Single and 2-dose vaccinations with MVA-BN® induce durable B cell memory responses in healthy volunteers that are comparable to older generation replicating smallpox vaccines

While the MVA-BN vaccine has been proven protective against smallpox and monkeypox, the long-term immunological persistence or booster effect has not been described. In this set of clinical studies, participants who had never been immunized against smallpox were randomized to receive, 4 weeks apart: 2 placebo vaccinations (PBO group, N =181); 1 MVA-BN vaccination followed by placebo(1×MVA group, N =181); or 2 MVA-BN vaccinations (2×MVA group, N = 183). In addition, participants with a history of smallpox vaccination received 1 MVA-BN booster (HSPX+ group, N = 200). The 1×MVA and 2×MVA groups responded with increases in neutralizing antibody (nAb) GMTs at Week 2 (5.1 and 4.8, respectively) that further increased at Week 4 (7.2 and 7.5). Two weeks after the second primary vaccination in the 2×MVA group (at Week 6), nAb GMT peaked (45.6) before stabilizing 2 weeks thereafter (at Week 8) (34.0). In the HSPX+ group, a rapid anamnestic response was observed with a peak nAb GMT at Week 2 (175.1) that was much larger than the peak responses in either of the primary vaccination (1× or 2×MVA) dose groups of smallpox vaccine-naïve subjects. Persistence of nAbs relative to baseline was observed at 6 months in all groups (highest in HSPX+), with a return to near baseline nAb levels 2 years later. Subsets of ∼75 participants each, who received primary vaccinations in the 1×MVA and 2×MVA groups, were administered an MVA-BN booster 2 years later. Both booster dose (BD) groups exhibited rapid anamnestic responses with nAb GMTs that peaked 2 weeks post-booster (80.7 and 125.3). These post-booster titers in the 1×MVA and 2×MVA groups were higher than those observed at any timepoint following primary vaccination, were comparable to HSPX+ subjects who had been administered a booster, and remained elevated at 6 months post-booster (25.6 and 49.3). The observed anamnestic responses, in the absence of sustained detectable nAbs, support the presence of durable immunological memory following MVA-BN immunization. No safety concerns were identified, and the most common adverse event following the 2-year MVA-BN booster was injection site erythema in 82.2% of participants. Clinical Trial Registry Numbers NCT00316524 and [NCT00686582][1] Highlights ### Competing Interest Statement The authors Daniela Reichhardt, Darja Schmidt, Jacqueline D Powell, Thomas PH Meyer, Gunter Silbernagl, Heinz Weidenthaler, and Liddy Chen are current or former employees and stakeholders of Bavarian Nordic GmbH; Laurence de Moerlooze is the company CMO and Paul Chaplin is the company CEO. ### Clinical Trial NCT00316524 and [NCT00686582][1] EudraCT 2005-001781-14 and 2007-006297-28 IND11596 DMID 05-0128 and 08-0018 ### Funding Statement The study was sponsored by Bavarian Nordic A/S and funded by the National Institute of Allergy and Infectious Diseases (N01-AI-40072) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Central Ethics Committee was the EC for the Medical Faculty of the Ludwig-Maximilians University, Munich, Germany Ethikkommission der Bayerischen Landesarztekammer (Ethics Committee of the Bavarian State Chamber of Physicians) was the EC for the site, Harrison Clinical Research Deutschland I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All clinical trial results are available online at: https://clinicaltrials.gov/ct2/show/results/[NCT00316524][2]?term=NCT00316524&draw=2&rank=1 https://clinicaltrials.gov/ct2/show/results/[NCT00686582][1]?term=NCT00316524&draw=2&rank=2 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00686582&atom=%2Fmedrxiv%2Fearly%2F2022%2F09%2F09%2F2022.09.07.22279689.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00316524&atom=%2Fmedrxiv%2Fearly%2F2022%2F09%2F09%2F2022.09.07.22279689.atom