Since the 2022 global mpox outbreak thrust the MVA-BN vaccine (marketed as JYNNEOS in the US) into mass deployment, a growing body of research has raised concerns about the durability of the immunity it induces. A new study from researchers at the NYU Langone Vaccine Center provides the most detailed picture yet of how antibody responses to MVA-BN evolve over time — and what a third booster dose can and cannot do to address the vaccine’s limitations.
What the Study Did
The research team, led by Aaron Oom and Kesi Wilson of the NYC Observational Study of Mpox Immunity (NYC OSMI) cohort, analyzed serological samples from 69 MVA-BN vaccinees — 39 with no prior smallpox vaccination (naive) and 30 with prior smallpox vaccination history (experienced) — tracked across up to six study visits spanning baseline through roughly 21 to 22 months after the second dose. A subset of four participants who received a third-dose MVA-BN booster was also analyzed.
The team employed two complementary methods: a microneutralization assay measuring the ability of antibodies to block monkeypox virus (MPXV) infection, and an expanded multiplexed immunoassay measuring IgG binding titers and avidity — a measure of antibody binding strength — against eight MPXV proteins and two vaccinia virus proteins. A machine learning approach was then applied to identify distinct immunological profiles across the cohort.
The Central Finding: Immunity Reverts to Baseline Within a Year
The study’s most consequential finding is that MVA-BN vaccinees without prior smallpox vaccination largely return to a pre-vaccination serological baseline within one year of completing the primary two-dose series. Machine learning clustering revealed three distinct seroprofiles in the cohort: a non-replicating-like group (NRL), a replicating-like group (RL), and a mixed population. Nearly all naive vaccinees at the one-year and two-year time points clustered within the NRL group — essentially indistinguishable from unvaccinated controls. This pattern was validated in an independent cohort, reinforcing its generalizability.
The underlying driver of this reversion appears to be antibody quality rather than quantity alone. IgG avidity — the strength and maturity of antibody binding — was consistently lower across naive vaccinees compared to those with prior smallpox vaccination history, and avidity emerged as the primary variable separating the two groups in the machine learning analysis. The implication is that the two-dose MVA-BN primary series elicits an antibody response that is not only short-lived but also qualitatively inferior to immunity generated by earlier replication-competent vaccinia-based vaccines.
Longer Dosing Intervals Produce Better — But Still Transient — Responses
One notable finding within the naive vaccinee group was the identification of a subset the authors call Robust Responders — approximately one-third of naive vaccinees at the peak response time point — who mounted substantially higher neutralizing antibody titers than the remainder of the group. The only statistically significant variable distinguishing Robust from Standard Responders was dosing interval: Robust Responders had a median interval of 58 days between doses compared to 34 days for Standard Responders.
This observation echoes patterns seen with COVID-19 mRNA vaccines, where longer dosing intervals consistently enhanced both humoral and cellular immunity. During the 2022 mpox outbreak, vaccine shortages inadvertently extended dosing intervals for many recipients — the data here suggest that may have been immunologically beneficial for those individuals. However, the advantage proved temporary: by the one-year time point, Robust and Standard Responders were serologically indistinguishable, with both groups having reverted toward baseline. Longer dosing intervals appear to enhance the magnitude but not the durability or quality of the antibody response.
A Third Dose Improves Antibody Quality — But Incompletely
The booster analysis, while limited to four participants, offers a meaningful signal. All four individuals showed clear immunological responses to the third MVA-BN dose, including one participant who had been a non-responder to the primary series. Notably, the third dose improved IgG avidity against several key MPXV proteins — specifically H3, M1, and VACV B5 — suggesting that boosting does more than simply raise antibody levels; it also matures the antibody response. This avidity improvement was not seen for all proteins tested, however, with MPXV A35 and its vaccinia homolog A33 showing no significant improvement.
What This Means for Mpox Policy and Orthopoxvirus Preparedness
The study’s findings carry direct implications for vaccination strategy. The standard two-dose MVA-BN series, as currently deployed, leaves immunologically naive individuals with protection that may erode to baseline within twelve months. Public health data showing that breakthrough cases in vaccinated individuals tend to be milder provide some reassurance, but the underlying immunological picture — low avidity, nondurable antibody responses — raises legitimate questions about whether the current schedule provides adequate protection against sustained exposure or future outbreak surges.
The booster data, while preliminary, suggest that a third dose is an accessible and biologically rational strategy for extending and improving protection, particularly for high-risk individuals or in the context of resurging transmission. The authors are careful to note, however, that the booster cohort was small, comprised only HIV-negative participants, and that humoral immunity represents only one dimension of vaccine-induced protection — the contributions of T cell memory and long-lived B cells remain incompletely characterized for MVA-BN.
The study also serves as a reminder that the era of population-wide smallpox vaccination — which conferred durable cross-protective immunity for decades — is now two generations past for most of the world. As the authors note, beyond mpox, other emerging orthopoxviruses pose a real future threat in a global population that is increasingly poxvirus-naive. These findings add urgency to the case for developing next-generation orthopoxvirus vaccines that can recapitulate the durable immunity of earlier replication-competent predecessors — without their associated safety risks.
Sources and further reading:
Oom AL, Wilson KK, Rettig S, et al. A comparison of two- and three-dose MVA-BN mpox vaccination series on anti-monkeypox virus immunity. NPJ Vaccines, 7 May 2026.