do vaccines have non-specific effects on other infectious diseases than the targeted one? Are there any harms from aluminum adjuvants? May there be adverse outcomes due to cumulative negative effects from different vaccines in the vaccine schedule even if individual vaccines are fine? The gold standard of medical research is the double-blind placebo controlled randomized trial, but there has been few of those for vaccines. We propose a set of such trials for childhood vaccines. By using factorial trial designs, and by linking trial data to electronic health records, one can answer multiple questions about multiple vaccines within the framework of two large, randomized trials, one for infants and toddlers ages 0\u0026ndash;5 years, and another for older children ages 9\u0026ndash;16 years.\u003c/p\u003e","manuscriptTitle":"Proposals for Post-Market Randomized Childhood Vaccine Trials with Ethical Designs","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-25 04:27:50","doi":"10.21203/rs.3.rs-7202535/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a3760fff-5d08-4a9c-9e0f-6a0f95caccfc","owner":[],"postedDate":"July 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":52041130,"name":"Epidemiology"}],"tags":[],"updatedAt":"2025-07-25T04:27:50+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-25 04:27:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7202535","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7202535","identity":"rs-7202535","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}