JYNNEOS VS. ACAM2000: A CRITICAL REVIEW OF THE SAFETY, EFFICACY AND REAL-WORLD EFFECTIVENESS OF MONKEYPOX VACCINES

JYNNEOS VS. ACAM2000: A CRITICAL REVIEW OF THE SAFETY, EFFICACY AND REAL-WORLD EFFECTIVENESS OF MONKEYPOX VACCINES | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 12 November 2025 V1 Latest version Share on JYNNEOS VS. ACAM2000: A CRITICAL REVIEW OF THE SAFETY, EFFICACY AND REAL-WORLD EFFECTIVENESS OF MONKEYPOX VACCINES Authors : Benish Javed , Ramna Zia 0000-0002-9655-722X [email protected] , and Muhammad Imran [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176292732.27824655/v1 464 views 120 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The current global outbreak of monkeypox, a zoonotic virus that shares similarities with smallpox (such as the characteristic rash and mode of transmission, though monkeypox generally has a lower fatality rate and less severe symptoms), has raised significant interest. Vaccination is seen as a critical preventive strategy, with the emergence of JYNNEOS and ACAM2000 as key options in recent times. This study aims to critically evaluate and compare the safety, efficacy, and real-world effectiveness of the two primary monkeypox vaccines JYNNEOS and ACAM2000 to guide clinical and public health decision-making. A comparative analytical review was conducted by synthesizing evidence from peer-reviewed studies, clinical trial data, and public health reports published between 2010 and 2025. Key parameters examined include immunogenicity, adverse event profiles, storage requirements, and suitability for different population groups. The findings suggest that JYNNEOS offers a more favorable safety profile with fewer serious adverse effects and is better suited for immuno-compromised individuals, while ACAM2000 demonstrates robust efficacy but poses higher risks of complications such as myocarditis, pericarditis, and progressive vaccinia due to its replication-competent vaccinia virus. Both vaccines show protective efficacy against monkeypox; however, JYNNEOS’s superior safety and ease of administration make it a more practical choice for widespread immunization efforts. This comparative review underscores the importance of tailoring vaccine strategies based on population risk factors and health infrastructure. Future research should focus on long-term effectiveness, potential for combination vaccine strategies, and preparedness against emerging orthopoxvirus threats. JYNNEOS VS. ACAM2000: A CRITICAL REVIEW OF THE SAFETY, EFFICACY AND REAL-WORLD EFFECTIVENESS OF MONKEYPOX VACCINES Ramna Zia 1*¥ , Benish Javed 2¥ , Muhammad Imran 3,4* 1 Department of Life Sciences, School of Science, University of Management and Technology, Lahore, Pakistan; [email protected] ; https://orcid.org/0000-0002-9655-722X 2 University Institute of Medical Lab Technology, Faculty of Allied Health Sciences, The University of Lahore, Lahore, Pakistan; [email protected] 3 Department of Surgery-Otolaryngology Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Adelaide 5011, Australia. 4 The Department of Surgery, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide 5000, Australia; [email protected] ; https://orcid.org/0009-0005-6402-1622 ¥ These authors contributed equally and share first authorship. *These authors share correspondence. Corresponding Author: *Ramna Zia Department of Life Sciences, School of Science, University of Management and Technology, Lahore, Pakistan; [email protected] ; https://orcid.org/0000-0002-9655-722X *Muhammad Imran Department of Surgery-Otolaryngology Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Adelaide 5011, Australia. The Department of Surgery, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide 5000, Australia; [email protected] ; https://orcid.org/0009-0005-6402-1622 Data Availability Statement: Relevant data generated and analyzed during this study can be obtained from the corresponding author upon request. Access to certain portions of the dataset may be limited in order to maintain patient confidentiality and to comply with institutional guidelines. Funding Statement: This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors. Conflict of Interest Disclosure: The authors of the manuscript have no financial or non-financial conflict of interest. Ethics Approval Statement: Not applicable Patient Consent Statement: Not applicable Clinical Trial Registration: Not applicable GRAPHICAL ABSTRACT ABSTRACT The current global outbreak of monkeypox, a zoonotic virus that shares similarities with smallpox (such as the characteristic rash and mode of transmission, though monkeypox generally has a lower fatality rate and less severe symptoms), has raised significant interest. Vaccination is seen as a critical preventive strategy, with the emergence of JYNNEOS and ACAM2000 as key options in recent times. This study aims to critically evaluate and compare the safety, efficacy, and real-world effectiveness of the two primary monkeypox vaccines JYNNEOS and ACAM2000 to guide clinical and public health decision-making. A comparative analytical review was conducted by synthesizing evidence from peer-reviewed studies, clinical trial data, and public health reports published between 2010 and 2025. Key parameters examined include immunogenicity, adverse event profiles, storage requirements, and suitability for different population groups. The findings suggest that JYNNEOS offers a more favorable safety profile with fewer serious adverse effects and is better suited for immuno-compromised individuals, while ACAM2000 demonstrates robust efficacy but poses higher risks of complications such as myocarditis, pericarditis, and progressive vaccinia due to its replication-competent vaccinia virus. Both vaccines show protective efficacy against monkeypox; however, JYNNEOS’s superior safety and ease of administration make it a more practical choice for widespread immunization efforts. This comparative review underscores the importance of tailoring vaccine strategies based on population risk factors and health infrastructure. Future research should focus on long-term effectiveness, potential for combination vaccine strategies, and preparedness against emerging orthopoxvirus threats. Keywords ACAM2000, JYNNEOS, monkeypox vaccines, vaccine efficacy, orthopoxvirus INTRODUCTION Monkeypox disease is a sequel to infection with monkeypox virus, which belongs to the category of orthopoxviruses in the family of poxviridae with variola virus and vaccinia viruses. Before 1970 there had been no known cases of MPXV infection in humans, and the virus had previously infected apes and monkeys. The monkey infections were initially described in laboratory and captive animals in 1958 in captive monkeys in Denmark. The earliest known case of human mpox occurred in August 1970 in a 9-month-old child in the Democratic Republic of the Congo (DRC)[1]. Afterwards, six additional instances of mpox were reported in Sierra Leone, Nigeria and Liberia in the period, September 1970- April 1971 [2]. Since this time, it has been also reported in multiple countries and currently has become endemic in Benin, the Central African Republic, Cameroon, the DRC, Ivory Coast, Nigeria, Gabon, Liberia, South Sudan, the Republic of Congo, and Sierra Leone. Since then, the cases of MPX have long been reported in areas that are not native to it. By late 2022, a total of 75,885 confirmed cases of monkeypox have been recorded across more than 101 nations that had not previously documented confirmed case of this disease[3-5]. While it is generally true that the condition is often self-limiting ertain individuals especially those who are immunocompromised, pregnant, or very young may develop severe complications, such as secondary bacterial infections, encephalitis, or respiratory distress, potentially leading to organ failure. In the most critical cases, these complications can result in death[6]. In early 2023, the World Health Organization (WHO) recorded 86,127 confirmed cases of mpox, including 97 fatalities in 110 countries where the disease had been historically uncommon given in figure 1[7]. Figure 1: Timeline of major events in monkeypox epidemiology and vaccine development, highlighting the progression from initial virus identification and early outbreaks to global spread and the approval of second-, third-, and emerging fourth-generation vaccines (1958–2024). In July 2024, there was a significant incline of 8.8 percent in the number of newly reported cases as compared to the previous month [8]. The largest proportions of cases reported during this time were from the Region of Americas (24.2%) and African Region (54.9%) [9]. Since January 1, 2022, globally, ten countries were most affected including: USA (33556 cases), Brazil (11841 cases), Spain (8104 cases), DRC (4385 cases), France (4283 cases), Colombia (4256 cases), Mexico (4132 cases), UK (4018 cases), Peru (3939 cases), and Germany (3886 cases), [8] as shown in figure 2. Figure 2: Reported Monkeypox Cases (2022–2024) in the Top 10 Most Affected Countries (WHO 2024). Interestingly, when combined, these countries contribute for 80% of the global case count[8]. According to the World Health Organization’s most recent situation report on Mpox, released on July 31, 2024, predicts that 22 different countries reported more cases during the most recent reporting month, with 35 countries confirming at least one case. Also, several other countries are seeing Mpox cases; these are Uganda, Kenya, Burundi, Rwanda and Cote d Ivoire [10]. MPXV, like other poxviruses, is included under the taxonomic family Poxviridae and the genus Orthopoxvirus. The exotic pet trade and international travel mostly facilitate the zoonotic transmission of MPX from animals to people. However, the present increase in cases is attributed to the quick transmission of the virus among humans.” The early manifestations of MPXV infection include elevated body temperature, cephalalgia, lumbago, lymphadenopathy, and a cutaneous eruption resembling the characteristic rash seen in varicella-zoster (chickenpox) virus infection. The majority of individuals afflicted with MPX often manifest very minimal symptoms with full recovery within two to four weeks[11, 12]. Figure 3: Pathogenesis and transmission of monkey pox disease [13]. Human infections usually follow direct exposure to a diseased animal or individual. Also, there is a possibility of spreading the virus in large slobbering or even touching an open wound including spreading through fomites i.e. contaminated objects[14]. It normally takes 7-21 days on average to incubate. But it can be abridged in case of exposure of great viral titer, i.e. in case of a bite, of a scrape or casual contact with the host. Fever, chills, malaise and subsequent appearance of a rash which spreads outwardly or centripetally to the palms and soles of the feet would be the major symptoms of a symptomatic case. An interesting fact is that a good percentage of cases that accordingly fit under this very category tend to have self-resolving behavior and do not require medical care. The maculopapular rash shows a sequential process as they change to the vesicular rash, pustular rash and eventually develop into the crusting rash within a period of two to four weeks. At the same time, the fever can continue for as long as a week. Unlike smallpox infections, MPX infections may come as lymphadenopathy. Remarkably, the current epidemic has revealed that the MPX can develop atypically without fever or rash but rather with the emergence of only one or several skin lesions which can be synchronous or asynchronous. These lesions are basically observed on the genitalia, oral mucosa and the rectal mucosa and they correspond with areas of body skin that come in contact with the other in the course of sex activity [15]. There exist vaccinations that provide protection against Monkeypox including second and third generation smallpox vaccines [16]. In 1980, the World Health Organization (WHO) declared the eradication of smallpox. However, in light of concerns about the potential for bioterrorism and the emergence of monkeypox outbreaks in the early 21st century, the licensing of new vaccinia-based smallpox vaccinations was deemed necessary. The first-generation smallpox vaccines, including Dryvax, were developed using the New York City Board of Health (NYCBH) strain of vaccinia, as along with the Lister/Elstree and Ikeda strains of vaccinia virus. These vaccines were traditionally produced by extracting lymph from animals and cultivating the virus on their skin[17]. According to the WHO (August 19, 2024), there are 46 Mpox vaccines undergoing preclinical testing while 28 are in various stages of clinical trials aimed to fill gaps in efficacy, safety, long-term immunity, and suitability for diverse populations. However, health authorities employed additional vaccinations linked to cross-protection in Mpox to control the recent outbreak. The smallpox vaccines ACAM2000, JYNNEOS, and LC16m8 provide cross-protection against Mpox [18]. In contrast, the production of the second and third generation vaccines included the use of cell culture methods, which were implemented with the objective of enhancing their safety profile. In the United States, there are two approved smallpox vaccinations, namely ACAM2000 and JYNNEOS[17]. ACAM2000 received its authorisation in 2007 by the US Food and Drug Administration (FDA). This is a second-generation, replicating vaccinia-based, smallpox vaccine. It has its origin in a cloned strain of Dryvax. The vaccine should be used as a way of active immunization against smallpox among individuals who are known to be at high risk of acquiring smallpox virus infection, yet it has not known to protect against monkeypox disease. However, some severe side effects, including myopericarditis in vaccinia-naive people, might occur following administration of ACAM2000. Usage is contraindicated in severe immunocompromised patients.” More attenuated vaccinia virus vaccines were developed via the method referred to as serial passage; the vaccinia virus is cultivated successively in primary cell culture or eggs [17, 19]. The principal vaccine now used for the smallpox in the United States is JYNNEOS, an FDA-approved, non-replicating attenuated vaccine of the third generation. Its licensure took place in 2019 for small pox and monkeypox[20]. The MVA attenuated strain which is derived from the Ankara strain of vaccinia virus, was subjected to over 500 serial passages in chick embryo fibroblast cells, resulted in 570 passes in total. As the progression of the 2022 outbreak unfolded, empirical evidence pertaining to vaccination efficacy indicates that the JYNNEOS vaccine provides a certain degree of protection against Monkeypox. As an example, in the United States, the prevalence of monkeypox was shown to be 14 times greater among men who had not received the JYNNEOS vaccination compared to those who received at least a single dose. This finding is globally relevant, as monkeypox outbreaks have been reported across Europe, South America, Asia, and Africa, highlighting the urgent need for effective vaccination strategies and public health responses worldwide not just in the U.S., but in all affected regions to prevent further international spread and mitigate health system burdens [21]. JYNNEOS is specifically recommended for the prophylaxis of smallpox and monkeypox infections in those aged 18 years and above who have been identified as being at a high risk for contracting smallpox and monkeypox. The main aim of this study is to comprehensively assess the efficacy of monkeypox vaccinations. This study seeks to compare the efficacy and safety of the JYNNEOS and ACAM2000 vaccines in preventing monkeypox infection. Given their differences in design and safety profiles, this comparison is essential to guide vaccine selection, particularly in high-risk populations and outbreak situations. NAVIGATING MONKEYPOX DISEASE: ESSENTIAL INFORMATION Monkeypox is classified under the taxonomic family Poxviridae, specifically in the subfamily Chordopoxvirinaess , genus Orthopoxvirus, and species Monkeypox virus . Electron microscopy reveals that the monkeypox virus has a relatively large size, measuring between 200 and 250 nanometers. Poxviruses have a brick-shaped morphology and possess a lipoprotein envelope that encloses a linear double-stranded DNA genome[22]. Poxviruses encode all proteins required for replication, transcription, assembly, and egress; they only utilize host ribosomes for mRNA translation given in figure 3[23]. or extracellular enveloped virus (EEV) into a human cell. This is followed by the subsequent takeover of cell machinery. “Upon entry, these particles possess the ability to undergo replication and subsequently infect the host organism. Viral proteins are produced by exploiting the translational apparatus of the host organism to transcribe the viral DNA, which has undergone replication within the host cell. Intracellularly, the viral DNA and proteins converge, leading to the process of assembly, ultimately resulting in cell lysis by exocytosis. In conclusion, the EMV and EEV virus particles are released from the host cell [23]. The virus from Johnnies shows it also as a zoonotic disease. Squirrels, rats, monkeys, prairie dogs, hedgehogs, pigs and mice in the African regions in which monkey pox was previously found, are extremely likely to be the animal host for the disease[24]. Monkeypox is an illness that had been endemic to the central and western parts of Africa, and an especially high prevalence was reported in the Democratic Republic of Congo. Monkeypox virus (MPXV) was named after it was first discovered in captive monkeys explaining why it is named monkeypox. Nevertheless, the existing evidence shows that MPXV natural reservoir is African rodents. MPXV have been observed in few species including squirrels, rats, mice, primates, prairie dogs and human beings [25]. So far, two genetically different clades have been identiified. The Congo Basin (Central African) clade has a higher frequency of reporting as compared to the west African clade and the Congo Basin group shows evidence of human to human spread, whereas the West African clade fails to carry this characteristic [26]. The existing information suggests that receiving the smallpox vaccine in the past could potentially offer protection against the monkeypox virus and perhaps enhance the clinical presentation of the illness [27]. Recent studies indicate that smallpox vaccination provides approximately 54% protection against monkeypox infection, with third-generation vaccines showing up to 64% efficacy in preventing severe disease [28]. Different smallpox vaccines in the US, the Strategic National Stockpile (SNS) currently holds three different smallpox vaccines licensed to vaccinate against smallpox (JYNNEOSTM or IMVAMUNE or IMVANEX or MVA-BN and ACAM2000), and one experimental smallpox vaccine that is potentially licensable to vaccinate against smallpox (the Aventis Pasteur Smallpox Vaccine (APSV) under an investigational new drug IND application) [29]. A detailed Mpox outbreak chronology is given below in table 1. Table 1. Mpox Outbreaks Chronology: Epidemiological Perspectives, Virus Evolution, and Public Health Responses 1958 Captive Monkeys (Denmark) First detection in research monkeys Preliminary categorization of MPOXV as a new member of Orthopoxvirus genus No significant response: virus remained restricted to non-human primates Early classification, virus confined to animals [30] 1970 Democratic Republic of Congo (DRC) First confirmed human case in a 9-month-old baby boy Genetically related to the smallpox causing virus i.e., Variola virus Partial public health initiatives; primary focus on smallpox surveillance Emergence in humans, limited response [31] 1970s-1980s Central & West Africa Sporadic cases in rural rainforest zones, specifically in Central Africa Recognition of two genetic linages: West African and Central African Public health focused on smallpox eradication; minimal attention to MPOXV Focus on smallpox eradication, MPOXV largely ignored [32, 33] 2003 USA (Imported Rodents) First outbreak documented outside Africa; associated with the rodents imported from Africa No major mutations noted Swift response; quarantine and monitoring of exposed humans and animals First international outbreak outside Africa [34] 2017–18 Nigeria Large outbreak with >200 confirmed cases and multiple demises Genetic studies showed similarity with West African lineage Improved surveillance, awareness programs, and vaccination of high risk contacts Significant resurgence, introduction of vaccination strategy [35] 2021–22 Global Spread (International) Multiple international outbreaks, including non-endemic countries Viral mutations suggest enhanced transmissibility WHO declared Public Health Emergency of International Concern (PHEIC); vaccination campaigns were launched Global spread, rapid response, vaccine introduction [36] 2022–23 Non-African Regions Endemic cases in regions outside Africa, suggesting local transmission Increased divergence; emergence of novel variants Sustained vaccination, case surveillance, community education, and development of diagnostics Local transmission in non-endemic countries [37] 2023–24 Ongoing Global Cases Persistent global cases, especially in immunocompromised individuals Ongoing studies on virus evolution and adaptation Strengthening international collaboration, research funding, and infrastructure Focus on vulnerable populations and ongoing evolution studies. [8] MONKEY POX VACCINE DEVELOPMENT Better MPXV vaccines that make reliable and long-lasting antibodies along with protection are required, as are inexpensive vaccines. Natural infection with MPXV-induced antibodies has a much greater titer than the MVA-BN vaccination, while the T cell responses appear to be comparable between the two [38]. There have been confirmed cases of MVA-BN vaccination recipients not receiving full protection [39]. Although, antibodies are considered to be associated with protection, however the predictor of immunity for mpox vaccinations has not yet been determined [40]. Various antibody functions, including neutralization and Fc-dependent effector activities against both extracellular enveloped virus (EEV) and intracellular mature virus (IMV), were shown to play imperative roles in suppressing MPXV viraemia in non-human primate models of mRNA vaccination. Additionally, lesion control specific antibodies regulate opsonophagocytic activities via neutrophil and NK cell-mediated mechanisms [41]. In order to avoid mpox, there need to be more immunogenic vaccines. Despite the fact that MPXV has approximately 190 genes, in their quest to design the subunit vaccines, there are some genes specifically aimed in recombinant technology. MPXV B6, A29, M1 and A35 are the most frequently selected target proteins when vaccines of next generation are to be used. A combination of host and viral membranes is achieved to permit the entry of pyxviruses into cells[42]. The MPXV M1 and A29 proteins facilitate the entry of the intracellular mature virus (IMV) form of MPXV into host cells, while the B6 and A35 proteins play a key role in the dissemination of the extracellular enveloped virus (EEV) form. These two forms—IMV and EEV—are distinct stages of the monkeypox virus, each playing a unique role in the viral life cycle and pathogenesis. The transfected cells showed high expression of mRNA vaccines, including modified proteins M1, B6, and A35, with altered transmembrane sections and cytoplasmic tails that are localized to the cell surfaces. The A29 protein engineered with the signal peptide of an influenza virus H1 hemagglutinin (HA), was released from the cells. In mice, mRNA vaccines produced higher neutralizing antibody titers than MVA[43]. Adding MPXV antigens is another way to enhance the existing poxvirus vaccines [44, 45]. UNDERSTANDING THE DIFFERENT MONKEYPOX VACCINES: OPTIONS AND INSIGHTS The immune system’s reactions to a specific orthopoxvirus may exhibit cross-reactivity towards other orthopoxviruses, leading to varied degrees of protective effects that are contingent upon the degree of genetic relatedness among the different orthopoxvirus strains. There exists a conception suggesting that the increase in monkeypox cases following the discontinuation of smallpox immunization may be attributed to a progressively immunologically inexperienced population[9]. The phenomenon of immunological cross-reactivity has facilitated the development of several animal models (such as rhesus macaques and cynomolgus monkeys, prairie dogs, and mice) for studying smallpox infection, which have been crucial in evaluating the efficacy of vaccinations and antiviral treatments[46]. There are two main causes of cross-reactivity.” The first is the vast number of common immune epitopes across orthopoxviruses due to their high degree of sequence similarity, particularly among immunologically important proteins such as hemagglutinin (HA), fusion protein (FP), A29, A35, B6, and M1. The second cause of cross-reactivity is the conserved nature of certain viral proteins across orthopoxviruses, which leads to similar immune responses, even in viruses with different genetic backgrounds[47]. Studies indicate that at least 24 membrane and structural proteins were targeted by the immune response. CD4 T cells primarily recognize structural proteins, and T-cell responses similarly recognize epitopes among a diverse set of viral proteins[48], whereas CD8 T cells target proteins that are synthesized during the early stages of the viral lifecycle, such as virulence factors(E3L, K3L, F1L, VGF, and B13R) [49]. The presence of a neutralizing antibody has been shown to associate with immunity against variola virus-caused smallpox in humans and other orthopoxviruses in animal models[50]. While T cells are not essential for providing protection, they contribute to the elimination of the virus. FIRST GENERATION VACCINES During the 20th century, various vaccinations were developed with the purpose of combating smallpox. These vaccines were made on the basis of vaccinia virus, which possess unique biological features such as reactogenicity, replication efficiency, tissue tropism, and safety profiles. These vaccines contained replicative viruses, which happened to be active and competent, in that they were of different degrees of reactogenicity in individuals. Other strains of the vaccinia virus, such as Lister/Elstree, New York City Board of Health (NYCBH, Dryvax® vaccine), EM-63 and Tian-Tan were used as vaccines in other countries in programmes to eradicate human smallpox. As an example, the Lister strain was commonly utilised in the United Kingdom and the NYCBH strain (Dryvax(r)) in the United States, the EM-63 strain in China and Tian-Tan strain in parts of Asia. A particular selection on these strains was that they possess a better safety profile, as compared with alternative strains, e.g. Copenhagen or Bern[51]. One notable distinction of these initial-generation vaccines lies in their capacity to infect diverse tissues. Consequently, the Lister vaccine was cultivated in the chick embryo chorioallantoic membrane (CAM), while the NYCBH vaccine was propagated using calf or water buffalo skin cells. Furthermore, they displayed variances in their way of appearance, either frozen or lyophilized [51, 52]. “The manufacture of these vaccinations saw a decline in tandem with the success made in eradicating smallpox, ultimately leading to their confinement in highly secure facilities due to the potential for misuse or accidental release of the virus, as smallpox is a highly contagious and deadly disease. Immunization for the general population in the United States was concluded in 1972, while the military population’s immunization efforts were terminated in 1989. The manufacturing of the Dryvax® vaccine was terminated in 1978, but with the retention of 15 million doses as a precautionary measure for emergency situations[51, 53]. SECOND GENERATION VACCINES (ACAM2000 VACCINE) ACAM2000®, a second-generation smallpox vaccine, is composed of live replicating vaccinia virus obtained from cell cultures in Vero Cells. On August 31, 2007, the U.S. Food and Drug Administration (FDA) approved ACAM2000 for the purpose of administering it to those who had an elevated susceptibility to getting smallpox[54]. The effectiveness of this vaccination in mitigating the elevated death ratio and acuteness of illness has been shown by many animal experiments conducted on prairie dogs and cynomolgus monkeys [55, 56]. There was no discernible shift in blood or chemical indicators that included white blood cell count, hemoglobin, red blood cell count, platelet count, differential leukocyte count, albumin, glucose, creatinine, and sodium; antibody tests during the first 15 days following immunization, according to one of the studies. In contrast to the control group, this was in line with the clinical signs shown in the immunized models. On the other hand, it was observed that the death rate decreased as time elapsed between the challenge and immunization, although no statistically significant survival advantage was computed. A single dosage of ACAM2000 (1.0 105 PFU) was employed in this investigation [56]. In another study, it was observed that the models( cynomolgus macaques) exhibited a survival rate of 100%, and the administration of a booster dosage resulted in the detection of minimal levels of viremia. Nevertheless, several clinical manifestations were seen, including the presence of lesions caused by vaccine. The findings of this study imply that the prime-boost strategy might be a valuable way for achieving an optimum vaccination response [57, 58]. A Phase III trial was conducted comparing ACAM2000 with Modified Vaccinia Ankara (MVA) a non-replicating smallpox vaccine candidate. The study revealed that MVA led to increased neutralizing antibody titers and reduced the adverse events paralleled to ACAM2000. Notably, in week 6 of MVA and week 4 of ACAM200, the geometric mean titer of neutralizing antibodies is 153.5 and 79.3, respectively. Further, the incidence of severe adverse events in MVA recipients was significantly less by number[59]. THIRD GENERATION VACCINE (JYNNEOS) MVA-BN (JYNNEOS) is a third-generation vaccine, and is defined by being a live non-replicating type of vaccine [60]. This strain is the so-called Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) an attenuated strain of the Vaccinia virus that has lost its capability to reproduce. Marketed in the United States as JYNNEOS 198, this vaccine has been approved to immunize against both monkey pox (MPX) and small pox (small pox)[61]. The immunization was approved by the Food and Drug Administration (FDA) in September 2019 to be undertaken by any persons over 18 years of age who are at high risk of being infected by the MPXV[62]. The effectiveness of MVA-BN vaccination towards the protection against MPX is estimated to be 85%. However, the efficiency and safety of this measure towards pregnant or milk producing women continues to attract controversy[63]. It is unknown whether JYNNEOS is excreted in human breast milk, which poses as a challenge to provide a clear question regarding the use of JYNNEOS in breastfeeding individuals. Because of the insufficient information on the possible transfer of the infection to the babies through the milk, all the healthcare providers should balance the advantages of getting immunized against the possible risks that are not known [64]. With about two weeks elapsed since the second injection of JYNNEOS vaccine, it has prompted the full production of antibodies by the immune system.Further studies are necessary on the durability of immune protection received by administration of JYNNEOS vaccine and effectiveness of additional and follow-up doses. Significant adverse consequences are of particular interest in regards to the risks of simultaneous administration of JYNNEOS and COVID-19 vaccines[61]. In response to statements issued by the Centers for Disease Control and Prevention (CDC) in May 2022, JYNNEOS is being utilized in the United States to provide the pre-exposure vaccination among occupationally high-risk individuals exposed to orthopoxviruses [65]. In the interim guidelines pertaining to monkeypox vaccinations, WHO has advised the administration of post-exposure prophylaxis (PEP) within a maximum of four days following initial exposure. Additionally, WHO recommends pre-exposure prophylaxis (PrEP) for individuals at risk, including healthcare workers, clinical laboratory personnel involved in diagnostic testing, laboratory staff handling orthopoxviruses, and other individuals deemed at risk as per national policy[66]. COMPARISON BETWEEN MONKEY POX VACCINES The efficacy of JYNNEOS and ACAM2000 across different age cohorts was assessed by SA Meo in 2022. He reported the barely noticeable side effects of the JYNNEOS vaccine, including fever, fatigue, headache, muscle soreness, nausea, swelling, redness, and itching at the injection site. In addition to an increased risk of cardiomyopathy and myopericarditis, the ACAM2000 vaccine can induce swelling, nausea, strictness of breath, fever, body aches, pain, vomiting, headache, muscle fatigue, skin redness, diarrhea, and wheezing [67]. JYNNEOS is a suitable option for active vaccination in the prevention of monkeypox illness among those below the age of 18, as well as those who are 18 years of age and over[68]. Nevertheless, there have been reports indicating that the ACAM2000 vaccination is not recommended for use in newborns, particularly those who are younger than one year of age due to the increased risk of severe adverse reactions such as progressive vaccinia, eczema vaccinatum, and encephalitis, which are more likely to occur in infants with underdeveloped immune systems. The JYNNEOS vaccine is cost effective compared to the ACAM2000 vaccine. The costs are USD 115.5 and USD 139 per dose, respectively [69]. While some wealthy countries like United States, Canada, and the United Kingdom are offering free immunization to their residents, others are transferring the financial burden to the public. It is crucial that public health efforts emphasize equitable and affordable access to vaccination for all individuals, as the health and survival of each member of a community are integral to collective societal well-being. Low-income nations should improve cold chain logistics, train healthcare workers, secure affordable vaccines through global partnerships, and run public awareness campaigns to ensure widespread immunization access. The preference for JYNNEOS vaccines is driven by their cost-effectiveness.” However, it is important to carefully consider the storage requirements associated with these vaccines. Although the JYNNEOS vaccine is more affordable, it must be stored between −15 °C to −25 °C, which is also the temperature range needed for the ACAM2000 vaccines [70, 71]. The issue of distribution is a significant barrier in low-income nations, since many of these countries are grappling with an energy crisis that hinders their ability to maintain optimal storage conditions, such as the provision of freezers. This provides a potential obstacle to ensuring the efficacy of both vaccinations[67]. Rao et al . (2022) [63] reported that there was a limited degree of confidence about some adverse like cutaneous reactions that may arise after the administration of JYNNEOS in comparison to ACAM2000. According to post-licensure surveillance data, the incidence of myopericarditis in ACAM2000 recipients has been estimated at approximately 5.7 cases per 1,000 primary vaccinees, highlighting a notable safety concern in its widespread use[72]. Conversely, there is a lack of recorded occurrences of similar adverse effects in relation to the administration of JYNNEOS vaccines to the general population. Current data/evidence suggest that the existing body of literature supports the JYNNEOS vaccine as a more favorable option to ACAM2000 for the purpose of immunization. Further research is needed to comprehensively assess the safety profile of JYNNEOS in broader population.[63]. In a clinical trial by Pittman et al . (2019)[59] the performance of neutralizing antibodies generated against ACAM2000 and vaccinia Ankara (MVA) was investigated. The vaccine for MVA produced an average of 153.5 neutralizing antibodies by week 6 in comparison to a GMT of 79.3 by week 4 with ACAM2000. Average concentration of neutralizing antibodies responding to only the single dose of MVA vaccination were measured at 16.2GMT, which is equal to 16.2 recorded for the ACAM2000 at the fourteenth day [59]. Numerous clinical trials have examined the pharmacological properties and contraindications of both vaccines as cited in table 2, which is also tested by various organizations and regulatory authorities including the U.S food and drug administration (FDA) and the centers of disease control and prevention (CDC). By the analysis of existing evidence on the clinical tests of the use of JYNNEOS on an emergency basis, no contraindications were identified. Nevertheless, it is not recommended to vaccinate people in case they have a prior medical history of atopic dermatitis or contain a sensitivity to one or more components of the vaccine. Appropriate safety has been demonstrated in immunocompromised people using JYNNEOS[73]. Nevertheless, it is important to note that the ACAM2000 vaccination contraindicated in those who are pregnant or nursing, as well as those with a documented medical history of diabetes mellitus, cardiomyopathy, high blood pressure, and coronary artery disease. People with mild to severe allergic reactions, as well as those with long-term immune-related conditions like lymphoma, leukemia, HIV infection, and AIDS, should not receive the ACAM2000 vaccine [74]. There are various distinctions between JYNNEOSTM and ACAM2000®. ACAM2000® is characterized as a replication-competent vaccinia virus, whereas JYNNEOSTM is classified as a replication-deficient modified vaccinia Ankara virus[75]. ACAM2000® elicits a significant cutaneous response like erythema, edema, and pruritus at the site of inoculation, but JYNNEOSTM does not induce such a reaction. “As a result, there exists a potential for unintended inoculation and autoinoculation with ACAM2000®, but no such risk is associated with JYNNEOSTM. The occurrence of eczema vaccinatum and progressive vaccinia may be attributed to unregulated viral reproduction in some people when using replication-competent vaccinia vaccines, such as ACAM2000®[76]. Progressive vaccinia is often seen in people with impaired immune systems, while eczema vaccinatum may manifest in individuals with atopic dermatitis or eczema. The guidelines suggest refraining from administering ACAM2000® to individuals who are immunosuppressed, such as those with HIV infection. Consequently, it is advisable to avoid using ACAM2000® in populations that have a higher likelihood of having undiagnosed HIV, which currently includes the majority of non-African cases[77]. Additionally, it is prudent to exercise caution in populations that may facilitate the wider transmission of monkeypox, such as sex workers[78]. Furthermore, it is important to note that unintended transmission may take place with vaccinations that have the ability to replicate, such as replication-competent vaccines. This transmission can occur vertically, leading to the development of fetal vaccinia, a condition that poses a significant risk to the fetus or infant and can potentially result in fatality. ACAM2000® has a higher incidence of some severe adverse events compared to JYNNEOSTM. These occurrences include myopericarditis, which is anticipated to manifest in about 5.7 cases per 1,000 individuals who get the main ACAM2000® vaccination, as well as post-vaccine encephalitis[79]. Table 2: Biological and pharmacological similarities and differences between the JYNNEOS and ACAM2000 vaccines [67] Common name Smallpox and mpox vaccine, live, non-replicating Smallpox vaccine, live replicating vaccinia virus Name of brand JYNNEOS, Imamune, Imvanex, MVA Vaccinia Ankara ACAM2000 Emergent Bio Solutions Kind of vaccine 3 rd generation vaccine [68] 2 nd generation vaccine [68] Manufacturer, city and country Bavarian Nordic, Hørsholm, Denmark Sanofi Pasteur Biologics LLC, Gaithersburg, MD, USA [66] Vaccine formation Made from the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) strain, a highly attenuated, non-replicating orthopoxvirus that does not cause smallpox or mpox [80] Derived from a viral strain known as vaccinia, which belongs to the poxvirus family [67] Replication-competent Live attenuated virus that cannot replicate [73] Live attenuated virus that can replicate[73] Origination source Derived from the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, non-replicating orthopoxvirus [81] Produced from a live vaccinia virus that was synthesized in Vero cells and was derived from a vaccine (Dryvax) previously produced in calf lymph by the process of plaque filtration [82] Efficacious lifespan The use of active vaccination as a preventive measure against monkeypox illness has been seen in two distinct age groups: persons below the age of 18, and those who are 18 years of age and over. The effectiveness of vaccination in newborns, particularly those under the age of one year, is limited, and it is contraindicated in this population[63] FDA approval On August 9, 2022, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) of JYNNEOS/interim. Subsequently, on September 2, 2022, a supplemental letter was issued. The Centers for Disease Control and Prevention (CDC) has granted interim authorization, effective from June 28, 2022, for the administration of the ACAM2000 vaccine as a prophylactic measure against monkeypox in individuals aged one year and above[74] Dose(s) For those under the age of 18, it is recommended to provide a subcutaneous injection consisting of two doses, with each dosage being 0.5 mL in volume. The time interval between the two events is 4 weeks, which is equivalent to 28 days. For individuals who are at least 18 years old, the recommended method of administration is an intradermal injection consisting of two doses, with each dosage being 0.1 mL in volume. The time interval between the two events is 4 weeks, which is equivalent to 28 days. A solitary administration of a 0.0025 mL droplet of vaccine that has been reconstituted [74] Booster shots It is advised that those who are exposed to high-virulent orthopoxvirus get a booster dosage every two years, whereas those who come into touch with low-virulent strains should receive a booster shot every ten years[73] To mitigate the heightened susceptibility to infection, it is recommended that researchers engaged in laboratory activities involving the manipulation of variola virus and monkeypox virus should have a booster shot every three years [63]. Route of administration Subcutaneous injection Percutaneous vaccination requires the skills of an experienced medical professional due to the scarification that results from repeatedly puncturing the skin with a droplet of vaccine. Subcutaneous, intradermal, intramuscular, and intravenous routes should not be used to administer ACAM2000[83] Vaccination cost The total cost of immunization per individual amounts to around USD 115[69] The total cost of immunization per individual amounts to around USD 139 [69] Storage The vaccine may be stored at temperatures ranging from -15 °C to -25 °C. After thawing, it can be maintained at temperatures between +2 °C and +8 °C for a duration of 8 weeks. The storage temperature for the product is maintained within the range of -15 °C to -25 °C, while the temperature during transportation is set at -10 °C. The reconstituted solution should be used within a time frame of 6 to 8 hours at an ambient temperature of 20 to 25 degrees Celsius. The reconstituted vaccine should be kept within a temperature range of 2–8 °C for a maximum duration of 30 days[69] Biological Basis The individual’s immune system generates humoral and cellular responses to orthopoxviruses, producing neutralizing antibodies that serve as a preventive measure against smallpox and monkeypox. The ACAM2000 vaccination elicits an immunological response, prompting the activation of antibodies and blood cells to combat infections. Real World effectiveness Demonstrated strong protective immunity in high-risk populations, including immunocompromised individuals. Lower risk of adverse effects makes it preferable in outbreak scenarios. Effective in producing immunity against smallpox, but with higher risk of adverse reactions. Shows efficacy in preventing monkeypox, but use is limited due to safety, especially in immunocompromised individuals. Side effects Mild side effects include pain at injection site, fatigue, headache, muscle aches. Rare cases of myocarditis/pericarditis. Safe for immuno-compromised people with eczema. More severe side effects include fever, rash, lymphadenopathy, myocarditis, pericarditis, encephalitis. Contraindicated in immunocompromised, pregnant, and individuals with skin disorders like eczema due to risk of progressive vaccinia and autoinoculation. FOURTH GENERATION VACCINES Vaccinations that use genetic code and protein scaffold as their foundational components are now undergoing intensive study and development, signifying the arrival of fourth generation of vaccinations. In a study involving nonhuman primates, it was shown that the pure protein ectodomains of A33 and B5, which were produced from extracellular vesicles (EV), together with L1 and A27 obtained from developed virus, in combination with the adjuvants Alhydrogel and CpG, exhibited full protection against the lethal Monkeypox virus (MPXV)[73]. The administration of two doses of a protein subunit vaccines with an adjuvant demonstrated efficacy in conferring protection in nonhuman primates.” A supplementary investigation revealed that rhesus macaques exhibited enhanced protection against severe MPX infection when administered a recombinant vaccination modality consisting of both DNA and proteins, as opposed to the administration of DNA or proteins alone. The development of a viable vaccine against live vaccinia virus (VACV) would be of significant value as it could offer broad protection against related poxviruses, enhance preparedness for future outbreaks, and reduce the risks associated with live-attenuated vaccines, making it safer and more effective for vulnerable populations. However, the practicality of identifying those at highest risk for consequences via large-scale population screening has challenges that limit its feasibility. Furthermore, this approach has the potential to be used for the immunization of individuals who exhibit reluctance towards receiving the VACV vaccine, thus offering a means to establish a secure foundation of protection against poxviruses[84, 85]. CONTRAINDICATIONS OF ACAM2000 AND JYNNEOS ACAM2000 ACAM2000 is not recommended for those who have illnesses that are known to cause immunosuppression, like HIV infection, leukemia, AIDS and lymphoma [63]. Individuals who are not recommended to receive the vaccine include patients who are transplant recipients, have metastatic cancer, suffering from autoimmune disease where immunodeficient condition is a clinical feature, and those receiving immune-suppressive treatment such as corticosteroids (at a dosage of ≥2 mg/kg body weight for a duration of ≥2 weeks). Additionally, individuals who have received stem cell transplants within the past 24 months, have been treated with TNF inhibitors, alkylating agents, radiation or antimetabolites are also directed against receiving the immunization People with significant dermatological conditions, including but not limited to ACAM2000 component allergies, dermatitis, eczema, psoriasis, or active exfoliative skin conditions such as herpes simplex virus infection, varicella-zoster virus infection, severe acne, burns, impetigo, or severe diaper rash, are more susceptible to complications. Therefore, if vaccination is necessary, it should be approached under strict medical supervision[86]. JYNNEOS People who have encountered negative response like erythema, edema, pruritus, or systemic symptoms like headache, myalgia, malaise, and fatigue to any components of the MVA-BN vaccination should exercise caution while using it. MVA-BN’s immunogenicity has been investigated in patients clinically diagnosed with atopic dermatitis, demonstrating its ability to elicit a neutralizing antibody response. Importantly, no significant safety issues such as severe allergic reactions and anaphylaxis were seen over the course of these studies. Nevertheless, individuals with atopic dermatitis may encounter heightened local skin responses, characterized by symptoms such as erythema, edema, and pruritus. Additionally, they may have various systemic manifestations, including headache, myalgia, malaise, and fatigue. Furthermore, there is a possibility of a resurgence or intensification of their dermatological illness[87]. Healthcare practitioners and vaccination administrators should possess the necessary readiness to effectively handle anaphylactic responses that may occur subsequent to the delivery of MVA-BN. The occurrence of adverse effects at the injection site was shown to be the most prevalent among vaccination recipients, with a frequency exceeding 10%. The observed symptoms at the local level encompassed induration, pain, swelling, itching and redness. Among the systemic symptoms muscular soreness, tiredness, myalgia, headache, nausea, and chills were prominent [88]. People with damaged immune systems, such as undergoing immunosuppressive treatment, might show a diminished immunological response to MVA-BN as a result of their impaired immune system defenses. No evidence of myopericarditis risk has been found in recipients of MVA-BN based on clinical investigations. Major contraindications related to monkeypox vaccine are given below in table 3: Table 3: Contraindication of ACAM2000 and JYNNEOS vaccines[73] Immunodeficient — ✓ Past atopic dermatitis experience ✓ ✓ Pregnancy — ✓ Breastfeeding — ✓ Infants (<1 year) — ✓ An allergic reaction to any vaccine ingredient ✓ ✓ Pre-existing cardiac disease such as cardiomyopathy or coronary artery disease — ✓ Cardiovascular risk factors including smoking, hypertension and diabetes — ✓ CONCLUSION ACAM2000 and JYNNEOS are two vaccines that have been approved by the United States Food and Drug Administration (FDA). These vaccines have shown efficacy in preventing monkeypox. ACAM2000 is a live-attenuated replicating vaccine, whereas JYNNEOS is a live-attenuated, non-replicating vaccine. The Food and Drug Administration (FDA) has approved JYNNEOS for its application in preventing infections with monkeypox and smallpox among newborns, kids, and adults who have an increased vulnerability to contracting these illnesses. The administration of vaccines against monkeypox may provide protection to individuals by stimulating the development of antibodies and inducing eventual immunity against monkeypox infection. The research indicates that both vaccines exhibit efficacy, however, JYNNEOS has a more pronounced overall impact compared to ACAM2000. The recent occurrences of epidemics on a global scale have once again emphasized the need for ongoing surveillance and the development of innovative preventive and treatment approaches. Based on the already accessible data, there is a clear necessity to progress the creation of a novel set of vaccines that are both effective and secure in combatting monkeypox. These vaccines should be designed to be inactivated or formulated as mRNA vaccines, with the aim of mitigating the risk of monkeypox reaching pandemic proportions as they do not carry the risk of virus replication, and for their rapid development, offering quick and effective responses to emerging diseases. Disclosure Statement: The authors report there are no competing interests to declare. Financial and Competing Interests Disclosure: The authors report no conflicts of interest. REFERENCE 1. Ladnyj I, Ziegler P, Kima E. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ. 1972; 2. Lourie B, et al. Human infection with monkeypox virus: laboratory investigation of six cases in West Africa. Bull World Health Organ. 1972; 3. Benites-Zapata VA, et al. Clinical features, hospitalisation and deaths associated with monkeypox: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob. 2022; https://doi.org/10.1186/s12941-022-00527-1 4. Ortiz-Martínez Y, et al. Monkeypox–a description of the clinical progression of skin lesions: a case report from Colorado, USA. Ther Adv Infect Dis. 2022; https://doi.org/10.1177/20499361221117726 5. Rodriguez-Morales AJ, et al. Latin America: Situation and preparedness facing the multi-country human monkeypox outbreak. Lancet Reg Health Am. 2022; https://doi.org/10.1016/j.lana.2022.100318 6. Sah R, et al. First Monkeypox deaths outside Africa: no room for complacency. Ther Adv Infect Dis. 2022; https://doi.org/10.1177/20499361221124027 7. Hatami H, Jamshidi P, Arbabi M, Safavi-Naini SAA, Farokh P, Izadi-Jorshari G, Sechi LA. Demographic, epidemiologic, and clinical characteristics of human monkeypox disease pre-and post-2022 outbreaks: a systematic review and meta-analysis. Biomedicines. 2023; https://doi.org/10.3390/biomedicines11030957 8. Jadhav V, et al. Global epidemiology, viral evolution, and public health responses: a systematic review on Mpox (1958–2024). J Glob Health. 2025; https://doi.org/10.7189/jogh.15.04061 9. Bunge EM, et al. The changing epidemiology of human monkeypox—A potential threat? A systematic review. PLoS Negl Trop Dis. 2022; https://doi.org/10.1371/journal.pntd.0010141 10. Beiras CG, et al. Concurrent outbreaks of mpox in Africa—an update. Lancet. 2025; https://doi.org/10.1016/s0140-6736(24)02353-5 11. Turner M, et al. Monkeypox in patient immunized with ACAM2000 smallpox vaccine during 2022 outbreak. Emerg Infect Dis. 2022; https://doi.org/10.3201/eid2811.221215 12. Adalja A, Inglesby T. A novel international monkeypox outbreak. Ann Intern Med. 2022; https://doi.org/10.7326/m22-1581 13. Kaler J, et al. Monkeypox: a comprehensive review of transmission, pathogenesis, and manifestation. Cureus. 2022; https://doi.org/10.7759/cureus.26531 14. Artenstein AW. New generation smallpox vaccines: a review of preclinical and clinical data. Rev Med Virol. 2008; https://doi.org/10.1002/rmv.571 15. Wiser I, Balicer RD, Cohen D. An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies. Vaccine. 2007; https://doi.org/10.1016/j.vaccine.2006.09.046 16. Harapan H, et al. Monkeypox: a comprehensive review. Viruses. 2022; https://doi.org/10.3390/v14102155 17. Gruber MF. Current status of monkeypox vaccines. NPJ Vaccines. 2022; https://doi.org/10.1038/s41541-022-00527-4 18. Dutta S, et al. Monkeypox: A comprehensive review on mutation, transmission, pathophysiology, and therapeutics. Int Immunopharmacol. 2025; https://doi.org/10.1016/j.intimp.2024.113813 19. McNeil MM, et al. Ischemic cardiac events and other adverse events following ACAM2000® smallpox vaccine in the Vaccine Adverse Event Reporting System. Vaccine. 2014; https://doi.org/10.1016/j.vaccine.2014.06.034 20. Payne AB, et al. Incidence of monkeypox among unvaccinated persons compared with persons receiving ≥1 JYNNEOS vaccine dose—32 US jurisdictions, July 31–September 3, 2022. MMWR Morb Mortal Wkly Rep. 2022; https://doi.org/10.15585/mmwr.mm7140e3 21. Winters M, Malik AA, Omer SB. Attitudes towards monkeypox vaccination and predictors of vaccination intentions among the US general public. PLoS One. 2022; https://doi.org/10.1371/journal.pone.0278622 22. Kugelman JR, et al. Genomic variability of monkeypox virus among humans, Democratic Republic of the Congo. Emerg Infect Dis. 2014; https://doi.org/10.3201/eid2002.130118 23. Alakunle E, et al. Monkeypox virus in Nigeria: infection biology, epidemiology, and evolution. Viruses. 2020; https://doi.org/10.3390/v12111257 24. Sklenovská N, Van Ranst M. Emergence of monkeypox as the most important orthopoxvirus infection in humans. Front Public Health. 2018; https://doi.org/10.3389/fpubh.2018.00241 25. Kumar N, et al. The 2022 outbreak and the pathobiology of the monkeypox virus. J Autoimmun. 2022; https://doi.org/10.1016/j.jaut.2022.102855 26. Heymann DL, Szczeniowski M, Esteves K. Re-emergence of monkeypox in Africa: a review of the past six years. Br Med Bull. 1998; https://doi.org/10.1093/oxfordjournals.bmb.a011720 27. Liu H, et al. Global perspectives on smallpox vaccine against monkeypox: a comprehensive meta-analysis and systematic review of effectiveness, protection, safety and cross-immunogenicity. Emerg Microbes Infect. 2024; https://doi.org/10.1080/22221751.2024.2387442 28. Ullah A, et al. An integrative reverse vaccinology, immunoinformatic, docking and simulation approaches towards designing of multi-epitopes based vaccine against monkeypox virus. J Biomol Struct Dyn. 2023; https://doi.org/10.1080/07391102.2022.2125441 29. Parker S, et al. Human monkeypox: an emerging zoonotic disease. Future Microbiol. 2007; https://doi.org/10.2217/17460913.2.1.17 30. Ježek Z, et al. Human monkeypox: clinical features of 282 patients. J Infect Dis. 1987; https://doi.org/10.1093/infdis/156.2.293 31. McCollum AM, Damon IK. Human monkeypox. Clin Infect Dis. 2014; https://doi.org/10.1093/cid/cit703 32. Sklenovská N, Van Ranst M. Emergence of monkeypox as the most important orthopoxvirus infection in humans. Front Public Health. 2018; https://doi.org/10.3389/fpubh.2018.00241 33. Centers for Disease Control and Prevention. Multistate outbreak of monkeypox—Illinois, Indiana, and Wisconsin, 2003. MMWR Morb Mortal Wkly Rep. 2003; 34. Yinka-Ogunleye A, et al. Outbreak of human monkeypox in Nigeria in 2017–18: a clinical and epidemiological report. Lancet Infect Dis. 2019; https://doi.org/10.1016/s1473-3099(19)30294-4 35. Thornhill JP, et al. Monkeypox virus infection in humans across 16 countries—April–June 2022. N Engl J Med. 2022; https://doi.org/10.1056/nejmoa2207323 36. Tarín-Vicente EJ, et al. Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study. Lancet. 2022; https://doi.org/10.1016/s0140-6736(22)01436-2 37. Cohn H, et al. Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study. Lancet Infect Dis. 2023; https://doi.org/10.1016/s1473-3099(23)00352-3 38. Allard R, et al. Breakthrough cases of mpox: One-dose vaccination is associated with milder clinical manifestations. J Infect Public Health. 2024; https://doi.org/10.1016/j.jiph.2024.02.015 39. Berry MT, et al. Predicting vaccine effectiveness for mpox. Nat Commun. 2024; https://doi.org/10.1038/s41467-024-48180-w 40. Mucker EM, et al. Comparison of protection against mpox following mRNA or modified vaccinia Ankara vaccination in nonhuman primates. Cell. 2024; https://doi.org/10.1016/j.cell.2024.08.043 41. Schin AM, Diesterbeck US, Moss B. Insights into the organization of the poxvirus multicomponent entry-fusion complex from proximity analyses in living infected cells. J Virol. 2021; https://doi.org/10.1128/JVI.00852-21 42. Freyn AW, et al. An mpox virus mRNA-lipid nanoparticle vaccine confers protection against lethal orthopoxviral challenge. Sci Transl Med. 2023; https://doi.org/10.1126/scitranslmed.adg3540 43. Jhancy M. Poxvirus Vaccines: Past, Present, and Future. Poxviruses. 2024; https://doi.org/10.1007/978-3-031-57165-7_17 44. Williamson AL. Approaches to Next-Generation Capripoxvirus and Monkeypox Virus Vaccines. Viruses. 2025; https://doi.org/10.3390/v17020186 45. Townsend M, et al. Humoral immunity to smallpox vaccines and monkeypox virus challenge: proteomic assessment and clinical correlations. J Virol. 2013; https://doi.org/10.1128/JVI.02089-12 46. Molero-Abraham M, et al. EPIPOX: immunoinformatic characterization of the shared T-cell epitome between variola virus and related pathogenic orthopoxviruses. J Immunol Res. 2015; https://doi.org/10.1155/2015/738020 47. Jing L, et al. An extremely diverse CD4 response to vaccinia virus in humans is revealed by proteome-wide T-cell profiling. J Virol. 2008; https://doi.org/10.1128/jvi.00453-08 48. Jing L, et al. Diversity in the acute CD8 T cell response to vaccinia virus in humans. J Immunol. 2005; https://doi.org/10.4049/jimmunol.175.11.7550 49. Sarkar J, Mitra A, Mukherjee M. The minimum protective level of antibodies in smallpox. Bull World Health Organ. 1975; 50. Melamed S, Israely T, Paran N. Challenges and achievements in prevention and treatment of smallpox. Vaccines. 2018; https://doi.org/10.3390/vaccines6010008 51. Collier LH. The development of a stable smallpox vaccine. Epidemiol Infect. 1955; https://doi.org/10.1017/s0950268805004280 52. Reina J, Iglesias C. Vaccines against monkeypox. Med Clin (Engl Ed). 2023; https://doi.org/10.1016/j.medcli.2023.01.001 53. Decker MD, et al. Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members. Vaccine. 2021; https://doi.org/10.1016/j.vaccine.2021.08.041 54. Keckler MS, et al. IMVAMUNE and ACAM2000 provide different protection against disease when administered postexposure in an intranasal monkeypox challenge prairie dog model. Vaccines. 2020; https://doi.org/10.3390/vaccines8030396 55. Marriott KA, et al. Clonal vaccinia virus grown in cell culture fully protects monkeys from lethal monkeypox challenge. Vaccine. 2008; https://doi.org/10.1016/j.vaccine.2007.10.063 56. Hatch GJ, et al. Assessment of the protective effect of Imvamune and Acam2000 vaccines against aerosolized monkeypox virus in cynomolgus macaques. J Virol. 2013; https://doi.org/10.1128/JVI.03481-12 57. Sudarmaji N, et al. Prevention and treatment of monkeypox: a systematic review of preclinical studies. Viruses. 2022; https://doi.org/10.3390/v14112496 58. Pittman PR, et al. Phase 3 efficacy trial of modified vaccinia Ankara as a vaccine against smallpox. N Engl J Med. 2019; https://doi.org/10.1056/nejmoa1817307 59. Anwar F, et al. Clinical manifestation, transmission, pathogenesis, and diagnosis of monkeypox virus: a comprehensive review. Life. 2023; https://doi.org/10.3390/life13020522 60. Chakraborty S, et al. Monkeypox vaccines and vaccination strategies: current knowledge and advances. An update–correspondence. Int J Surg. 2022; https://doi.org/10.1016/j.ijsu.2022.106869 61. Bloch EM, et al. The potential role of passive antibody-based therapies as treatments for monkeypox. MBio. 2022; https://doi.org/10.1128/mbio.02862-22 62. Rao AK, et al. Use of JYNNEOS (smallpox and monkeypox vaccine, live, nonreplicating) for preexposure vaccination of persons at risk for occupational exposure to orthopoxviruses: recommendations of the Advisory Committee on Immunization Practices—United States, 2022. MMWR Morb Mortal Wkly Rep. 2022; https://doi.org/10.15585/mmwr.mm7422a3 63. Merad Y, et al. Outcomes of post-exposure vaccination by modified vaccinia Ankara to prevent mpox (formerly monkeypox): a retrospective observational study in Lyon, France, June to August 2022. Euro Surveill. 2022; https://doi.org/10.2807/1560-7917.es.2022.27.50.2200882 64. de Nicolas-Ruanes B, et al. Monkeypox virus case with maculopapular exanthem and proctitis during the Spanish outbreak in 2022. J Eur Acad Dermatol Venereol. 2022; https://doi.org/10.1111/jdv.18300 65. World Health Organization. Vaccines and immunization for monkeypox: interim guidance, 14 June 2022. World Health Organization. 2022; 66. Meo SA, et al. Comparison of biological, pharmacological characteristics, indications, contraindications and adverse effects of JYNNEOS and ACAM2000 monkeypox vaccines. Vaccines. 2022; https://doi.org/10.3390/vaccines10111971 67. Ahmed SF, et al. Vaccinia-virus-based vaccines are expected to elicit highly cross-reactive immunity to the 2022 monkeypox virus. Viruses. 2022; https://doi.org/10.3390/v14091960 68. Lambert de Rouvroit A, Heegaard ED. Total costs associated with replicating and non-replicating smallpox vaccines. Glob Secur Health Sci Policy. 2016; https://doi.org/10.7717/peerj.9272 69. Chandran D, et al. Major advances in monkeypox vaccine research and development–an update. J Pure Appl Microbiol. 2022; https://doi.org/10.3389/fimmu.2024.1456060 70. Saadh MJ, et al. Progress and prospects on vaccine development against monkeypox infection. Microb Pathog. 2023; https://doi.org/10.1016/j.micpath.2023.106156 71. Centers for Disease Control and Prevention. Cardiac adverse events following smallpox vaccination—United States, 2003. MMWR Morb Mortal Wkly Rep. 2003; 72. Abdelaal A, et al. Preventing the next pandemic: is live vaccine efficacious against monkeypox, or is there a need for killed virus and mRNA vaccines? Vaccines. 2022; https://doi.org/10.3390/vaccines10091419 73. Salcedo RM, Madariaga MG. Monkeypox (hMPXV infection): a practical review. Am J Med. 2022; https://doi.org/10.1016/j.amjmed.2022.10.023 74. Nyame J, et al. Challenges in the treatment and prevention of monkeypox infection; a comprehensive review. Acta Trop. 2023; https://doi.org/10.1016/j.actatropica.2023.106960 75. Hagen CJ, et al. Antibiotic-dependent expression of early transcription factor subunits leads to stringent control of vaccinia virus replication. Virus Res. 2014;181:43–52. https://doi.org/10.1016/j.virusres.2013.12.033 76. Vandormael A, et al. High percentage of undiagnosed HIV cases within a hyperendemic South African community: a population-based study. J Epidemiol Community Health. 2018;72(2):168–172. https://doi.org/10.1136/jech-2017-209713 77. Crum-Cianflone NF, Sullivan E. Vaccinations for the HIV-infected adult: a review of the current recommendations, part II. Infect Dis Ther. 2017;6:333–361. https://doi.org/10.1007/s40121-017-0166-x 78. Shrestha AB, et al. Concerns over cardiovascular manifestations associated with monkeypox immunization: a literature review. Ann Med Surg. 2023;85(6):2797. https://doi.org/10.1097/MS9.0000000000000861 79. Centers for Disease Control and Prevention. 2022 monkeypox outbreak global map. CDC. 2022. https://doi.org/10.1097/JNC.0000000000000365 80. Tomita N, et al. An open-label, non-randomized study investigating the safety and efficacy of smallpox vaccine, LC16, as post-exposure prophylaxis for mpox. Hum Vaccin Immunother. 2023;19(2):2242219. https://doi.org/10.1080/21645515.2023.2242219 81. World Health Organization. Vaccines and immunization for monkeypox: interim guidance, 24 August 2022. World Health Organization. 2022. 82. Cabanillas B, et al. A compilation answering 50 questions on Monkeypox virus and the current Monkeypox outbreak. Allergy. 2023;78(3):639–662. https://doi.org/10.1111/all.15633 83. Chopra H, et al. FDA approved vaccines for monkeypox: current eminence. Int J Surg. 2022;105:106896. https://doi.org/10.1016/j.ijsu.2022.106896 84. Lahariya C, Thakur A, Dudeja N. Monkeypox disease outbreak (2022): epidemiology, challenges, and the way forward. Indian Pediatr. 2022;59(8):636–642. https://doi.org/10.1007/s13312-022-2578-2 85. Petersen BW, et al. Use of vaccinia virus smallpox vaccine in laboratory and health care personnel at risk for occupational exposure to orthopoxviruses—recommendations of the Advisory Committee on Immunization Practices (ACIP), 2015. MMWR Morb Mortal Wkly Rep. 2016;65(10):257–262. https://doi.org/10.15585/mmwr.mm6510a2 86. Petersen BW, et al. Vaccinating against monkeypox in the Democratic Republic of the Congo. Antiviral Res. 2019;162:171–177. https://doi.org/10.1016/j.antiviral.2018.11.004 87. Ilic I, Zivanovic Macuzic I, Ilic M. Global outbreak of human Monkeypox in 2022: update of epidemiology. Trop Med Infect Dis. 2022;7(10):264. https://doi.org/10.3390/tropicalmed7100264 88. Arness MK, et al. Myopericarditis following smallpox vaccination. Am J Epidemiol. 2004;160(7):642–651. https://doi.org/10.1093/aje/kwh269 Information & Authors Information Version history V1 Version 1 12 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Benish Javed The University of Lahore View all articles by this author Ramna Zia 0000-0002-9655-722X [email protected] University of Management and Technology School of Health Sciences View all articles by this author Muhammad Imran [email protected] The University of Adelaide View all articles by this author Metrics & Citations Metrics Article Usage 464 views 120 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Benish Javed, Ramna Zia, Muhammad Imran. JYNNEOS VS. ACAM2000: A CRITICAL REVIEW OF THE SAFETY, EFFICACY AND REAL-WORLD EFFECTIVENESS OF MONKEYPOX VACCINES. 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