One- and Two-Dose Vaccinations With Modified Vaccinia Ankara-Bavarian Nordic Induce Durable B-Cell Memory Responses Comparable to Replicating Smallpox Vaccines

Abstract

Background: Although modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccination is approved for smallpox and monkeypox prevention, immunological persistence and booster effects remain undescribed.

Methods: Participants naive to smallpox vaccination were randomized to 1 dose MVA-BN (1×MVA, n = 181), 2 doses MVA-BN (2×MVA, n = 183), or placebo (n = 181). Participants with previous smallpox vaccination received 1 MVA-BN booster (HSPX, n = 200). Subsets of the formerly naive groups (approximately 75 each) received an MVA-BN booster 2 years later.

Results: Neutralizing antibody (nAb) geometric mean titers (GMTs) increased from 1.1 (baseline, both naive groups) to 7.2 and 7.5 (week 4, 1×MVA and 2×MVA, respectively), and further to 45.6 (week 6, 2×MVA after second vaccination). In HSPX, nAb GMT rapidly increased from 21.6 (baseline) to 175.1 (week 2). At 2 years, GMTs for 1×MVA, 2×MVA, and HSPX were 1.1, 1.3, and 10.3, respectively. After boosting in the previously naive groups, nAb GMTs increased rapidly in 2 weeks to 80.7 (1×MVA) and 125.3 (2×MVA), higher than after primary vaccination and comparable to boosted HSPX subjects. Six months after boosting, GMTs were 25.6 (1×MVA) and 49.3 (2×MVA). No safety concerns were identified.

Conclusions: Anamnestic responses to boosting without sustained high nAb titers support presence of durable immunological memory following primary MVA-BN immunization. Clinical Trials Registration. NCT00316524 and NCT00686582.

Keywords: booster; memory response; monkeypox; orthopoxvirus; recall response; revaccination; vaccinia experienced.

Figure 1.

Participant disposition for initial and follow-up MVA-BN vaccination studies. ^aThe per protocol set comprised the subset of participants who received all vaccinations and adhered to all protocol conditions without major protocol deviations. Abbreviations: BD, booster dose; HSPX, history of smallpox vaccine positive; MVA, modified vaccinia Ankara; MVA-BN, modified vaccinia Ankara-Bavarian Nordic; n, total number of participants per group; PBO, placebo.

Figure 2.

GMTs over time in the initial (A and C) and follow-up (B and D) studies. Dashed lines connect postbooster data points. The 1-week postvaccination time point for the follow-up study (week 109), included in Supplementary Table 1, has been omitted from this figure to facilitate comparisons of immune response kinetics between studies. In A and C, the 2-year follow-up time point (at week 108) depicts immunogenicity data obtained from all 304 participants in the follow-up study who provided blood draws 2 years after MVA-BN and included 92 participants in the 2×MVA group, 91 participants in the 1×MVA group, and 121 participants in the HSPX group (for additional details see Figure 1). Abbreviations: BD, booster dose; ELISA, enzyme-linked immunosorbent assay; GMT, geometric mean titer; HSPX, history of smallpox vaccine positive; n, total number of participants per group; PBO, placebo; PRNT, plaque reduction neutralization test.

Figure 3.

A and B, Seroconversion rates over time in the initial and follow-up studies. The 2-year follow-up time point (at week 108) depicts immunogenicity data obtained from participants who provided blood draws 2 years following primary immunization with MVA-BN and included 92 participants in the 2×MVA group and 91 participants in the 1×MVA group (for additional details see Figure 1). Abbreviations: BD, booster dose; ELISA, enzyme-linked immunosorbent assay; n, total number of participants per group; PB, postbooster; PBO, placebo; PRNT, plaque reduction neutralization test; SC, seroconversion.