Effectiveness, immunogenicity, and safety of vaccines against COVID-19 and mpox in healthy individuals and at-risk populations

Global outbreaks of emerging viruses, like the SARS-CoV-2 pandemic and global MPXV spread since 2022, have caused major morbidity, mortality, and economic disruption. Vaccinating at-risk populations is crucial for outbreak control. However, early data on safety, immunogenicity, and effectiveness of heterologous COVID-19 vaccination and the smallpox vaccine MVA-BN against mpox were scarce. In May 2021, heterologous COVID-19 vaccination with a vector-based dose followed by an mRNA dose was recommended, despite a lack of clinical data. We prospectively enrolled 380 healthcare workers who received homologous BNT162b2 (=mRNA, BNT-BNT), homologous ChAdOx1 nCov-19 (=vector-based, ChAd-ChAd), or heterologous ChAd-BNT vaccination. Systemic reactogenicity of ChAd-BNT was similar to BNT-BNT and ChAd-ChAd. Anti-RBD, anti-S1, and anti-full-spike IgG levels were comparable, but ID50 neutralization titres were significantly higher after ChAd-BNT: 2.6-fold and 4.5-fold higher against SARS-CoV-2 variant B.1.1.7 (alpha), and 5.8-fold and 8.7-fold higher against immune-escape variant B.1.351 (beta), compared to BNT-BNT and ChAd-ChAd, respectively. T cell responses were significantly higher with median 2.4-fold and 4.5-fold increases compared to BNT-BNT and ChAd-ChAd, respectively. Heterologous ChAd-BNT boosting with a 10–12-week interval was well-tolerated and showed enhanced immunogenicity compared to homologous 3-week BNT-BNT and 10–12-week ChAd-ChAd regimens. Heterologous vaccination can offer advantages over homologous regimens and may mitigate vaccine supply shortages and thus represent a promising strategy for future outbreaks. MVA-BN vaccination was recommended early during the global mpox outbreak in 2022, despite limited clinical data on safety and effectiveness of MVA-BN against mpox. We investigated safety and effectiveness of MVA-BN in men who have sex with men with changing sexual partners, including people living with HIV (PLWH) and those with prior childhood smallpox vaccination (SV). We prospectively enrolled 6,459 participants, and showed that MVA-BN was safe, including in PLWH and SV. PLWH had reduced reactogenicity. Rapidly declining case numbers in 2022 made vaccine effectiveness assessment impossible in the prospective cohort. We thus enrolled 9,175 additional participants in a retrospective cohort, in an emulated target trial. One dose of MVA-BN conferred significant protection ≥14 days post-vaccination, but effectiveness was reduced in PLWH, highlighting the need to complete the recommended two-dose series. MVA-BN also reduced mpox symptom severity in vaccinated compared to unvaccinated individuals. A multi-faceted vaccine research approach, particularly during public health emergencies, complementing randomized trials with immunogenicity studies and combining prospective safety with retrospective effectiveness analyses using target trial emulation, can provide critical data to inform vaccination strategies in dynamic outbreak scenarios.