Preliminary safety data from a randomised trial of early versus standard timing of administration of measles-rubella vaccine in Ugandan infants

Preliminary safety data from a randomised trial of early versus standard timing of administration of measles-rubella vaccine in Ugandan infants | 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 Clinical trial Preliminary safety data from a randomised trial of early versus standard timing of administration of measles-rubella vaccine in Ugandan infants Gerald Bright Businge, Natalie G Marchevsky, Ezekiel Mupere, Sarah Kelly, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8180519/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Measles remains a major cause of child morbidity and mortality in low-resource settings. Young infants are particularly at risk of severe disease, with many lacking protective levels of maternal antibodies by six months. Vaccination before nine months in high-burden settings may confer earlier protection; however, concerns exist about its effectiveness at this age. We present early findings on enrolment, safety, and breakthrough infections following the administration of a registered measles-containing vaccine at six months versus nine months (MR1) with a subsequent booster (MR2) at 12 or 18 months of age. Methods We conducted an open-label randomised controlled non-inferiority trial at four health facilities in Kampala, Uganda. Infants aged 24–28 weeks were randomly assigned to receive MR at six and 12 months (group A), nine and 18 months (group B) or six and 18 months (group C). Infants were electronically randomised in a 1:1:1 ratio using block randomisation of varying sizes, stratified by site, maternal HIV status and baseline haemoglobin level. Caretakers recorded solicited reactions on paper diary cards, with safety-related events evaluated. Findings: 450 infants received MR1 and were enrolled. No differences in local or systemic post-vaccination events between the six and nine months MR1 groups were observed [Local: 21·2% versus 21·9% (p = 0·959), systemic: 29·2% vs 27·7% (p = 0·845)]. Most local reactions were mild and within the first four days. The majority (5/6) of hospitalisations followed common childhood illnesses, with one non-vaccine-related death six months post-MR1. Sixteen laboratory-confirmed cases of measles (10) and rubella (6), and three clinical measles cases before MR1 were registered. Most measles cases (70·0%) occurred in group C, with no measles cases registered two weeks post-MR2. Conclusion We provide further evidence on the safety of administering a measles-containing vaccine at six months of age. Trial registration: The trial was registered on 31st October 2024 with Clinicaltrials.gov with the identifier NCT06667206. Copyright: Licence CC BY Measles Early vaccination safety high-burden settings reactogenicity Figures Figure 1 Figure 2 Figure 3 Introduction Measles remains a leading cause of child mortality, especially in low-resource settings (LRS), where case-fatality rates can reach 3–30%.[ 1 ] Young children under five, the malnourished (particularly vitamin A deficient), those living in overcrowded conditions, or immunocompromised individuals (e.g. advanced HIV) are most at risk.[ 1 , 2 ] Complications include otitis media (5–15%), pneumonia, croup (5–10%), and in LRS, chronic diarrhoea with protein-losing enteropathy.[ 2 ] Global measles cases rose by over 300% between 2020 and 2023, with the WHO African Region contributing 60–70% of the global burden.[ 3 ] In East Africa, an estimated 14 million children under five live in high-incidence areas, with 8–12 million still un- or under-vaccinated.[ 4 ] In 2020, measles caused 7·5 million infections and 60,700 deaths globally—65% of which occurred in Africa.[ 5 ] During the COVID-19 pandemic, 17 large outbreaks were reported in the region, underscoring weak routine immunisation systems.[ 6 ] Measles survivors also suffer long-term health impacts, with over 15 million disability-adjusted life years lost annually—most preventable by vaccination.[ 7 ] Infants under 6 months, who are not yet eligible for routine vaccination, are disproportionately affected. Though they represent just 1·6% of the global population, they accounted for 4·3% of measles cases in a 2011to 2016 epidemiological survey —most in the African Region (37·2%)[ 8 ]. Measles virus is a monotypic, single-stranded RNA virus ( Morbillivirus ) with key antigens haemagglutinin (H) and fusion (F) proteins. Lifelong immunity follows infection due to neutralising antibodies (against H) and long-lasting T-cell responses.[ 9 , 10 ] Maternal antibodies usually provide passive protection for 6–9 months, but levels vary, especially in infants of vaccinated mothers who transmit fewer antibodies than those with natural infection.[ 11 – 13 ] A multicentre study found > 50% of infants had lost protective antibody levels by 6 months.[ 12 ] The WHO recommends two doses of measles-rubella (MR) vaccine. In high-incidence areas, MR1 is given at 9 months when maternal antibodies have typically waned and risk of exposure is high.[ 6 ] However, some infants may be vulnerable earlier. Administering MR1 at 6 months could bridge this gap, though the immune response may be weaker. In Uganda, measles outbreaks remain frequent, with a concerning representation of children under 9 months of age – timing of MR1.[ 14 – 16 ] The national immunisation schedule recommends MR1 at 9 months and MR2 at 18 months.[ 17 ] While earlier MR1 may yield lower antibody responses, studies suggest T-cell responses are preserved, and the second dose can boost immunity regardless of MR1 timing.[ 18 – 21 ] The balance lies between offering early protection and ensuring strong, lasting immunity. In comparison to the current strategy of not vaccinating this age group at all, the benefits of administration at this age are likely to be substantial. This study evaluates protective antibody responses in children receiving early (6 months) versus standard (9 months) MR1, and early (12 months) versus standard (18 months) MR2, in a high-incidence setting. We present early findings on enrolment, safety, and breakthrough infections. Methods Study design BoostME is a multicentre open-label randomised controlled non-inferiority clinical trial, investigating immune responses in children given two doses of MR vaccine at different timepoints. Infants allocated to group A receive MR at 6 and 12 months, group B at 9 and 18 months, and group C at 6 and 18 months of age. The vaccine used in the trial is the live attenuated, freeze-dried Measles and Rubella Vaccine, manufactured by Biological E. Limited, Telangana, India. The vaccine was provided by the Ugandan Expanded Program on Immunisation programme (UNEPI) and is the same vaccine used in the national programme. All vaccines are stored at Makerere University Johns Hopkins University Research Collaboration (MU-JHU) pharmacy at 2–8°C in a temperature monitored refrigerator. Participants Participants were infants attending the immunisation clinics at Mulago National Referral Hospital (MUL), Kisenyi Health Centre IV (KIS), Kawaala Health Centre IV (KAW) and Komamboga Health Centre III (KOM), aged 23–28 weeks at the time of screening. Infants were included in the trial only if they had received all previous infant vaccines per the Uganda Immunisation schedule, with exemption made for any potentially missed vaccinations at birth. Infants’ caretakers were required to confirm they had no plans to relocate outside the study sites’ geographical area during the study, and to provide informed consent for their infant’s participation in the trial. The exclusion criteria included children deemed not healthy enough to be vaccinated in the opinion of the investigators, a recent family history of measles infection since the infant’s birth, previous receipt of any measles vaccination, a family history of congenital or hereditary immunodeficiency other than HIV, receipt of more than one week of immunosuppressant or immune modifying drugs, major congenital defects or serious chronic illness likely to modify immune responses or the ability to comply with the requirements of the study, a history of any neurological disorders or seizures, administration of immunoglobulins and/or any blood products since birth or planned administration during the study period and any other abnormalities or medical history that contraindicate measles vaccination. Any child who withdrew or was discontinued from the study prior to receipt of MR1 was replaced by an additional infant. To maintain a randomised population, infants replacing the exited participants underwent the randomisation process as opposed to being directly allocated the replaced participant’s vaccination group. Recruitment ended once 450 randomised children had received their first dose of vaccine. Allocation and randomisation Infants were randomised in a 1:1:1 ratio to Group A (6 and 12 months), B (9 and 18 months), and C (6 and 18 months). Block randomisation was used with randomly varying block size stratified by site (MUL, KIS, KAW, KOM), maternal HIV status (positive, negative), and infant anaemia (< 8.0g/dl, ≥ 8.0g/dl). Randomisation was performed electronically, with full allocation concealment, using the built-in validated Research Electronic Data Capture (REDCap) randomisation system. Sample size calculation The study was powered for two primary comparisons with appropriate alpha adjustment. With 118 participants per group the study would have 90% power to determine if long term protection in those who received early vaccination (6 months) is non-inferior to those who received standard vaccination at 9 months of age, assuming 95% of participants have protective levels of antibody (> 120 mIU/mL) at 2·5 years of age in the standard group. Similarly, the study would have 90% power to determine if the response to a booster dose at 12 months of age is non-inferior to the response at 18 months of age in those who received an early first dose at 6 months of age. These calculations used a 10% non-inferiority margin and alpha of 0·0125. Thus 354 participants were required for the full study. We aimed to recruit 450 participants to allow for at least 20% loss to follow up. Data collection Demographic, anthropometric data and clinical evaluation are performed at screening, enrolment and subsequent study follow-up visits. Blood samples for immunogenicity assessments are collected at five timepoints; prior to both the first and second measles-rubella vaccine doses, four weeks post each vaccine, and at two and half years of age (Table 1 ). Yellow fever (YF) vaccine is administered at 9 months of age, as per the routine immunisation schedule, except for infants in group B, who received it four weeks later to avoid co-administration of YF and MR vaccine. At each vaccination visit, study participant caretakers are trained to monitor and record local and systemic reactions using a 7-day paper diary card, specifically adapted for low literacy population. Table 1 Summary of study procedures 6 months 7 months 9 months 10 months 12 months 13 months 18 months 19 months 2·5 years Group A: 6 & 12 months MR1 Blood draw 1 Blood draw 2 YF MR2 Blood draw 3 Blood draw 4 Blood draw 5 Group B: 9 & 18 months MR1 Blood draw 1 YF Blood draw 2 MR2 Blood draw 3 Blood draw 4 Blood draw 5 Group C: 6 & 18 months MR1 Blood draw 1 Blood draw 2 YF MR2 Blood draw 3 Blood draw 4 Blood draw 5 MR: measles-rubella vaccine YF: Yellow Fever vaccine (Routine) Outcomes Safety outcome measures Local and systemic reactions were captured in the diary cards for 7 days post-vaccination. All Serious Adverse Events (SAEs) and positive measles polymerase chain reaction (PCR), measles immunoglobin M (IgM), and/or positive rubella IgM in children presenting with febrile illness and rashes were collected throughout the study. Local and systemic reactions were graded as grade 1 (mild), grade 2 (moderate), grade 3 (severe) and grade 4 (supplementary table 1 ). Adverse events were graded as grade 1–5 (supplementary table 2 ). Primary outcome measures The primary outcome measure of the study is the geometric mean and proportion of participants with protective levels of measles neutralising antibodies at 2.5 years of age. Protective antibody levels are defined as Plaque Reduction Neutralising Titres (PRNT) > 120 mIU/mL. Secondary outcome measures Secondary outcomes of the study include measles PRNT and IgG concentrations one month after the first dose in infants receiving an early (6 months) compared to standard (9 months) dose of measles-containing vaccine (MCV); infant humoral and cellular immune response to first and second doses in children with lower or higher baseline (pre-vaccination) titres; infant PRNT and IgG responses post MR1 and MR2 given for the different vaccination schedules; anti-rubella IgG; and the effect of a measles vaccination clinical trial on public perceptions of measles immunisation. Measles and rubella cases Infants presenting to the study site clinics with measles-like illness (any or all of cough, coryza and conjunctivitis plus a maculopapular rash with or without fever) and, with or without a history of contact with an individual with a measles-like illness in the community had a blood and oral/nasopharyngeal specimen collected. Both the respiratory and blood specimens were tested for measles nucleic material and IgM, as well as rubella IgM, at the Uganda Virus Research Institute (UVRI). This is the national measles laboratory and supports UNEPI - Ministry of Health. The laboratory is a regional WHO Measles/Rubella Reference Laboratory that also serves Comoros, Burundi, Eritrea, Ethiopia, Kenya, Tanzania, Rwanda and the Republic of South Sudan.[ 22 ] Infants seen at the study clinic before MR1 with a history of contact or measles-like illness, or laboratory confirmed measles, were withdrawn from the study, and replaced. Statistical analysis For this report we present baseline characteristics in all randomised infants, and safety and reactogenicity data after the first dose of MR vaccine. Analysis of SAEs up to 30 days post-first dose of vaccine and measles and rubella cases are presented descriptively in all vaccinated infants. For reactogenicity, we compared proportions of post-MR1 reactions in infants with available diary data using chi-square tests and fisher’s exact tests, where appropriate. Clinical and/or laboratory confirmed measles and rubella cases are descriptively summarised for all randomised infants and presented according to randomised group and timing of infection. Cumulative incidence of measles cases is presented using the Kaplan-Meier method. Data analysis was performed in R (version 4·4·3), using data extracted from the clinical database on 8 August 2025. Results Participants Between 21 November 2023 and 26 September 2024, we randomised 477 participants, with 450 receiving MR1. Twenty-seven infants who were randomised but withdrawn from the trial by their caretakers or met an exclusion criterion before MR1 were replaced with a newly randomised participant (Fig. 1 ). More participants in group B withdrew before vaccination, in the three months between randomisation (at 6 months of age) and vaccination (at 9 months of age), than in groups A and C, where randomisation and vaccination generally occurred in the same week. Demographic characteristics The median age at enrolment was 26 weeks (Interquartile range (IQR): 26–27 weeks). One hundred fifty-eight infants (35·1%) were randomised to receive MR vaccine at 6–12 months, 137 infants (30·4%) at 9–18 months and 155 infants (34·4%) at 6–18 months of age. Overall, slightly more female infants were enrolled (53·5%). Baseline characteristics were similar across randomised groups (Table 2 ). Table 2 Baseline characteristics of randomised participants (N = 477) Characteristic 1 6 & 12 months Group A (N = 160) 9 & 18 months Group B (N = 159) 6 & 18 months Group C (N = 158) Overall (N = 477) Sex Female 90 (56.3%) 75 (47.2%) 90 (57.0%) 255 (53.5%) Male 70 (43.8%) 84 (52.8%) 68 (43.0%) 222 (46.5%) Age at randomisation (weeks) Median [Q1, Q3] 26.0 [26.0, 27.0] 26.0 [26.0, 27.0] 26.0 [26.0, 27.0] 26.0 [26.0, 27.0] Nationality Ugandan 159 (99.4%) 157 (98.7%) 157 (99.4%) 473 (99.2%) South Sudanese 0 (0%) 0 (0%) 1 (0.6%) 1 (0.2%) Congolese 1 (0.6%) 1 (0.6%) 0 (0%) 2 (0.4%) Pakistan 0 (0%) 1 (0.6%) 0 (0%) 1 (0.2%) Race Black 160 (100%) 158 (99.4%) 158 (100%) 476 (99.8%) Mixed Race 0 (0%) 1 (0.6%) 0 (0%) 1 (0.2%) Haemoglobin (g/dL) 11.2 [10.4, 12.0] 11.0 [10.2, 11.8] 11.0 [10.3, 11.8] 11.0 [10.3, 11.9] Breastfeeding 158 (98.8%) 151 (95.0%) 153 (96.8%) 462 (96.9%) Anthropometry Weight at screening (kg) 7.6 [6.8, 8.2] 7.3 [6.8, 8.1] 7.4 [6.7, 8.0] 7.4 [6.8, 8.1] Length at screening (cm) 66.0 [64.0, 67.6] 65.5 [64.0, 67.3] 65.8 [64.0, 67.5] 65.8 [64.0, 67.4] Head Circumference at screening (cm) 43.5 [42.6, 44.5] 43.6 [42.5, 44.5] 43.4 [42.5, 44.5] 43.5 [42.5, 44.5] MUAC at screening (cm) 14.4 [13.6, 15.2] 14.4 [13.5, 15.0] 14.4 [13.5, 15.1] 14.4 [13.5, 15.1] Maternal HIV status Positive 19 (11.9%) 16 (10.1%) 17 (10.8%) 52 (10.9%) Negative 141 (88.1%) 143 (89.9%) 141 (89.2%) 425 (89.1%) Infant HIV status at 6 weeks of age 2 Negative 18 (94·7%) 16 (100%) 17 (100%) 51 (98.1%) Missing 1 (5·3%) 0 (0%) 0 (0%) 1 (1·9%) 1 Median [IQR] was reported for continuous variables; n (%) for categorical variables 2 Only infants exposed to HIV (through maternal HIV status) were tested Local reactions There were no statistically significant differences in the severity and proportion of infants experiencing local reactions after the first dose of vaccine between those vaccinated at 6 and 9 months of age. Overall, 21·2% of infants who received MR1 at 6 months registered at least one local reaction within 7 days post-vaccination compared to 21·9% of infants who received MR1 at 9 months (p = 0·959) (Table 3 ). Most local reactions were mild and occurred in the first four days post-vaccination in both 6 and 9 months arms (Fig. 2 ). Systemic reactions Systemic reactions were reported in similar proportions of infants receiving MR1 at 6 and 9 months (29·2% vs 27·7%, p = 0·845; Table 3 ). Fever rates did not differ significantly (p = 0·781), with 1·9% of 6-month recipients and 1·5% of 9-month recipients experiencing moderate/severe fever, mostly within 48 hours and on day 4, respectively (Fig. 2 ). Rashes occurred in 11·8% of 6-month MR1 recipients (11·2% mild, 0·6% moderate) and 6·6% of 9-month recipients, with no significant difference (p = 0·125). Most rash events occurred between days 2–5 post-vaccination. Mild to moderate wheezing or breathing difficulties were reported in 10·3% (6-month) and 10·9% (9-month) of infants (p = 0·957), mostly between days 2–6. Drowsiness, all mild and typically within 72 hours, occurred in 13·8% of 6-month and 14·6% of 9-month recipients (p = 0·935). Muscle pain was reported in 5·1% of 6-month and 2·9% of 9-month recipients (p = 0·456), mostly mild and within 3 days. One severe case at day 6 in a 6-month recipient resolved within 24 hours. Overall, adverse events were comparable between groups, with no statistically significant differences across key symptoms. Table 3 Solicited local and systemic reactions during days 1–7 after first vaccination Symptom 6-month MR1 (N = 312) 9-month MR1 (N = 137) p-value Any local 66 (21·2%) 30 (21·9%) 0·959 Redness 21 (6·7%) 8 (5·8%) 0·884 Swelling 28 (9·0%) 12 (8·8%) 1·000 Tenderness 39 (12·5%) 20 (14·6%) 0·650 Any systemic 91 (29·2%) 38 (27·7%) 0·845 Fever ≥ 38°C 10 (3·2%) 5 (3·6%) 0·781 1 Rash 37 (11·9%) 9 (6·6%) 0·125 Difficulty breathing/wheeze 32 (10·3%) 15 (10·9%) 0·957 Drowsiness 43 (13·8%) 20 (14·6%) 0·935 Muscle pain 16 (5·1%) 4 (2·9%) 0·456 1 1 Fisher’s exact test Six serious adverse events (SAEs) occurred within 30 days of MR1 vaccination: four in the 9-month group and two in the 6-month group. Most (5/6) were due to infections or infestations, including diarrhoea (2 cases), malaria, pneumonia, and sepsis. One infant in the 6-month group was hospitalised for intussusception. None of the SAEs were considered related to the vaccine (Table 4 ). One unrelated death from acute hydrocephalus occurred six months post-MR1 in a 12-month-old child in the 6–18 month schedule group. Table 4 Summary of Serious Adverse Events up to 30 days post-MR1 MedDRA System Organ Class Preferred Term, n (%) 6-month MR1 (N = 313) 9-month MR1 (N = 137) Overall (N = 450) Number of serious adverse events 2 (33·3%) 4 (66·7%) 6 (100%) Gastrointestinal disorders 1 (50·0%) 0 (0%) 1 (16·7%) Intussusception 1 (50·0%) 0 (0%) 1 (16·7%) Infections and infestations 1 (50·0%) 4 (100%) 5 (83·3) Diarrhoea infectious 0 (0%) 1 (25·0%) 1 (16·7%) Gastroenteritis 0 (0%) 1 (25·0%) 1 (16·7%) Malaria 0 (0%) 1 (25·0%) 1 (16·7%) Pneumonia 1 (50·0%) 0 (0%) 1 (16·7%) Sepsis 0 (0%) 1 (25·0%) 1 (16·7%) MedDRA: Medical Dictionary for Regulatory Activities Measles and rubella cases Sixteen laboratory-confirmed cases were detected among 72 children with morbilliform rashes: ten measles and six rubella (Table 5 , Fig. 3 ). Three additional clinical measles cases occurred prior to MR1 without confirmatory testing and subsequently withdrawn from further study participation. Three measles cases were in children born to HIV-positive mothers. Of the ten confirmed measles cases, one occurred before MR1, eight between MR1 and MR2 in children vaccinated at 6 months, and one shortly after MR2. Most measles cases (7/10, 70·0%) occurred in the 6 − 18 month schedule group, likely due to the longer interval between doses. No measles cases were detected more than two weeks after MR2, though follow-up is ongoing. Seven rubella cases were confirmed by IgM, in two infants within each vaccination group. One child in the 9-month group had two rubella episodes six months apart. Most rubella cases (6/7) occurred before MR2; one occurred 47 days post-MR2 in the 6–12 month group. Table 5 Infants with diagnosed measles or rubella Timepoint Event Randomised group 6 & 12 months (N = 160) 9 & 18 months (N = 159) 6 & 18 months (N = 158) All Measles Clinical diagnosis only* 3 (1·9%) PCR+/IgM+ 2 (1·3%) 1 (0·6%) 7 (4·4%) Rubella (IgM+) 2 (1·3%) 2 (1·3%) † 2 (1·3%) Before MR1 Measles Clinical diagnosis only* 3 (1·9%) PCR+/IgM+ 0 (0·0%) 1 (0·6%) € 0 (0·0%) Rubella (IgM+) 0 (0·0%) 0 (0·0%) 0 (0·0%) After MR1 before MR2 Measles (PCR+/IgM+) 2 (1·3%)** 0 (0·0%) 6 (3·8%)*** ,$ Rubella (IgM+) 1 (0·6%) 2 (1·3%) † 2 (1·3%) After MR2 Measles (PCR+/IgM+) 0 (0·0%) 0 (0·0%) 1 (0·6%) ¥ Rubella (IgM+) 1 (0·6%) 0 (0·0%) 0 (0·0%) * Withdrawn from the study prior to MR1 vaccination due to clinical measles diagnoses that were not laboratory-confirmed (no samples for testing) € 1 infant was exposed to HIV + mother, taking ART during pregnancy $ 2 infants were exposed to HIV + mother, taking ART during pregnancy ** 1 infant had positive measles PCR and IgM samples 4 days post-MR1 vaccination *** 1 infant had positive measles PCR and IgM samples 11 days post-MR1 vaccination and a history of exposure to measles in their neighborhood. This infant died from acute hydrocephalus 198 days post-MR1 vaccination (187 days after positive measles samples), deemed not related to MR vaccination † 1 infant had 2 positive rubella IgM samples prior to MR2 vaccination: 14 and 201 days post-MR1 vaccination ¥ 1 infant had positive measles PCR and IgM samples 6 days post-MR2 vaccination Discussion To our knowledge, this is the first randomised clinical trial to assess the safety, tolerability, and immunogenicity of early MR vaccine administration at 6 months (early prime) versus the standard 9-month schedule in a high-burden setting using a licensed vaccine. We demonstrate that MR1 at 6 months is well tolerated, with a safety profile comparable to MR1 at 9 months. However, all breakthrough measles cases occurred in the 6-month group, suggesting a potential trade-off between early protection and optimal immunogenicity. The similar number of rubella cases across groups highlights the ongoing circulation of both viruses in this setting. No significant differences were observed in local reactions following MR1 at 6 months (21.2%) vs 9 months (21·9%). These findings align with prior studies from the Netherlands and Ghana, and with systematic reviews of MCV safety. In the Dutch study, local reactions ranged from 5% to 10% depending on age at vaccination (p = 0·08).[ 24 ] The Ghana study reported no difference in local events between infants receiving AIK-C at 6 months and Schwarz strain at 9 months.[ 25 ] Nic Lochlainn et al similarly reported no significant risk difference in local reactions by age.[ 23 ] Notably, local reactions may also result from injection trauma, as demonstrated by comparable local event rates after MCV or sterile water injection in young infants.[ 26 ] Systemic reactogenicity was also similar between groups (29·2% vs 27·7%, p = 0·845), consistent with meta-analyses showing no differences in fever (0·02, 95% CI − 0·02 to 0·05) or rash (0·00, 95% CI − 0·06 to 0·06) by age.[ 23 ] The Ghana study reported higher fever in the 6-month group (21·7% vs 11·4%, p = 0·01) but no overall differences in systemic events.[ 25 ] In contrast, the Dutch study observed fewer systemic events in the 6-month group, with rash the only significantly different event across ages (8% under 9 months vs 20% at 9–11 months and 18% at 12–14 months, p = 0·0004). Post-vaccination reactions were mild and self-limiting, with minimal recurrence after MR2 dosing, except in rare cases of anaphylaxis.[ 1 , 27 ] One child required surgery for intussusception, and five others were hospitalised for common infectious illnesses. None of these serious adverse events were attributed to vaccination. Consistent with Uganda’s IDSR guidelines, children presenting with febrile maculopapular rashes were tested for measles and rubella.[ 28 ] Ten laboratory-confirmed measles cases were observed: one prior to MR1, eight post-MR1 in the 6-month group, and one post-MR2. Most (7/10, 70·0%) occurred in children following the 6–18 month schedule, suggesting that a shorter interval between MR1 and MR2 may reduce breakthrough risk. By contrast, four pre-vaccination measles cases occurred in the 9-month group during the short 3-month wait period, illustrating the vulnerability of infants in high-burden settings under current policy. Two measles cases occurred 2–14 days post-MR1 with no known contact and were adjudicated as possibly vaccine-related. Although rash and mild illness may occur after MCV due to vaccine viral replication, true vaccine-associated measles is rare.[ 29 – 32 ] In a Chinese study of 15,000 genotyped cases, only 0·67% were vaccine-associated, nearly all after the first dose.[ 33 ] In the absence of sequencing, it is unclear whether post-vaccination cases in our study were wild-type or vaccine-strain. While rare severe vaccine-strain disease has been reported in immunocompromised individuals, transmission from vaccine-related cases remains largely theoretical.[ 34 , 35 ] All breakthrough measles cases in our study presented with rash and fever or coryza. As expected, these infections were mild to moderate, consistent with prior reports of milder disease in vaccinated children.[ 1 , 36 , 37 ] A second vaccine dose is needed to ensure protection in initial non-responders, who may represent up to 15% of children. Immunological analyses are underway to further explore this. We also detected seven rubella events in six children, occurring in two infants in each vaccination group. One child in the 9–18 month group had two confirmed rubella episodes. Most cases (6/7) occurred after MR1 but before MR2, including one case 47 days post-MR2. Although a single rubella vaccine dose is 94–100% effective,[ 38 , 39 ] sporadic post-vaccination cases have been reported. In a cohort of over 77,000 children, Geier et al reported 57 rubella cases among 33,000 vaccinated individuals, most of which were mild.[ 40 ] Rubella is less infectious than measles but often transmitted by asymptomatic carriers.[ 39 , 41 , 42 ] In our study, 4 of 6 rubella cases, including the post-MR2 case, had contact with an individual with a measles-like illness. These findings support the view that rubella cases in vaccinated children are often associated with prolonged or close exposure to infectious contacts. Due to the small number of measles and rubella cases, our study is not powered to compare vaccine efficacy between 6- and 9-month schedules. Similarly, rubella cases were too few to draw firm conclusions on schedule effectiveness. Nevertheless, high community coverage (≥ 95%) remains critical to interrupt transmission of both viruses. Strengths and Limitations The diagnosis of measles/rubella requires keen clinician observation and a high index of suspicion. While children presenting to the study clinics with a measles-like illness were investigated, we acknowledge that some children might have sought medical attention at other health care facilities outside the study sites and therefore were not captured. Second, we were unable to determine at the time of presentation if the breakthrough cases were due to primary or secondary vaccine failure. We were equally unable to obtain measles/rubella genetic characterisation to rule out the possibility of a vaccine strain in the measles/rubella cases recorded after vaccination. Despite these limitations, the study design has adequately enabled the recording and follow-up of all adverse events, including measles/rubella events, across the three vaccination groups for an extended observation timeline. The pre- and post-vaccination sample collection schedule provides a valuable opportunity in assessing the short- and long-term immunological response following an early and standard measles and rubella vaccination schedule. Additionally, we will be able to determine the amount and potential influence of pre-vaccination measles antibodies in Ugandan infants. Implications of results and conclusion This study provides further evidence supporting the safety of administering a measles-containing vaccine at 6 months of age. The occurrence of measles and rubella cases in children who had received at least one vaccine dose underscores the continued widespread transmission of both viruses among Ugandan infants and highlights the urgent need to achieve and maintain high two-dose vaccine coverage. Although all breakthrough measles cases occurred in children who received MR1 at 6 months, the number of cases is too small to draw definitive conclusions about differences in vaccine efficacy between schedules. Immunogenicity analyses will help determine whether these cases occurred in vaccine non-responders. An extension of the trial is underway to increase sample size and evaluate the clinical impact of vaccine timing more robustly. Declarations Ethical consideration Ethical approval for the BoostME study was obtained from the Mulago Hospital Research Ethics Committee (MHREC 2023-86), the Uganda National Council for Science and Technology (HS2883ES), the National Drug Authority (CTC 250/2023) and Oxford Tropical Research Ethics Committee (2-23). The clinical trial is registered on ClinicalTrials.gov (NCT06667206). The nature and aim of the study were explained to potential participants’ parents/guardians prior to signing the study written informed consent form. All study procedures were adherent to the research guidelines of the Uganda National Council for Science and Technology, the National Drug Authority, and the principles of the Declaration of Helsinki. Data collection is ongoing at the time of submission. Consent for Publication Not Applicable Contributors MV, KLD, MK and SK designed the study. PM, EM, KLD, AE, FA, BK and GB provided onsite supervision and guidance on study execution and data collection. VT, CK, NGM, IK and YFM extracted and checked the data. GB, NGM, and IK performed the analysis. MV, KLD, and EM provided overall coordination and supervision of this work. MV, KLD and GB performed the relevant literature reviews. All authors contributed intellectually to the work and reviewed the final manuscript for accuracy and completeness. All authors had access to the study data and accept responsibility for the decision to submit for publication. Funding The funders of this clinical trial (Gates Foundation) had no role in the study design, collection of data, data analysis and its interpretation or the generation of this report. Declaration of Competing Interest This work was supported, in whole or in part, by the Gates Foundation [INV-048650]. The Gates Foundation grant funding was awarded to Oxford University for this trial. The conclusions and opinions expressed in this work are those of the author(s) alone and shall not be attributed to the Foundation. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. Data Availability As per the Gates Foundation Open Access policy, datasets presented in this report are available to download as supplementary files. As the study is still ongoing, these files are preliminary and may undergo review and updates due to standard data cleaning processes. Therefore, future data downloads and publications may differ from the supplementary files available with this publication. Acknowledgements The authors would like to appreciate the following people/institutions for their contribution to this work: the study participants and their caretakers who dedicated their time to attend all study visits, the Ministry of Health - Uganda for their support in providing the measles and rubella and Yellow Fever vaccines, the administrative units of Mulago National Referral Hospital, Kisenyi, Kawaala and Komamboga Health Centres for accommodating and supporting study activities at their premises, the MUJHU Care Ltd Community Advisory Board for their in depth guidance on community engagements and sensitisation. The authors also appreciate the insightful recommendations provided by doctors Alane Izu, Sabrina Kitaka and Victoria Nambasa, who comprised this clinical trial’s Data and Safety Monitoring Board. References World Health Organisation. The immunological basis for immunization series: module 7: measles: update 2020. World Health Organization; 2020. Sarker SA, Wahed MA, Rahaman MM, Alam AN, Islam A, Jahan F. Persistent protein losing enteropathy in post measles diarrhoea. Arch Dis Child. 1986;61:739–43. https://doi.org/10.1136/adc.61.8.739 . Minta AA. Progress Toward Measles Elimination — Worldwide, 2000–2023. MMWR Morb Mortal Wkly Rep. 2024;73. https://doi.org/10.15585/mmwr.mm7345a4 . Takahashi S, Metcalf CJE, Ferrari MJ, Tatem AJ, Lessler J. The geography of measles vaccination in the African Great Lakes region. Nat Commun. 2017;8:15585. https://doi.org/10.1038/ncomms15585 . Dixon MG, Ferrari M, Antoni S, Li X, Portnoy A, Lambert B, et al. Progress Toward Regional Measles Elimination - Worldwide, 2000–2020. MMWR Morb Mortal Wkly Rep. 2021;70:1563–9. https://doi.org/10.15585/mmwr.mm7045a1 . World Health Organisation (WHO). Measles and Rubella Strategic Framework 2021–2030. 1st ed. Geneva: World Health Organization; 2021. Gastañaduy PA, Goodson JL, Panagiotakopoulos L, Rota PA, Orenstein WA, Patel M. Measles in the 21st Century: Progress Toward Achieving and Sustaining Elimination. J Infect Dis. 2021;224:S420–8. https://doi.org/10.1093/infdis/jiaa793 . World Health Organisation. Epidemiology of measles in infants younger than 6 months: analysis of surveillance data 2011–2016. n.d. Laksono BM, de Vries RD, McQuaid S, Duprex WP, de Swart RL. Measles Virus Host Invasion Pathogenesis Viruses. 2016;8:210. https://doi.org/10.3390/v8080210 . Moss WJ, Polack FP. Immune responses to measles and measles vaccine: challenges for measles control. Viral Immunol. 2001;14:297–309. https://doi.org/10.1089/08828240152716556 . Niewiesk S. Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies. Front Immunol. 2014;5:446. https://doi.org/10.3389/fimmu.2014.00446 . Tiley KS, Overbeek H, ten H, Basnet S, van Binnendijk R, Clarke E, Cose S, et al. The waning of maternal measles antibodies: a multi-country maternal-infant seroprevalence study. J Infect. 2025;106531. https://doi.org/10.1016/j.jinf.2025.106531 . Dixon MG, Tapia MD, Wannemuehler K, Luce R, Papania M, Sow S, et al. Measles susceptibility in maternal-infant dyads—Bamako. Mali Vaccine. 2022;40:1316–22. https://doi.org/10.1016/j.vaccine.2022.01.012 . Okiror Okello E, Migisha R, Ampaire I, Nsubuga F, Nalwanga J, Kwizera P, et al. Measles outbreak investigation in Kakumiro District, Uganda, February–May 2024. Discov Public Health. 2025;22:52. https://doi.org/10.1186/s12982-025-00446-4 . Kizito SN, Simbwa B, Thomas K, Akuguzibwe R, Sembatya I, Nsubuga E et al. Measles outbreak propagated by visiting a health facility, in a refugee hosting community, Kiryandongo District, Western Uganda, August 2022–May 2023 n.d. Biribawa C, Atuhairwe JA, Bulage L, Okethwangu DO, Kwesiga B, Ario AR, et al. Measles outbreak amplified in a pediatric ward: Lyantonde District, Uganda, August 2017. BMC Infect Dis. 2020;20:398. https://doi.org/10.1186/s12879-020-05120-5 . WHO Immunization Data portal - Detail Page. Immun Data n.d. https://immunizationdata.who.int/global/wiise-detail-page (accessed September 25, 2025). Principi N, Esposito S. Early vaccination: a provisional measure to prevent measles in infants. Lancet Infect Dis. 2019;19:1157–8. https://doi.org/10.1016/S1473-3099(19)30520-1 . Nic Lochlainn LM, de Gier B, van der Maas N, van Binnendijk R, Strebel PM, Goodman T, et al. Effect of measles vaccination in infants younger than 9 months on the immune response to subsequent measles vaccine doses: a systematic review and meta-analysis. Lancet Infect Dis. 2019;19:1246–54. https://doi.org/10.1016/S1473-3099(19)30396-2 . Gans H, Yasukawa L, Rinki M, DeHovitz R, Forghani B, Beeler J, et al. Immune responses to measles and mumps vaccination of infants at 6, 9, and 12 months. J Infect Dis. 2001;184:817–26. https://doi.org/10.1086/323346 . Brinkman ID, Butler AL, de Wit J, van Binnendijk RS, Alter G, van Baarle D. Measles Vaccination Elicits a Polyfunctional Antibody Response, Which Decays More Rapidly in Early Vaccinated Children. J Infect Dis. 2022;225:1755–64. https://doi.org/10.1093/infdis/jiab318 . EPI Lab | Uganda Virus Research Institute n.d. https://www.uvri.go.ug/epi-lab (accessed November 18, 2024). Nic Lochlainn LM, de Gier B, van der Maas N, Strebel PM, Goodman T, van Binnendijk RS, et al. Immunogenicity, effectiveness, and safety of measles vaccination in infants younger than 9 months: a systematic review and meta-analysis. Lancet Infect Dis. 2019;19:1235–45. https://doi.org/10.1016/S1473-3099(19)30395-0 . Van Der Maas NAT, Woudenberg T, Hahné SJM, De Melker HE. Tolerability of Early Measles-Mumps-Rubella Vaccination in Infants Aged 6–14 Months During a Measles Outbreak in The Netherlands in 2013–2014. J Infect Dis. 2016;213:1466–71. https://doi.org/10.1093/infdis/jiv756 . Nkrumah FK, Osei-Kwasi M, Dunyo SK, Koram KA, Afari EA. Comparison of AIK-C measles vaccine in infants at 6 months with Schwarz vaccine at 9 months: a randomized controlled trial in Ghana. Bull World Health Organ. 1998;76 4:353–9. Vittrup DM, Jensen A, Sørensen JK, Zimakoff AC, Malon M, Charabi S et al. Immunogenicity and reactogenicity following MMR vaccination in 5–7-month-old infants: a double-blind placebo-controlled randomized clinical trial in 6540 Danish infants. eClinicalMedicine 2024;68. https://doi.org/10.1016/j.eclinm.2023.102421 World Health Organization. Measles vaccines: WHO position paper – April 2017. Update 2009. Geneva: World Health Organization; 2009. MoH U. Uganda 3rd IDSR Technical Guidelines for Integrated Disease Surveillance. 2021. Chap. 4: Manual for the Laboratory-based Surveillance of Measles, Rubella, and Congenital Rubella Syndrome n.d. https://www.who.int/publications/m/item/chapter-4-manual-for-the-laboratory-based-surveillance-of-measles-rubella-and-congenital-rubella-syndrome (accessed June 20, 2025). World Health Organisation. Information sheet observed rate of vaccine reactions measles, mumps and rubella vaccines. Geneva: 2014. CDC, Chapter. 13: Measles. Epidemiol Prev Vaccine-Prev Dis 2024. https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-13-measles.html (accessed June 20, 2025). National measles. guidelines July 2024 2024. Cui A, Wang H, Zhu Z, Mao N, Song J, Zhang Y, et al. Measles Vaccine-Associated Rash Illness in China: an Emerging Issue in the Process of Measles Elimination. J Clin Microbiol. 2020;58. https://doi.org/10.1128/JCM.01472-20 . Hau M, Schwartz KL, Frenette C, Mogck I, Gubbay JB, Severini A, et al. Local public health response to vaccine-associated measles: case report. BMC Public Health. 2013;13:269. https://doi.org/10.1186/1471-2458-13-269 . Millson D, BROTHER-TO-SISTER TRANSMISSION OF MEASLES AFTER MEASLES, MUMPS, AND RUBELLA IMMUNISATION. Lancet. 1989;333:271. https://doi.org/10.1016/S0140-6736(89)91274-9 . De Serres G, Gay NJ, Farrington CP. Epidemiology of Transmissible Diseases after Elimination. Am J Epidemiol. 2000;151:1039–48. https://doi.org/10.1093/oxfordjournals.aje.a010145 . Canada PHA. accessed April 10, of. Measles vaccines: Canadian immunization guide 2007. https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html (2025). CDC. Rubella Vaccine Recommendations. Rubella Ger Measles Three-Day Measles 2025. https://www.cdc.gov/rubella/hcp/vaccine-considerations/index.html (accessed July 12, 2025). Organization WH. Rubella: vaccine preventable diseases surveillance standards. 2018. Geier DA, Geier MR, Childhood MMR. Vaccination Effectiveness Against Rubella: A Longitudinal Cohort Study. Glob Pediatr Health. 2022;9:2333794X221094266. https://doi.org/10.1177/2333794X221094266 . CDC. Rubella Symptoms and Complications. Rubella Ger Measles Three-Day Measles 2025. https://www.cdc.gov/rubella/signs-symptoms/index.html (accessed July 12, 2025). Best JM, Rubella. Semin Fetal Neonatal Med. 2007;12:182–92. https://doi.org/10.1016/j.siny.2007.01.017 . Additional Declarations No competing interests reported. Supplementary Files Dataset1BaselineCharacteristicsdatarandomised.csv Dataset2BaselineCharacteristicsdatavaccinated.csv Dataset3SeriousAdverseEvents.csv Dataset4ReactogenicityData.xlsx Dataset5MeaslesRubellaData.xlsx Dataset6CummulativeIncidencedata.xlsx SupplementaryTables.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 19 Jan, 2026 Reviews received at journal 17 Jan, 2026 Reviewers agreed at journal 05 Jan, 2026 Reviews received at journal 29 Dec, 2025 Reviewers agreed at journal 21 Dec, 2025 Reviewers invited by journal 08 Dec, 2025 Editor assigned by journal 06 Dec, 2025 Submission checks completed at journal 06 Dec, 2025 First submitted to journal 27 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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08:30:32","extension":"xml","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":153420,"visible":true,"origin":"","legend":"","description":"","filename":"8ed29395a5474c5a803c9ecbfd6ae63c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/bcc946ec73b1a1e39493b574.xml"},{"id":98047821,"identity":"3ba9b064-b4ae-4b23-80af-000f32e8f1f4","added_by":"auto","created_at":"2025-12-12 08:30:32","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":166466,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/1d974e9e8117f4547f700128.html"},{"id":98427195,"identity":"6f8fede5-7b9d-42da-834b-6ddcac3cb39d","added_by":"auto","created_at":"2025-12-17 16:39:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1038714,"visible":true,"origin":"","legend":"\u003cp\u003eRandomisation, enrolment and vaccination flow diagram\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/8f67844a3dde42be51e1e036.png"},{"id":98047823,"identity":"681cf7df-0a8a-4435-8f11-e69271e63311","added_by":"auto","created_at":"2025-12-12 08:30:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":372177,"visible":true,"origin":"","legend":"\u003cp\u003eSolicited local and systemic reactions\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/f81745d1604dbd4783297bd2.png"},{"id":98427414,"identity":"ad0cb47e-25ee-453e-b3fc-8f483d117f3b","added_by":"auto","created_at":"2025-12-17 16:40:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":336762,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of A) all measles cases, B) measles cases before MR2\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/8369841667936555c09f842e.png"},{"id":98623648,"identity":"3ac48db9-4180-467e-8e56-e59c7269a57b","added_by":"auto","created_at":"2025-12-19 17:07:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3140709,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/64043354-f2f1-4a72-aa6f-28bd94aaa0fc.pdf"},{"id":98427454,"identity":"dea77641-b9a9-40e9-9dfe-4a9c8d08aebd","added_by":"auto","created_at":"2025-12-17 16:40:28","extension":"csv","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33012,"visible":true,"origin":"","legend":"","description":"","filename":"Dataset1BaselineCharacteristicsdatarandomised.csv","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/1ef8b9fca11993b7717fa5cc.csv"},{"id":98426864,"identity":"c19d9a08-b097-4d81-95b0-287f93d6f165","added_by":"auto","created_at":"2025-12-17 16:38:52","extension":"csv","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":31170,"visible":true,"origin":"","legend":"","description":"","filename":"Dataset2BaselineCharacteristicsdatavaccinated.csv","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/a8428bba21cd3f43890b48b9.csv"},{"id":98428198,"identity":"784d1232-22ff-4ff3-9413-35e0d2012f34","added_by":"auto","created_at":"2025-12-17 16:41:45","extension":"csv","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":606,"visible":true,"origin":"","legend":"","description":"","filename":"Dataset3SeriousAdverseEvents.csv","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/a17c9460de914227b9173570.csv"},{"id":98047813,"identity":"fa9d1716-4f8e-45ea-8063-11c5f7069de9","added_by":"auto","created_at":"2025-12-12 08:30:32","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":88991,"visible":true,"origin":"","legend":"","description":"","filename":"Dataset4ReactogenicityData.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/f088c2a5e6b333be953b4d84.xlsx"},{"id":98425482,"identity":"aa19ada1-778c-4e39-b5b8-c81c30bd9557","added_by":"auto","created_at":"2025-12-17 16:34:50","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":7403,"visible":true,"origin":"","legend":"","description":"","filename":"Dataset5MeaslesRubellaData.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/8a4f28b94bfb370d1c3c3c53.xlsx"},{"id":98047830,"identity":"c412fe7c-4ae2-4f13-8d95-11197577e1f0","added_by":"auto","created_at":"2025-12-12 08:30:32","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":25749,"visible":true,"origin":"","legend":"","description":"","filename":"Dataset6CummulativeIncidencedata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/189b2f87d22502b13e873316.xlsx"},{"id":98427707,"identity":"b7c1d378-a5b3-4c83-a393-0ffc9c769769","added_by":"auto","created_at":"2025-12-17 16:41:00","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":23946,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8180519/v1/02139abe9da4d0ebb79e1222.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Preliminary safety data from a randomised trial of early versus standard timing of administration of measles-rubella vaccine in Ugandan infants","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMeasles remains a leading cause of child mortality, especially in low-resource settings (LRS), where case-fatality rates can reach 3\u0026ndash;30%.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Young children under five, the malnourished (particularly vitamin A deficient), those living in overcrowded conditions, or immunocompromised individuals (e.g. advanced HIV) are most at risk.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Complications include otitis media (5\u0026ndash;15%), pneumonia, croup (5\u0026ndash;10%), and in LRS, chronic diarrhoea with protein-losing enteropathy.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eGlobal measles cases rose by over 300% between 2020 and 2023, with the WHO African Region contributing 60\u0026ndash;70% of the global burden.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] In East Africa, an estimated 14\u0026nbsp;million children under five live in high-incidence areas, with 8\u0026ndash;12\u0026nbsp;million still un- or under-vaccinated.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] In 2020, measles caused 7\u0026middot;5\u0026nbsp;million infections and 60,700 deaths globally\u0026mdash;65% of which occurred in Africa.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] During the COVID-19 pandemic, 17 large outbreaks were reported in the region, underscoring weak routine immunisation systems.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Measles survivors also suffer long-term health impacts, with over 15\u0026nbsp;million disability-adjusted life years lost annually\u0026mdash;most preventable by vaccination.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eInfants under 6 months, who are not yet eligible for routine vaccination, are disproportionately affected. Though they represent just 1\u0026middot;6% of the global population, they accounted for 4\u0026middot;3% of measles cases in a 2011to 2016 epidemiological survey \u0026mdash;most in the African Region (37\u0026middot;2%)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMeasles virus is a monotypic, single-stranded RNA virus (\u003cem\u003eMorbillivirus\u003c/em\u003e) with key antigens haemagglutinin (H) and fusion (F) proteins. Lifelong immunity follows infection due to neutralising antibodies (against H) and long-lasting T-cell responses.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Maternal antibodies usually provide passive protection for 6\u0026ndash;9 months, but levels vary, especially in infants of vaccinated mothers who transmit fewer antibodies than those with natural infection.[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] A multicentre study found\u0026thinsp;\u0026gt;\u0026thinsp;50% of infants had lost protective antibody levels by 6 months.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe WHO recommends two doses of measles-rubella (MR) vaccine. In high-incidence areas, MR1 is given at 9 months when maternal antibodies have typically waned and risk of exposure is high.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] However, some infants may be vulnerable earlier. Administering MR1 at 6 months could bridge this gap, though the immune response may be weaker.\u003c/p\u003e\u003cp\u003eIn Uganda, measles outbreaks remain frequent, with a concerning representation of children under 9 months of age \u0026ndash; timing of MR1.[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] The national immunisation schedule recommends MR1 at 9 months and MR2 at 18 months.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] While earlier MR1 may yield lower antibody responses, studies suggest T-cell responses are preserved, and the second dose can boost immunity regardless of MR1 timing.[\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] The balance lies between offering early protection and ensuring strong, lasting immunity. In comparison to the current strategy of not vaccinating this age group at all, the benefits of administration at this age are likely to be substantial.\u003c/p\u003e\u003cp\u003eThis study evaluates protective antibody responses in children receiving early (6 months) versus standard (9 months) MR1, and early (12 months) versus standard (18 months) MR2, in a high-incidence setting. We present early findings on enrolment, safety, and breakthrough infections.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eBoostME is a multicentre open-label randomised controlled non-inferiority clinical trial, investigating immune responses in children given two doses of MR vaccine at different timepoints. Infants allocated to group A receive MR at 6 and 12 months, group B at 9 and 18 months, and group C at 6 and 18 months of age.\u003c/p\u003e\u003cp\u003eThe vaccine used in the trial is the live attenuated, freeze-dried Measles and Rubella Vaccine, manufactured by Biological E. Limited, Telangana, India. The vaccine was provided by the Ugandan Expanded Program on Immunisation programme (UNEPI) and is the same vaccine used in the national programme. All vaccines are stored at Makerere University Johns Hopkins University Research Collaboration (MU-JHU) pharmacy at 2\u0026ndash;8\u0026deg;C in a temperature monitored refrigerator.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eParticipants were infants attending the immunisation clinics at Mulago National Referral Hospital (MUL), Kisenyi Health Centre IV (KIS), Kawaala Health Centre IV (KAW) and Komamboga Health Centre III (KOM), aged 23\u0026ndash;28 weeks at the time of screening. Infants were included in the trial only if they had received all previous infant vaccines per the Uganda Immunisation schedule, with exemption made for any potentially missed vaccinations at birth. Infants\u0026rsquo; caretakers were required to confirm they had no plans to relocate outside the study sites\u0026rsquo; geographical area during the study, and to provide informed consent for their infant\u0026rsquo;s participation in the trial.\u003c/p\u003e\u003cp\u003eThe exclusion criteria included children deemed not healthy enough to be vaccinated in the opinion of the investigators, a recent family history of measles infection since the infant\u0026rsquo;s birth, previous receipt of any measles vaccination, a family history of congenital or hereditary immunodeficiency other than HIV, receipt of more than one week of immunosuppressant or immune modifying drugs, major congenital defects or serious chronic illness likely to modify immune responses or the ability to comply with the requirements of the study, a history of any neurological disorders or seizures, administration of immunoglobulins and/or any blood products since birth or planned administration during the study period and any other abnormalities or medical history that contraindicate measles vaccination.\u003c/p\u003e\u003cp\u003eAny child who withdrew or was discontinued from the study prior to receipt of MR1 was replaced by an additional infant. To maintain a randomised population, infants replacing the exited participants underwent the randomisation process as opposed to being directly allocated the replaced participant\u0026rsquo;s vaccination group. Recruitment ended once 450 randomised children had received their first dose of vaccine.\u003c/p\u003e\n\u003ch3\u003eAllocation and randomisation\u003c/h3\u003e\n\u003cp\u003eInfants were randomised in a 1:1:1 ratio to Group A (6 and 12 months), B (9 and 18 months), and C (6 and 18 months). Block randomisation was used with randomly varying block size stratified by site (MUL, KIS, KAW, KOM), maternal HIV status (positive, negative), and infant anaemia (\u0026lt;\u0026thinsp;8.0g/dl, \u0026ge;\u0026thinsp;8.0g/dl). Randomisation was performed electronically, with full allocation concealment, using the built-in validated Research Electronic Data Capture (REDCap) randomisation system.\u003c/p\u003e\n\u003ch3\u003eSample size calculation\u003c/h3\u003e\n\u003cp\u003eThe study was powered for two primary comparisons with appropriate alpha adjustment. With 118 participants per group the study would have 90% power to determine if long term protection in those who received early vaccination (6 months) is non-inferior to those who received standard vaccination at 9 months of age, assuming 95% of participants have protective levels of antibody (\u0026gt;\u0026thinsp;120 mIU/mL) at 2\u0026middot;5 years of age in the standard group.\u003c/p\u003e\u003cp\u003eSimilarly, the study would have 90% power to determine if the response to a booster dose at 12 months of age is non-inferior to the response at 18 months of age in those who received an early first dose at 6 months of age. These calculations used a 10% non-inferiority margin and alpha of 0\u0026middot;0125. Thus 354 participants were required for the full study. We aimed to recruit 450 participants to allow for at least 20% loss to follow up.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eDemographic, anthropometric data and clinical evaluation are performed at screening, enrolment and subsequent study follow-up visits. Blood samples for immunogenicity assessments are collected at five timepoints; prior to both the first and second measles-rubella vaccine doses, four weeks post each vaccine, and at two and half years of age (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Yellow fever (YF) vaccine is administered at 9 months of age, as per the routine immunisation schedule, except for infants in group B, who received it four weeks later to avoid co-administration of YF and MR vaccine.\u003c/p\u003e\u003cp\u003eAt each vaccination visit, study participant caretakers are trained to monitor and record local and systemic reactions using a 7-day paper diary card, specifically adapted for low literacy population.\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\u003eSummary of study procedures\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\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\u003e6 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e13 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e19 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2\u0026middot;5 years\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup A:\u003c/p\u003e\u003cp\u003e6 \u0026amp; 12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMR1\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBlood draw 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood draw 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYF\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\u003eMR2\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBlood draw 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBlood draw 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eBlood draw 5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup B:\u003c/p\u003e\u003cp\u003e9 \u0026amp; 18 months\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\u003cp\u003e\u003cb\u003eMR1\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBlood draw 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYF\u003c/p\u003e\u003cp\u003eBlood draw 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003eMR2\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBlood draw 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBlood draw 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eBlood draw 5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup C:\u003c/p\u003e\u003cp\u003e6 \u0026amp; 18 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMR1\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBlood draw 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBlood draw 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003eMR2\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBlood draw 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBlood draw 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eBlood draw 5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eMR: measles-rubella vaccine\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"10\"\u003eYF: Yellow Fever vaccine (Routine)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eOutcomes\u003c/h2\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003eSafety outcome measures\u003c/h2\u003e\u003cp\u003eLocal and systemic reactions were captured in the diary cards for 7 days post-vaccination. All Serious Adverse Events (SAEs) and positive measles polymerase chain reaction (PCR), measles immunoglobin M (IgM), and/or positive rubella IgM in children presenting with febrile illness and rashes were collected throughout the study.\u003c/p\u003e\u003cp\u003eLocal and systemic reactions were graded as grade 1 (mild), grade 2 (moderate), grade 3 (severe) and grade 4 (supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Adverse events were graded as grade 1\u0026ndash;5 (supplementary table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003ePrimary outcome measures\u003c/h3\u003e\n\u003cp\u003eThe primary outcome measure of the study is the geometric mean and proportion of participants with protective levels of measles neutralising antibodies at 2.5 years of age. Protective antibody levels are defined as Plaque Reduction Neutralising Titres (PRNT)\u0026thinsp;\u0026gt;\u0026thinsp;120 mIU/mL.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSecondary outcome measures\u003c/h2\u003e\u003cp\u003eSecondary outcomes of the study include measles PRNT and IgG concentrations one month after the first dose in infants receiving an early (6 months) compared to standard (9 months) dose of measles-containing vaccine (MCV); infant humoral and cellular immune response to first and second doses in children with lower or higher baseline (pre-vaccination) titres; infant PRNT and IgG responses post MR1 and MR2 given for the different vaccination schedules; anti-rubella IgG; and the effect of a measles vaccination clinical trial on public perceptions of measles immunisation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eMeasles and rubella cases\u003c/h2\u003e\u003cp\u003eInfants presenting to the study site clinics with measles-like illness (any or all of cough, coryza and conjunctivitis plus a maculopapular rash with or without fever) and, with or without a history of contact with an individual with a measles-like illness in the community had a blood and oral/nasopharyngeal specimen collected. Both the respiratory and blood specimens were tested for measles nucleic material and IgM, as well as rubella IgM, at the Uganda Virus Research Institute (UVRI). This is the national measles laboratory and supports UNEPI - Ministry of Health. The laboratory is a regional WHO Measles/Rubella Reference Laboratory that also serves Comoros, Burundi, Eritrea, Ethiopia, Kenya, Tanzania, Rwanda and the Republic of South Sudan.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eInfants seen at the study clinic before MR1 with a history of contact or measles-like illness, or laboratory confirmed measles, were withdrawn from the study, and replaced.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eFor this report we present baseline characteristics in all randomised infants, and safety and reactogenicity data after the first dose of MR vaccine. Analysis of SAEs up to 30 days post-first dose of vaccine and measles and rubella cases are presented descriptively in all vaccinated infants. For reactogenicity, we compared proportions of post-MR1 reactions in infants with available diary data using chi-square tests and fisher\u0026rsquo;s exact tests, where appropriate.\u003c/p\u003e\u003cp\u003eClinical and/or laboratory confirmed measles and rubella cases are descriptively summarised for all randomised infants and presented according to randomised group and timing of infection. Cumulative incidence of measles cases is presented using the Kaplan-Meier method.\u003c/p\u003e\u003cp\u003eData analysis was performed in R (version 4\u0026middot;4\u0026middot;3), using data extracted from the clinical database on 8 August 2025.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003eBetween 21 November 2023 and 26 September 2024, we randomised 477 participants, with 450 receiving MR1. Twenty-seven infants who were randomised but withdrawn from the trial by their caretakers or met an exclusion criterion before MR1 were replaced with a newly randomised participant (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). More participants in group B withdrew before vaccination, in the three months between randomisation (at 6 months of age) and vaccination (at 9 months of age), than in groups A and C, where randomisation and vaccination generally occurred in the same week.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eDemographic characteristics\u003c/h2\u003e\u003cp\u003eThe median age at enrolment was 26 weeks (Interquartile range (IQR): 26\u0026ndash;27 weeks). One hundred fifty-eight infants (35\u0026middot;1%) were randomised to receive MR vaccine at 6\u0026ndash;12 months, 137 infants (30\u0026middot;4%) at 9\u0026ndash;18 months and 155 infants (34\u0026middot;4%) at 6\u0026ndash;18 months of age. Overall, slightly more female infants were enrolled (53\u0026middot;5%). Baseline characteristics were similar across randomised groups (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003eBaseline characteristics of randomised participants (N\u0026thinsp;=\u0026thinsp;477)\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\u003eCharacteristic\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 \u0026amp; 12 months Group A\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;160)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 \u0026amp; 18 months\u003c/p\u003e\u003cp\u003eGroup B\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;159)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 \u0026amp; 18 months\u003c/p\u003e\u003cp\u003eGroup C\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;158)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOverall\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;477)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90 (56.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75 (47.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90 (57.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e255 (53.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70 (43.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e84 (52.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e68 (43.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e222 (46.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at randomisation (weeks)\u003c/b\u003e\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\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian [Q1, Q3]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26.0 [26.0, 27.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.0 [26.0, 27.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26.0 [26.0, 27.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e26.0 [26.0, 27.0]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNationality\u003c/b\u003e\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\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUgandan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e159 (99.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e157 (98.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e157 (99.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e473 (99.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSouth Sudanese\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongolese\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (0.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePakistan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRace\u003c/b\u003e\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\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlack\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e160 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e158 (99.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e158 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e476 (99.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMixed Race\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHaemoglobin (g/dL)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.2 [10.4, 12.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.0 [10.2, 11.8]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11.0 [10.3, 11.8]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11.0 [10.3, 11.9]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBreastfeeding\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e158 (98.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e151 (95.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e153 (96.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e462 (96.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnthropometry\u003c/b\u003e\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\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight at screening (kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.6 [6.8, 8.2]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.3 [6.8, 8.1]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.4 [6.7, 8.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.4 [6.8, 8.1]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength at screening (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.0 [64.0, 67.6]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65.5 [64.0, 67.3]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65.8 [64.0, 67.5]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e65.8 [64.0, 67.4]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHead Circumference at screening (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.5 [42.6, 44.5]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.6 [42.5, 44.5]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e43.4 [42.5, 44.5]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e43.5 [42.5, 44.5]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMUAC at screening (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.4 [13.6, 15.2]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14.4 [13.5, 15.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14.4 [13.5, 15.1]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14.4 [13.5, 15.1]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMaternal HIV status\u003c/b\u003e\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\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (11.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (10.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17 (10.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e52 (10.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e141 (88.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e143 (89.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e141 (89.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e425 (89.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eInfant HIV status at 6 weeks of age\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\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\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (94\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e51 (98.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (5\u0026middot;3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (1\u0026middot;9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e1\u003c/sup\u003e Median [IQR] was reported for continuous variables; n (%) for categorical variables\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e2\u003c/sup\u003e Only infants exposed to HIV (through maternal HIV status) were tested\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eLocal reactions\u003c/h2\u003e\u003cp\u003eThere were no statistically significant differences in the severity and proportion of infants experiencing local reactions after the first dose of vaccine between those vaccinated at 6 and 9 months of age. Overall, 21\u0026middot;2% of infants who received MR1 at 6 months registered at least one local reaction within 7 days post-vaccination compared to 21\u0026middot;9% of infants who received MR1 at 9 months (p\u0026thinsp;=\u0026thinsp;0\u0026middot;959) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Most local reactions were mild and occurred in the first four days post-vaccination in both 6 and 9 months arms (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eSystemic reactions\u003c/h2\u003e\u003cp\u003eSystemic reactions were reported in similar proportions of infants receiving MR1 at 6 and 9 months (29\u0026middot;2% vs 27\u0026middot;7%, p\u0026thinsp;=\u0026thinsp;0\u0026middot;845; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Fever rates did not differ significantly (p\u0026thinsp;=\u0026thinsp;0\u0026middot;781), with 1\u0026middot;9% of 6-month recipients and 1\u0026middot;5% of 9-month recipients experiencing moderate/severe fever, mostly within 48 hours and on day 4, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eRashes occurred in 11\u0026middot;8% of 6-month MR1 recipients (11\u0026middot;2% mild, 0\u0026middot;6% moderate) and 6\u0026middot;6% of 9-month recipients, with no significant difference (p\u0026thinsp;=\u0026thinsp;0\u0026middot;125). Most rash events occurred between days 2\u0026ndash;5 post-vaccination.\u003c/p\u003e\u003cp\u003eMild to moderate wheezing or breathing difficulties were reported in 10\u0026middot;3% (6-month) and 10\u0026middot;9% (9-month) of infants (p\u0026thinsp;=\u0026thinsp;0\u0026middot;957), mostly between days 2\u0026ndash;6. Drowsiness, all mild and typically within 72 hours, occurred in 13\u0026middot;8% of 6-month and 14\u0026middot;6% of 9-month recipients (p\u0026thinsp;=\u0026thinsp;0\u0026middot;935).\u003c/p\u003e\u003cp\u003eMuscle pain was reported in 5\u0026middot;1% of 6-month and 2\u0026middot;9% of 9-month recipients (p\u0026thinsp;=\u0026thinsp;0\u0026middot;456), mostly mild and within 3 days. One severe case at day 6 in a 6-month recipient resolved within 24 hours.\u003c/p\u003e\u003cp\u003eOverall, adverse events were comparable between groups, with no statistically significant differences across key symptoms.\u003c/p\u003e\u003cp\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\u003eSolicited local and systemic reactions during days 1\u0026ndash;7 after first vaccination\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\u003eSymptom\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6-month MR1 (N\u0026thinsp;=\u0026thinsp;312)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9-month MR1\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;137)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\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\u003eAny local\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66 (21\u0026middot;2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 (21\u0026middot;9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;959\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRedness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (6\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (5\u0026middot;8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;884\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSwelling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (9\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (8\u0026middot;8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u0026middot;000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTenderness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (12\u0026middot;5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (14\u0026middot;6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;650\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAny systemic\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e91 (29\u0026middot;2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38 (27\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;845\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFever\u0026thinsp;\u0026ge;\u0026thinsp;38\u0026deg;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (3\u0026middot;2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (3\u0026middot;6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;781\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRash\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37 (11\u0026middot;9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (6\u0026middot;6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;125\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDifficulty breathing/wheeze\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32 (10\u0026middot;3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (10\u0026middot;9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;957\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrowsiness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (13\u0026middot;8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (14\u0026middot;6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;935\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMuscle pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (5\u0026middot;1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (2\u0026middot;9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026middot;456\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e1\u003c/sup\u003e Fisher\u0026rsquo;s exact test\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSix serious adverse events (SAEs) occurred within 30 days of MR1 vaccination: four in the 9-month group and two in the 6-month group. Most (5/6) were due to infections or infestations, including diarrhoea (2 cases), malaria, pneumonia, and sepsis. One infant in the 6-month group was hospitalised for intussusception. None of the SAEs were considered related to the vaccine (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOne unrelated death from acute hydrocephalus occurred six months post-MR1 in a 12-month-old child in the 6\u0026ndash;18 month schedule group.\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\u003eSummary of Serious Adverse Events up to 30 days post-MR1\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\u003eMedDRA System Organ Class Preferred Term, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6-month MR1 (N\u0026thinsp;=\u0026thinsp;313)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9-month MR1 (N\u0026thinsp;=\u0026thinsp;137)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOverall (N\u0026thinsp;=\u0026thinsp;450)\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\u003eNumber of serious adverse events\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (33\u0026middot;3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (66\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (100%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGastrointestinal disorders\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1 (50\u0026middot;0%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0 (0%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e1 (16\u0026middot;7%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntussusception\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (50\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (16\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eInfections and infestations\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1 (50\u0026middot;0%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4 (100%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e5 (83\u0026middot;3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhoea infectious\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (25\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (16\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastroenteritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (25\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (16\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalaria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (25\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (16\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (50\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (16\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSepsis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (25\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (16\u0026middot;7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eMedDRA: Medical Dictionary for Regulatory Activities\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eMeasles and rubella cases\u003c/h2\u003e\u003cp\u003eSixteen laboratory-confirmed cases were detected among 72 children with morbilliform rashes: ten measles and six rubella (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Three additional clinical measles cases occurred prior to MR1 without confirmatory testing and subsequently withdrawn from further study participation. Three measles cases were in children born to HIV-positive mothers.\u003c/p\u003e\u003cp\u003eOf the ten confirmed measles cases, one occurred before MR1, eight between MR1 and MR2 in children vaccinated at 6 months, and one shortly after MR2. Most measles cases (7/10, 70\u0026middot;0%) occurred in the 6 \u0026minus;\u0026thinsp;18 month schedule group, likely due to the longer interval between doses. No measles cases were detected more than two weeks after MR2, though follow-up is ongoing.\u003c/p\u003e\u003cp\u003eSeven rubella cases were confirmed by IgM, in two infants within each vaccination group. One child in the 9-month group had two rubella episodes six months apart. Most rubella cases (6/7) occurred before MR2; one occurred 47 days post-MR2 in the 6\u0026ndash;12 month group.\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\u003eInfants with diagnosed measles or rubella\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\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eTimepoint\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c3\" namest=\"c2\" rowspan=\"2\"\u003e\u003cp\u003eEvent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u003cp\u003eRandomised group\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 \u0026amp; 12 months (N\u0026thinsp;=\u0026thinsp;160)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9 \u0026amp; 18 months (N\u0026thinsp;=\u0026thinsp;159)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6 \u0026amp; 18 months (N\u0026thinsp;=\u0026thinsp;158)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eAll\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eMeasles\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eClinical diagnosis only*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (1\u0026middot;9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003ePCR+/IgM+\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1\u0026middot;3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (0\u0026middot;6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7 (4\u0026middot;4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eRubella (IgM+)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1\u0026middot;3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (1\u0026middot;3%)\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (1\u0026middot;3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eBefore MR1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eMeasles\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eClinical diagnosis only*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (1\u0026middot;9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003ePCR+/IgM+\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (0\u0026middot;6%)\u003csup\u003e\u0026euro;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eRubella (IgM+)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eAfter MR1 before MR2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMeasles (PCR+/IgM+)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (1\u0026middot;3%)**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6 (3\u0026middot;8%)***\u003csup\u003e,$\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eRubella (IgM+)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0\u0026middot;6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (1\u0026middot;3%)\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 (1\u0026middot;3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eAfter MR2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMeasles (PCR+/IgM+)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1 (0\u0026middot;6%)\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eRubella (IgM+)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (0\u0026middot;6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0\u0026middot;0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003e*\u003c/b\u003e Withdrawn from the study prior to MR1 vaccination due to clinical measles diagnoses that were not laboratory-confirmed (no samples for testing)\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003e\u0026euro;\u003c/b\u003e\u003c/sup\u003e 1 infant was exposed to HIV\u0026thinsp;+\u0026thinsp;mother, taking ART during pregnancy\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003e$\u003c/b\u003e\u003c/sup\u003e 2 infants were exposed to HIV\u0026thinsp;+\u0026thinsp;mother, taking ART during pregnancy\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003e**\u003c/b\u003e 1 infant had positive measles PCR and IgM samples 4 days post-MR1 vaccination\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003e***\u003c/b\u003e 1 infant had positive measles PCR and IgM samples 11 days post-MR1 vaccination and a history of exposure to measles in their neighborhood. This infant died from acute hydrocephalus 198 days post-MR1 vaccination (187 days after positive measles samples), deemed not related to MR vaccination\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e 1 infant had 2 positive rubella IgM samples prior to MR2 vaccination: 14 and 201 days post-MR1 vaccination\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cb\u003e\u0026yen;\u003c/b\u003e\u003c/sup\u003e 1 infant had positive measles PCR and IgM samples 6 days post-MR2 vaccination\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first randomised clinical trial to assess the safety, tolerability, and immunogenicity of early MR vaccine administration at 6 months (early prime) versus the standard 9-month schedule in a high-burden setting using a licensed vaccine. We demonstrate that MR1 at 6 months is well tolerated, with a safety profile comparable to MR1 at 9 months. However, all breakthrough measles cases occurred in the 6-month group, suggesting a potential trade-off between early protection and optimal immunogenicity. The similar number of rubella cases across groups highlights the ongoing circulation of both viruses in this setting.\u003c/p\u003e\u003cp\u003eNo significant differences were observed in local reactions following MR1 at 6 months (21.2%) vs 9 months (21·9%). These findings align with prior studies from the Netherlands and Ghana, and with systematic reviews of MCV safety. In the Dutch study, local reactions ranged from 5% to 10% depending on age at vaccination (p = 0·08).[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] The Ghana study reported no difference in local events between infants receiving AIK-C at 6 months and Schwarz strain at 9 months.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] Nic Lochlainn et al similarly reported no significant risk difference in local reactions by age.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Notably, local reactions may also result from injection trauma, as demonstrated by comparable local event rates after MCV or sterile water injection in young infants.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eSystemic reactogenicity was also similar between groups (29·2% vs 27·7%, p = 0·845), consistent with meta-analyses showing no differences in fever (0·02, 95% CI − 0·02 to 0·05) or rash (0·00, 95% CI − 0·06 to 0·06) by age.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] The Ghana study reported higher fever in the 6-month group (21·7% vs 11·4%, p = 0·01) but no overall differences in systemic events.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] In contrast, the Dutch study observed fewer systemic events in the 6-month group, with rash the only significantly different event across ages (8% under 9 months vs 20% at 9–11 months and 18% at 12–14 months, p = 0·0004). Post-vaccination reactions were mild and self-limiting, with minimal recurrence after MR2 dosing, except in rare cases of anaphylaxis.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eOne child required surgery for intussusception, and five others were hospitalised for common infectious illnesses. None of these serious adverse events were attributed to vaccination.\u003c/p\u003e\u003cp\u003e Consistent with Uganda’s IDSR guidelines, children presenting with febrile maculopapular rashes were tested for measles and rubella.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Ten laboratory-confirmed measles cases were observed: one prior to MR1, eight post-MR1 in the 6-month group, and one post-MR2. Most (7/10, 70·0%) occurred in children following the 6–18 month schedule, suggesting that a shorter interval between MR1 and MR2 may reduce breakthrough risk. By contrast, four pre-vaccination measles cases occurred in the 9-month group during the short 3-month wait period, illustrating the vulnerability of infants in high-burden settings under current policy.\u003c/p\u003e\u003cp\u003eTwo measles cases occurred 2–14 days post-MR1 with no known contact and were adjudicated as possibly vaccine-related. Although rash and mild illness may occur after MCV due to vaccine viral replication, true vaccine-associated measles is rare.[\u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e–\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] In a Chinese study of 15,000 genotyped cases, only 0·67% were vaccine-associated, nearly all after the first dose.[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] In the absence of sequencing, it is unclear whether post-vaccination cases in our study were wild-type or vaccine-strain. While rare severe vaccine-strain disease has been reported in immunocompromised individuals, transmission from vaccine-related cases remains largely theoretical.[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eAll breakthrough measles cases in our study presented with rash and fever or coryza. As expected, these infections were mild to moderate, consistent with prior reports of milder disease in vaccinated children.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] A second vaccine dose is needed to ensure protection in initial non-responders, who may represent up to 15% of children. Immunological analyses are underway to further explore this.\u003c/p\u003e\u003cp\u003eWe also detected seven rubella events in six children, occurring in two infants in each vaccination group. One child in the 9–18 month group had two confirmed rubella episodes. Most cases (6/7) occurred after MR1 but before MR2, including one case 47 days post-MR2. Although a single rubella vaccine dose is 94–100% effective,[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] sporadic post-vaccination cases have been reported. In a cohort of over 77,000 children, Geier et al reported 57 rubella cases among 33,000 vaccinated individuals, most of which were mild.[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eRubella is less infectious than measles but often transmitted by asymptomatic carriers.[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] In our study, 4 of 6 rubella cases, including the post-MR2 case, had contact with an individual with a measles-like illness. These findings support the view that rubella cases in vaccinated children are often associated with prolonged or close exposure to infectious contacts.\u003c/p\u003e\u003cp\u003eDue to the small number of measles and rubella cases, our study is not powered to compare vaccine efficacy between 6- and 9-month schedules. Similarly, rubella cases were too few to draw firm conclusions on schedule effectiveness. Nevertheless, high community coverage (≥ 95%) remains critical to interrupt transmission of both viruses.\u003c/p\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and Limitations\u003c/h2\u003e\u003cp\u003eThe diagnosis of measles/rubella requires keen clinician observation and a high index of suspicion. While children presenting to the study clinics with a measles-like illness were investigated, we acknowledge that some children might have sought medical attention at other health care facilities outside the study sites and therefore were not captured. Second, we were unable to determine at the time of presentation if the breakthrough cases were due to primary or secondary vaccine failure. We were equally unable to obtain measles/rubella genetic characterisation to rule out the possibility of a vaccine strain in the measles/rubella cases recorded after vaccination.\u003c/p\u003e\u003cp\u003eDespite these limitations, the study design has adequately enabled the recording and follow-up of all adverse events, including measles/rubella events, across the three vaccination groups for an extended observation timeline. The pre- and post-vaccination sample collection schedule provides a valuable opportunity in assessing the short- and long-term immunological response following an early and standard measles and rubella vaccination schedule. Additionally, we will be able to determine the amount and potential influence of pre-vaccination measles antibodies in Ugandan infants.\u003c/p\u003e\u003c/div\u003e"},{"header":"Implications of results and conclusion","content":"\u003cp\u003eThis study provides further evidence supporting the safety of administering a measles-containing vaccine at 6 months of age. The occurrence of measles and rubella cases in children who had received at least one vaccine dose underscores the continued widespread transmission of both viruses among Ugandan infants and highlights the urgent need to achieve and maintain high two-dose vaccine coverage.\u003c/p\u003e\u003cp\u003eAlthough all breakthrough measles cases occurred in children who received MR1 at 6 months, the number of cases is too small to draw definitive conclusions about differences in vaccine efficacy between schedules. Immunogenicity analyses will help determine whether these cases occurred in vaccine non-responders. An extension of the trial is underway to increase sample size and evaluate the clinical impact of vaccine timing more robustly.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical consideration\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for the BoostME\u003cem\u003e\u0026nbsp;\u003c/em\u003estudy was obtained from the Mulago Hospital Research Ethics Committee (MHREC 2023-86), the Uganda National Council for Science and Technology (HS2883ES), the National Drug Authority (CTC 250/2023) and Oxford Tropical Research Ethics Committee (2-23). The clinical trial is registered on ClinicalTrials.gov (NCT06667206). The nature and aim of the study were explained to potential participants\u0026rsquo; parents/guardians prior to signing the study written informed consent form. All study procedures were adherent to the research guidelines of the Uganda National Council for Science and Technology, the National Drug Authority, and the principles of the Declaration of Helsinki. Data collection is ongoing at the time of submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for Publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eContributors\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMV, KLD, MK and SK designed the study. PM, EM, KLD, AE, FA, BK and GB provided onsite supervision and guidance on study execution and data collection. VT, CK, NGM, IK and YFM extracted and checked the data. GB, NGM, and IK performed the analysis. MV, KLD, and EM provided overall coordination and supervision of this work. MV, KLD and GB performed the relevant literature reviews. All authors contributed intellectually to the work and reviewed the final manuscript for accuracy and completeness. All authors had access to the study data and accept responsibility for the decision to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funders of this clinical trial (Gates Foundation) had no role in the study design, collection of data, data analysis and its interpretation or the generation of this report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDeclaration of Competing Interest\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported, in whole or in part, by the Gates Foundation [INV-048650]. The Gates Foundation grant funding was awarded to Oxford University for this trial. The conclusions and opinions expressed in this work are those of the author(s) alone and shall not be attributed to the Foundation. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData Availability\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs per the Gates Foundation Open Access policy, datasets presented in this report are available to download as supplementary files. As the study is still ongoing, these files are preliminary and may undergo review and updates due to standard data cleaning processes. Therefore, future data downloads and publications may differ from the supplementary files available with this publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to appreciate the following people/institutions for their contribution to this work: the study participants and their caretakers who dedicated their time to attend all study visits, the Ministry of Health - Uganda for their support in providing the measles and rubella and Yellow Fever vaccines, the administrative units of Mulago National Referral Hospital, Kisenyi, Kawaala and Komamboga Health Centres for accommodating and supporting study activities at their premises, the MUJHU Care Ltd Community Advisory Board for their in depth guidance on community engagements and sensitisation. The authors also appreciate the insightful recommendations provided by doctors Alane Izu, Sabrina Kitaka and Victoria Nambasa, who comprised this clinical trial\u0026rsquo;s Data and Safety Monitoring Board.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organisation. The immunological basis for immunization series: module 7: measles: update 2020. World Health Organization; 2020.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSarker SA, Wahed MA, Rahaman MM, Alam AN, Islam A, Jahan F. Persistent protein losing enteropathy in post measles diarrhoea. Arch Dis Child. 1986;61:739\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/adc.61.8.739\u003c/span\u003e\u003cspan address=\"10.1136/adc.61.8.739\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMinta AA. Progress Toward Measles Elimination \u0026mdash; Worldwide, 2000\u0026ndash;2023. MMWR Morb Mortal Wkly Rep. 2024;73. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.15585/mmwr.mm7345a4\u003c/span\u003e\u003cspan address=\"10.15585/mmwr.mm7345a4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTakahashi S, Metcalf CJE, Ferrari MJ, Tatem AJ, Lessler J. The geography of measles vaccination in the African Great Lakes region. Nat Commun. 2017;8:15585. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/ncomms15585\u003c/span\u003e\u003cspan address=\"10.1038/ncomms15585\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDixon MG, Ferrari M, Antoni S, Li X, Portnoy A, Lambert B, et al. Progress Toward Regional Measles Elimination - Worldwide, 2000\u0026ndash;2020. MMWR Morb Mortal Wkly Rep. 2021;70:1563\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.15585/mmwr.mm7045a1\u003c/span\u003e\u003cspan address=\"10.15585/mmwr.mm7045a1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organisation (WHO). Measles and Rubella Strategic Framework 2021\u0026ndash;2030. 1st ed. Geneva: World Health Organization; 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGasta\u0026ntilde;aduy PA, Goodson JL, Panagiotakopoulos L, Rota PA, Orenstein WA, Patel M. Measles in the 21st Century: Progress Toward Achieving and Sustaining Elimination. J Infect Dis. 2021;224:S420\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/infdis/jiaa793\u003c/span\u003e\u003cspan address=\"10.1093/infdis/jiaa793\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organisation. Epidemiology of measles in infants younger than 6 months: analysis of surveillance data 2011\u0026ndash;2016. n.d.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaksono BM, de Vries RD, McQuaid S, Duprex WP, de Swart RL. Measles Virus Host Invasion Pathogenesis Viruses. 2016;8:210. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/v8080210\u003c/span\u003e\u003cspan address=\"10.3390/v8080210\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoss WJ, Polack FP. Immune responses to measles and measles vaccine: challenges for measles control. Viral Immunol. 2001;14:297\u0026ndash;309. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1089/08828240152716556\u003c/span\u003e\u003cspan address=\"10.1089/08828240152716556\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNiewiesk S. Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies. Front Immunol. 2014;5:446. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fimmu.2014.00446\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2014.00446\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTiley KS, Overbeek H, ten H, Basnet S, van Binnendijk R, Clarke E, Cose S, et al. The waning of maternal measles antibodies: a multi-country maternal-infant seroprevalence study. J Infect. 2025;106531. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jinf.2025.106531\u003c/span\u003e\u003cspan address=\"10.1016/j.jinf.2025.106531\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDixon MG, Tapia MD, Wannemuehler K, Luce R, Papania M, Sow S, et al. Measles susceptibility in maternal-infant dyads\u0026mdash;Bamako. Mali Vaccine. 2022;40:1316\u0026ndash;22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.vaccine.2022.01.012\u003c/span\u003e\u003cspan address=\"10.1016/j.vaccine.2022.01.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOkiror Okello E, Migisha R, Ampaire I, Nsubuga F, Nalwanga J, Kwizera P, et al. Measles outbreak investigation in Kakumiro District, Uganda, February\u0026ndash;May 2024. Discov Public Health. 2025;22:52. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12982-025-00446-4\u003c/span\u003e\u003cspan address=\"10.1186/s12982-025-00446-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKizito SN, Simbwa B, Thomas K, Akuguzibwe R, Sembatya I, Nsubuga E et al. Measles outbreak propagated by visiting a health facility, in a refugee hosting community, Kiryandongo District, Western Uganda, August 2022\u0026ndash;May 2023 n.d.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBiribawa C, Atuhairwe JA, Bulage L, Okethwangu DO, Kwesiga B, Ario AR, et al. Measles outbreak amplified in a pediatric ward: Lyantonde District, Uganda, August 2017. BMC Infect Dis. 2020;20:398. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12879-020-05120-5\u003c/span\u003e\u003cspan address=\"10.1186/s12879-020-05120-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWHO Immunization Data portal - Detail Page. Immun Data n.d. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://immunizationdata.who.int/global/wiise-detail-page\u003c/span\u003e\u003cspan address=\"https://immunizationdata.who.int/global/wiise-detail-page\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed September 25, 2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePrincipi N, Esposito S. Early vaccination: a provisional measure to prevent measles in infants. Lancet Infect Dis. 2019;19:1157\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S1473-3099(19)30520-1\u003c/span\u003e\u003cspan address=\"10.1016/S1473-3099(19)30520-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNic Lochlainn LM, de Gier B, van der Maas N, van Binnendijk R, Strebel PM, Goodman T, et al. Effect of measles vaccination in infants younger than 9 months on the immune response to subsequent measles vaccine doses: a systematic review and meta-analysis. Lancet Infect Dis. 2019;19:1246\u0026ndash;54. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S1473-3099(19)30396-2\u003c/span\u003e\u003cspan address=\"10.1016/S1473-3099(19)30396-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGans H, Yasukawa L, Rinki M, DeHovitz R, Forghani B, Beeler J, et al. Immune responses to measles and mumps vaccination of infants at 6, 9, and 12 months. J Infect Dis. 2001;184:817\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1086/323346\u003c/span\u003e\u003cspan address=\"10.1086/323346\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrinkman ID, Butler AL, de Wit J, van Binnendijk RS, Alter G, van Baarle D. Measles Vaccination Elicits a Polyfunctional Antibody Response, Which Decays More Rapidly in Early Vaccinated Children. J Infect Dis. 2022;225:1755\u0026ndash;64. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/infdis/jiab318\u003c/span\u003e\u003cspan address=\"10.1093/infdis/jiab318\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEPI Lab | Uganda Virus Research Institute n.d. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.uvri.go.ug/epi-lab\u003c/span\u003e\u003cspan address=\"https://www.uvri.go.ug/epi-lab\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed November 18, 2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNic Lochlainn LM, de Gier B, van der Maas N, Strebel PM, Goodman T, van Binnendijk RS, et al. Immunogenicity, effectiveness, and safety of measles vaccination in infants younger than 9 months: a systematic review and meta-analysis. Lancet Infect Dis. 2019;19:1235\u0026ndash;45. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S1473-3099(19)30395-0\u003c/span\u003e\u003cspan address=\"10.1016/S1473-3099(19)30395-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVan Der Maas NAT, Woudenberg T, Hahn\u0026eacute; SJM, De Melker HE. Tolerability of Early Measles-Mumps-Rubella Vaccination in Infants Aged 6\u0026ndash;14 Months During a Measles Outbreak in The Netherlands in 2013\u0026ndash;2014. J Infect Dis. 2016;213:1466\u0026ndash;71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/infdis/jiv756\u003c/span\u003e\u003cspan address=\"10.1093/infdis/jiv756\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNkrumah FK, Osei-Kwasi M, Dunyo SK, Koram KA, Afari EA. Comparison of AIK-C measles vaccine in infants at 6 months with Schwarz vaccine at 9 months: a randomized controlled trial in Ghana. Bull World Health Organ. 1998;76 4:353\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVittrup DM, Jensen A, S\u0026oslash;rensen JK, Zimakoff AC, Malon M, Charabi S et al. Immunogenicity and reactogenicity following MMR vaccination in 5\u0026ndash;7-month-old infants: a double-blind placebo-controlled randomized clinical trial in 6540 Danish infants. eClinicalMedicine 2024;68. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.eclinm.2023.102421\u003c/span\u003e\u003cspan address=\"10.1016/j.eclinm.2023.102421\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Measles vaccines: WHO position paper \u0026ndash; April 2017. Update 2009. Geneva: World Health Organization; 2009.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoH U. Uganda 3rd IDSR Technical Guidelines for Integrated Disease Surveillance. 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChap. 4: Manual for the Laboratory-based Surveillance of Measles, Rubella, and Congenital Rubella Syndrome n.d. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/publications/m/item/chapter-4-manual-for-the-laboratory-based-surveillance-of-measles-rubella-and-congenital-rubella-syndrome\u003c/span\u003e\u003cspan address=\"https://www.who.int/publications/m/item/chapter-4-manual-for-the-laboratory-based-surveillance-of-measles-rubella-and-congenital-rubella-syndrome\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed June 20, 2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organisation. Information sheet observed rate of vaccine reactions measles, mumps and rubella vaccines. Geneva: 2014.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCDC, Chapter. 13: Measles. Epidemiol Prev Vaccine-Prev Dis 2024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-13-measles.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-13-measles.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed June 20, 2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNational measles. guidelines July 2024 2024.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCui A, Wang H, Zhu Z, Mao N, Song J, Zhang Y, et al. Measles Vaccine-Associated Rash Illness in China: an Emerging Issue in the Process of Measles Elimination. J Clin Microbiol. 2020;58. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1128/JCM.01472-20\u003c/span\u003e\u003cspan address=\"10.1128/JCM.01472-20\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHau M, Schwartz KL, Frenette C, Mogck I, Gubbay JB, Severini A, et al. Local public health response to vaccine-associated measles: case report. BMC Public Health. 2013;13:269. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/1471-2458-13-269\u003c/span\u003e\u003cspan address=\"10.1186/1471-2458-13-269\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMillson D, BROTHER-TO-SISTER TRANSMISSION OF MEASLES AFTER MEASLES, MUMPS, AND RUBELLA IMMUNISATION. Lancet. 1989;333:271. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(89)91274-9\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(89)91274-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDe Serres G, Gay NJ, Farrington CP. Epidemiology of Transmissible Diseases after Elimination. Am J Epidemiol. 2000;151:1039\u0026ndash;48. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/oxfordjournals.aje.a010145\u003c/span\u003e\u003cspan address=\"10.1093/oxfordjournals.aje.a010145\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCanada PHA. accessed April 10, of. Measles vaccines: Canadian immunization guide 2007. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html\u003c/span\u003e\u003cspan address=\"https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-12-measles-vaccine.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCDC. Rubella Vaccine Recommendations. Rubella Ger Measles Three-Day Measles 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/rubella/hcp/vaccine-considerations/index.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/rubella/hcp/vaccine-considerations/index.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed July 12, 2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrganization WH. Rubella: vaccine preventable diseases surveillance standards. 2018.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGeier DA, Geier MR, Childhood MMR. Vaccination Effectiveness Against Rubella: A Longitudinal Cohort Study. Glob Pediatr Health. 2022;9:2333794X221094266. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/2333794X221094266\u003c/span\u003e\u003cspan address=\"10.1177/2333794X221094266\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCDC. Rubella Symptoms and Complications. Rubella Ger Measles Three-Day Measles 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/rubella/signs-symptoms/index.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/rubella/signs-symptoms/index.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed July 12, 2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBest JM, Rubella. Semin Fetal Neonatal Med. 2007;12:182\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.siny.2007.01.017\u003c/span\u003e\u003cspan address=\"10.1016/j.siny.2007.01.017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Measles, Early vaccination, safety, high-burden settings, reactogenicity","lastPublishedDoi":"10.21203/rs.3.rs-8180519/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8180519/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeasles remains a major cause of child morbidity and mortality in low-resource settings. Young infants are particularly at risk of severe disease, with many lacking protective levels of maternal antibodies by six months. Vaccination before nine months in high-burden settings may confer earlier protection; however, concerns exist about its effectiveness at this age. We present early findings on enrolment, safety, and breakthrough infections following the administration of a registered measles-containing vaccine at six months versus nine months (MR1) with a subsequent booster (MR2) at 12 or 18 months of age.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted an open-label randomised controlled non-inferiority trial at four health facilities in Kampala, Uganda. Infants aged 24–28 weeks were randomly assigned to receive MR at six and 12 months (group A), nine and 18 months (group B) or six and 18 months (group C). Infants were electronically randomised in a 1:1:1 ratio using block randomisation of varying sizes, stratified by site, maternal HIV status and baseline haemoglobin level. Caretakers recorded solicited reactions on paper diary cards, with safety-related events evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e450 infants received MR1 and were enrolled. No differences in local or systemic post-vaccination events between the six and nine months MR1 groups were observed [Local: 21·2% versus 21·9% (p = 0·959), systemic: 29·2% vs 27·7% (p = 0·845)]. Most local reactions were mild and within the first four days. The majority (5/6) of hospitalisations followed common childhood illnesses, with one non-vaccine-related death six months post-MR1. Sixteen laboratory-confirmed cases of measles (10) and rubella (6), and three clinical measles cases before MR1 were registered. Most measles cases (70·0%) occurred in group C, with no measles cases registered two weeks post-MR2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe provide further evidence on the safety of administering a measles-containing vaccine at six months of age.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial was registered on 31st October 2024 with Clinicaltrials.gov with the identifier NCT06667206.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCopyright: \u003c/strong\u003eLicence\u003cstrong\u003e CC BY\u003c/strong\u003e\u003c/p\u003e","manuscriptTitle":"Preliminary safety data from a randomised trial of early versus standard timing of administration of measles-rubella vaccine in Ugandan infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-12 08:30:24","doi":"10.21203/rs.3.rs-8180519/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-19T06:47:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-18T01:08:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146564479509223206911994688290281115674","date":"2026-01-06T00:52:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-29T05:11:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"244742394077875594767540360847627935197","date":"2025-12-22T02:28:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-08T13:04:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-06T08:19:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-06T08:17:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Medicine","date":"2025-11-27T12:48:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"935ae446-7c14-495c-8688-b1e53da913f1","owner":[],"postedDate":"December 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-03T06:08:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-12 08:30:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8180519","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8180519","identity":"rs-8180519","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}