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A research letter published in JAMA looks at the decline of Mpox antibody responses after vaccination.
Dr Jake Dunning, Senior Research Fellow, Pandemic Sciences Institute, University of Oxford, said:
“Studies like this help improve our understanding of real-life use of new vaccines for important global health threats, such as mpox; however, they are just one piece of a quite complicated jigsaw when it comes to understanding vaccine effectiveness. Waning antibodies over time is predictable for many vaccines, including MVA-BN; however, this study does not provide proof that antibody waning results in waning protection against mpox infection or severe mpox disease in real life. To answer that important question, we need to look at the totality of data from different types of studies, including longitudinal vaccine effectiveness studies where one looks at rates of clinically apparent mpox infections in those who have been vaccinated and those who have not, over time.
“For some infectious diseases, while antibody levels may decline over time following vaccination, the immune system may have been effectively primed by vaccination; this would mean that, as long as the person’s immune system is working normally, if they meet the pathogen in the future (and the pathogen has not changed significantly), their immune system will rapidly recognise the pathogen, triggering different immune responses, including more rapid production of antibodies by a ‘forewarned’ immune system. These antibodies, along with other immune responses, help prevent and/or clear infections or prevent illness arising or progressing if infection does occur.
“We do not know the answer yet for MVA-BN, in terms of the duration of real-life protection against mpox and other orthopox infections. We do not know for sure how long the recommended and approved two-dose regimen will protect people and whether boosters will be needed, because we do not have those cumulative, real-life data yet. In some settings or outbreaks, there may not be a need to provide very long-lasting protection. For example, there could be a strategy to provide just enough to help protect the individual during a period of increased exposure risk and to help bring an outbreak under control, particularly in a country where recurring mpox outbreaks are not an issue (such as a short lived outbreak following introduction of mpox, and the country does not have the infected animal reservoirs).
“Selecting any vaccine requires considerations of the pros and cons, including how it is administered, stability and storage conditions, who can safely receive it, and what side effects it may cause, and MVA-BN has many advantages in this area compared to traditional vaccinia vaccines that were used previously for smallpox eradication.
“This study highlights another important question – what are the best biological markers to indicate protection against future mpox infection or mpox illness? Looking at anti-vaccinia antibody levels following vaccination is relatively easy, but possibly is too simplistic, and we should consider the role of other parts of the immune system, such as T and B lymphocytes. Vaccines designed to protect people against smallpox and mpox may differ in their ability to stimulate different parts of the immune system, including the parts that have longer-term ‘memory’ functions and protect us if we encounter the pathogen months, years, or even decades later; therefore, it’s important that current and future immunogenicity studies examine different components of the human immune response to smallpox/mpox vaccines, and that vaccine effectiveness studies are done alongside, across different mpox outbreaks, settings and populations.”
Prof Paul Hunter, Professor in Medicine, University of East Anglia (UEA), said:
“The vaccine reports antibody levels over time after vaccine with the modified vaccinia Ankara–Bavarian Nordic (MVA-BN; Jynneos) vaccine, a vaccine designed for smallpox.
“The paper showed that indeed IgG and neutralising antibodies to Monkeypox did fall over time after a natural infection and after vaccination. Neutralizing antibody levels at 9 months after vaccine were not that different to pre vaccine levels but 9 months after an infection, levels were still high. Also, in general, people who had two doses of vaccine showed rather better IgG antibodies than those who only had one dose.
“But this does not mean that the vaccine is no longer protective a year later. No vaccine, including vaccines effective against mpox are 100% effective and protective effects wanes over time. Cases of mpox have been reported in people who have been vaccinated. However, as we saw with covid, infections after vaccine tend to be less severe. Also, it is well known that for some infections someone can still have an important degree of protection even when antibody levels fall. The reason for this is that after vaccination memory B cells develop and even when IgG levels fall such cells can start to produce antibodies again after a few days. The incubation period for mpox is around 12 days long enough for these memory B cells to start producing Ab again and so give a degree of protection against severe disease.”
Dr Alexis Robert, Research Fellow at the London School of Hygiene and Tropical Medicine, said:
“This new research letter from Collier et al shows that Mpox antibody response declined with time since vaccination in 47 individuals vaccinated with the modified vaccinia Ankara–Bavarian Nordic. The antibody level after one year was back to the pre-vaccination levels for some of the Mpox antigens. The Mpox outbreak declared in the United Kingdom in 2022 was brought into control through declines in transmission rate from behavioural changes, and targeted vaccination of at-risk groups. The waning highlighted by Collier et al is therefore important to investigate, especially since vaccination of high-risk group was credited for reducing the risk of Mpox resurgence since 2022 (Brand et al, 2023).
“Mpox is an infectious disease associated with severe illness. To assess the current Mpox outbreak risks, we need to understand the level of immunity in the population. As highlighted by the authors, the study uses a limited sample size (25 1-dose recipients, 22 2-dose recipients), so the results need to be confirmed with larger, more representative samples, to get a full picture of the level of protection in the vaccinated population. In such a small sample, the effect of individual features cannot be analysed: for instance, the age at vaccination, or medical history could impact the response of individuals. Future analyses with larger sample size should identify factors that contribute to this decrease, so we better understand what it means for the level of immunity in the population.
“Finally, antibody concentration will need to be connected to infection risks through epidemiological investigations. This will show how vaccinated individuals contribute to outbreaks: are they as likely be infected as unvaccinated individuals? Are their symptoms milder? Are they as likely to transmit? If so, catch up campaigns may be needed to bring transmission risk down, and control Mpox outbreaks.”
Dr Jonas Albarnaz, Institute Fellow at The Pirbright Institute, said:
What are the implications for the UK as the Modified Vaccinia Ankara vaccine is used widely?
“This report that the antibody response against mpox induced by MVA-BN vaccine wanes by 6-12 months post-vaccination is disappointing. Vaccination remains the best strategy to prevent mpox and is recommended to individuals at higher risk of infection, which include contacts of mpox cases, healthcare workers, and people with multiple sexual partners. MVA-BN requires the intradermal injection of two doses four weeks apart, and this study suggests that boosters might be required to maintain vaccine effectiveness.
“A few weeks ago, the results of a recent clinical trial in DRC that showed the antiviral drug tecovirimat did not improve clade 1 mpox disease duration and mortality. Now, these findings that MVA-BN protective immunity against mpox wanes quickly further highlight that we need to double down on our efforts to understand monkeypox virus and develop more potent and efficacious intervention strategies against mpox.
Is this good quality research? Are the conclusions backed up by solid data?
“The research was well conducted, and the data support the conclusions. However, the authors highlighted that this was an observational study with a small sample size and that larger studies would be necessary to assess MVA effectiveness over time.
How does this work fit with the existing evidence?
“These findings support recent reports of mpox infections in people that have been vaccinated with 2 doses of MVA-BN for >6 months.”
Dr Boghuma Titanji, Assistant Professor of Medicine, Emory University, said:
“This study is crucial as it examines individuals who received one or two doses of the MVA-BN vaccine or recovered from an mpox infection. The authors found that vaccine-induced neutralizing antibodies and T-cell responses declined significantly within 6-12 months. This raises concerns that previously vaccinated individuals may become more susceptible to mpox as their immunity wanes, suggesting that additional booster doses could be beneficial. Some countries, like the United Kingdom, are already recommending booster doses, though other nations have not yet updated their vaccination guidelines accordingly.
“It is reassuring that nearly two years after the peak of the mpox outbreak in North America and Europe, case numbers have remained low, and post-vaccine infections are rare. This suggests that immunity might not be solely dependent on antibody levels and that other immune factors not yet defined could still offer protection. While the findings need confirmation in larger cohorts including representation of key groups like pregnant people and children, they are important for guiding future vaccination strategies, especially for vulnerable groups at higher risk of exposure.
“Additionally, special attention must be given to understanding vaccine responses and immunity durability in immunocompromised individuals, such as those with HIV. This group is particularly vulnerable to severe mpox and poor outcomes, highlighting the need for tailored vaccination guidelines to protect them effectively.”
Prof Thomas House, Professor of Mathematical Statistics, University of Manchester, said:
“This result is, as the authors state, consistent with epidemiological evidence that Mpox can infect both those vaccinated and those previously infected. These epidemiological observations would usually suggest that antibodies wane over time, and this paper provides direct biological evidence for that hypothesis. It is important to note that the efficacy concerned is against infection; expected severity of disease and infectiousness if infected may remain much lower amongst those vaccinated than not even after antibodies have waned.”
‘Decline of Mpox Antibody Responses After Modified Vaccinia Ankara–Bavarian Nordic Vaccination’ by Ai-ris Y. Collier et al. was published in JAMA at 4:30pm BST on Thursday 3rd October.
DOI: 10.1001/jama.2024.20951
Declared interests
Dr Dunning: I am an investigator in a study looking at immune responses to and tolerability of MVA-BN in healthcare workers, which is not industry funded. I am a member of the WHO Emergency Committee for Mpox and a member of UKHSA’s Technical Advisory Group on mpox . I speak independently and views expressed do not necessarily represent those of my associated institutions, NHS England, UKHSA, or WHO. I have no commercial or financial interests to declare.
Prof Hunter: No COIs.
Dr Robert: No conflicts interests to declare.
Dr Jonas Albarnaz: No conflicts of interest to declare.
Dr Boghuma Titanji: I have no conflicts of interest to declare.
Prof House: No COIs.
For all other experts, no reply to our request for DOIs was received.