A randomized phase 3 trial to assess the immunogenicity and safety of 3 consecutively produced lots of freeze-dried MVA-BN® vaccine in healthy adults

Overton, Edgar T.; Schmidt, D; Vidojkovic, Sanja; Menius, Erika; Nopora, Katrin; Maclennan, Jane; Weidenthaler, Heinz

doi:10.1016/j.vaccine.2022.10.056

Cited by 12 publications

(14 citation statements)

References 35 publications

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“…In examining the antibody response to the MVA‐BN vaccine, our findings corroborate what has been previously described: a 5–7‐fold rise in neutralizing antibodies and 100% seroconversion in the 2nd week following the second dose of MVA‐BN 35–37 . Previous studies indicated that the maximal humoral response to MVA‐BN peaks at 2 weeks following the second dose, 12,38,39 contrasting our findings, which display peak VACV IgG titers in the 5th week after the second dose.…”

Section: Discussionsupporting

confidence: 90%

“…In examining the antibody response to the MVA-BN vaccine, our findings corroborate what has been previously described: a 5-7-fold rise in neutralizing antibodies and 100% seroconversion in the 2nd week following the second dose of MVA-BN. [35][36][37] Previous studies indicated that the maximal humoral response to MVA-BN peaks at 2 weeks following the second dose, 12,38,39 contrasting our findings, which display peak VACV IgG titers in the 5th week after the second dose. The continued rise in antibody titers beyond the 2nd week may be explained by different methodologies, with IFA detecting antibodies against a breadth of epitopes rather than an enzymelinked immunosorbent assay (ELISA) with a single defined VACV protein.…”

Section: The Antibody Response Of the Mva-bn Vaccinecontrasting

confidence: 89%

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Characterizing the acute antibody response of monkeypox and MVA‐BN vaccine following an Australian outbreak

Asquith,

Hueston,

Dwyer

et al. 2024

Journal of Medical Virology

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In response to the emergence of the monkeypox virus (MPXV) in Australia in May 2022, we developed and evaluated indirect immunofluorescence assays (IFA) for MPXV and Vaccinia virus (VACV) IgG and IgM antibodies using serum samples from patients with nucleic acid amplification test (NAAT)‐confirmed mpox and uninfected unvaccinated controls. Additionally, 47 healthcare workers receiving two doses of the third‐generation smallpox vaccine Modified Vaccinia Ankara‐Bavarian Nordic (MVA‐BN) undertook serial serum collection to describe the serological response to vaccination. MPXV antibodies were detected in 16/18 individuals with NAAT‐confirmed mpox (sensitivity 0.89, specificity 1.00), and VACV antibodies were detected in 28/29 individuals who received two doses of MVA‐BN vaccine (sensitivity 0.97, specificity 1.00). Detectable antibody in subjects historically vaccinated with early‐generation vaccines against smallpox was found in 7/7 subjects, at a median of 48 years following vaccination. MPXV NAAT‐positive patients with serum samples collected within the first 14 days after rash onset had detectable IgG and IgM in 9/12 and 5/12 of patients, respectively, with maintenance of IgG and disappearance of IgM titers after 60 days. While specificity was high when testing unvaccinated and uninfected subjects, significant cross‐reactivity between MPXV and VACV antibodies was observed.

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Section: Discussionsupporting

confidence: 90%

Section: The Antibody Response Of the Mva-bn Vaccinecontrasting

confidence: 89%

Characterizing the acute antibody response of monkeypox and MVA‐BN vaccine following an Australian outbreak

Asquith,

Hueston,

Dwyer

et al. 2024

Journal of Medical Virology

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“…A single RCT (13%) assessed three consecutive manufactured lots of MVA vaccine, all of which led to a consistent immunogenicity and safety profile [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Immunogenicity and Safety of Modified Vaccinia Ankara (MVA) Vaccine—A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Nave,

Margalit,

Tau

et al. 2023

Vaccines

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Prevention of mpox has become an important public health interest. We aimed to evaluate the safety and immunogenicity of the Modified Vaccinia Ankara (MVA) vaccine. We conducted a systematic review and meta-analysis of randomized-controlled trials (RCTs) comparing MVA versus no intervention, placebo, or another vaccine. Outcomes included safety and immunogenicity outcomes. We also performed a systematic review of RCTs evaluating various MVA regimens. Fifteen publications were included in the quantitative meta-analysis. All but one (ACAM2000) compared MVA with placebo. We found that cardiovascular adverse events following two MVA doses were significantly more common compared to placebo (relative risk [RR] 4.07, 95% confidence interval [CI] 1.10–15.10), though serious adverse events (SAEs) were not significantly different. Following a single MVA dose, no difference was demonstrated in any adverse event outcomes. Seroconversion rates were significantly higher compared with placebo after a single or two doses. None of the RCTs evaluated clinical effectiveness in preventing mpox. This meta-analysis provides reassuring results concerning the immunogenicity and safety of MVA. Further studies are needed to confirm the immunogenicity of a single dose and its clinical effectiveness. A single vaccine dose may be considered according to vaccine availability, with preference for two doses.

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“…S2). A subset of 12 trials were identified that reported vaccinia-binding titers in healthy individuals [23][24][25][26][27][28][29][30][31][32][33][34][35] , and one further trial was published only on the clinicaltrials.gov database 36 (Table S2). These trials used similar methodologies to assess vaccinia-binding, allowing comparison of immunogenicity between trials.…”

Section: Search Results Of Vaccine Effectiveness and Immunogenicity S...mentioning

confidence: 99%

Predicting vaccine effectiveness in Mpox

Berry,

Khan,

Schlub

et al. 2023

Preprint

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The Modified Vaccinia Ankara vaccine developed by Bavarian Nordic (MVA-BN) was widely deployed to prevent Mpox during the 2022 global outbreak. This vaccine was initially approved for Mpox based on its reported immunogenicity and effectiveness in animal models, rather than evidence of clinical efficacy. However no validated correlate of protection after vaccination has been identified. Here we performed a systematic search and meta-analysis of the available data to test whether vaccinia-binding ELISA endpoint titer is predictive of vaccine effectiveness against Mpox. We observe a significant correlation between vaccine effectiveness and vaccinia-binding antibody titers, consistent with the existing assumption that antibody levels may be a correlate of protection. Combining this data with analysis of antibody kinetics after vaccination, we predict the durability of protection after vaccination and the impact of dose spacing. Although further work is required to validate this correlate, this study provides the first evidence-based approach for using antibody measurements to predict the effectiveness of Mpox vaccination.Mpox virus (formerly Monkeypox) is a zoonotic virus endemic in West Africa, with significant outbreaks in 1980-1986 and in 1997-19981, resulting in over 20,000 total recorded cases. Prior to 2017, these outbreaks were typically small and initiated by zoonotic transmission followed by self-terminating human-to-human chains of transmission2. However, since 2017, there has been a resurgence of Mpox in Nigeria, Democratic Republic of the Congo (DRC) and other parts of Africa, attributed to waning immunity from smallpox vaccines and accumulation of cohorts that have never been vaccinated against smallpox3. In 2022, a global outbreak of Mpox resulted in 91000+ confirmed cases in 115 countries and established chains of human-human transmission leading to a renewed focus on vaccination as a preventative measure for Mpox4.Although there is no Mpox-specific vaccine, first generation smallpox vaccination was observed to protect individuals against Mpox infection during the 1980-1986 Mpox outbreak in the DRC (then Zaire)5-8, with an estimated vaccine effectiveness of approximately 85%5, and this has also been observed in similar subsequent studies9-11. However, the livereplicating vaccinia vaccines (first and second-generation) have significant risks of serious vaccine adverse events12, which led to the development of the third-generation Modified Vaccinia Ankara live-attenuated (replication deficient) vaccine (MVA-BN). Prior to the 2022 Mpox outbreak, MVA-BN was approved by the FDA for use as a Smallpox and Mpox vaccine (two doses of 1 × 108TCID via subcutaneous injection). Given the challenge of directly assessing the efficacy of this vaccine in an RCT, regulatory approval was based on demonstrated non-inferior immunogenicity profile and improved safety compared to the second-generation ACAM2000 vaccine13. In particular, comparing vaccinia neutralizing antibody titers induced by vaccination of MVA-BN and ACAM2000, it was deemed “reasonable to expect that this regimen of the vaccine is effective in smallpox vaccinia-naïve as well as in smallpox vaccine experienced individuals”13. This was supported by studies in nonhuman primates implicating antibodies directly in mediating protection against lethal Mpox challenge14.Analysis of case data during the 2022 global outbreak indicates that the MVA-BN vaccine is effective for prevention of Mpox15-20, and affirms the decisions to use these vaccines during the outbreaks. However, important questions remain to be addressed. Firstly, how does MVA-BN effectiveness compare with the protection conferred by the live replicating smallpox vaccines, and how many doses are required? Further, is the protection from MVA-BN vaccination expected to be durable, and will further booster doses be required to confer durable protection against Mpox and protect individuals in potential future outbreaks?Here we address these questions by aggregating the available data on the effectiveness of different vaccinia-based vaccination regimes in protection against Mpox. We compare protection from first generation smallpox vaccines with the protection conferred by one or two doses of the MVA-BN vaccine. Further, given the assumed role of antibodies, we aggregate data on vaccinia-specific ELISA endpoint titers (here after referred to as vaccinia-binding titers) after MVA-BN vaccination (which have been shown to correlate with neutralizing antibody titers to Mpox after vaccinia vaccination21), and study the relationship between antibody levels and effectiveness. Finally, we analyze the kinetics of antibody decay over time to predict the duration of protection afforded by 1, 2 or 3 doses of vaccination. This work offers a data-driven approach to support public health decision making on Mpox vaccination and boosting campaigns.

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A randomized phase 3 trial to assess the immunogenicity and safety of 3 consecutively produced lots of freeze-dried MVA-BN® vaccine in healthy adults

Cited by 12 publications

References 35 publications

Characterizing the acute antibody response of monkeypox and MVA‐BN vaccine following an Australian outbreak

Characterizing the acute antibody response of monkeypox and MVA‐BN vaccine following an Australian outbreak

Immunogenicity and Safety of Modified Vaccinia Ankara (MVA) Vaccine—A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Predicting vaccine effectiveness in Mpox

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