Are antibodies induced by historic smallpox vaccination cross-reactive with the monkeypox virus?

In a recent study posted to the medRxiv* preprint server, researchers measured the monkeypox virus (MPXV)-neutralizing antibodies produced by the vaccinia virus (VACV) vaccine, modified vaccinia virus Ankara (MVA) vaccine, and monkeypox virus (MPXV) to understand the efficacy of the MVA-Bavarian Nordic (MVA-BN) vaccine currently being used against monkeypox.

Background

On July 23, 2022, the World Health Organization (WHO) declared the monkeypox outbreak a public health emergency of international concern (PHEIC). Monkeypox is a zoonotic disease caused by the monkeypox virus, which is closely related to the smallpox-causing variola virus and belongs to the Poxviridae family containing double-stranded deoxyribonucleic acid viruses.

Smallpox has been eradicated using a strategy of isolating and quarantining active cases and administering three generations of vaccines. The first two generations of smallpox vaccines consisted of cultured infectious VACV. The third generation of vaccines involved further attenuated VACV, known as MVA.

Studies have shown the VACV vaccine to be reasonably effective against MPX in the Democratic Republic of Congo. The MVA vaccine induced antibodies and T cells in non-human primates. Consequently, the MVA-BN was approved for vaccination against monkeypox under different names in Canada, the United States, and Europe. However, studies on the efficacy of the vaccine in generating MPXV-neutralizing antibodies are lacking.

About the study

The present study used neutralization assays and enzyme-linked immunosorbent assay (ELISA) to measure VACV-, MVA-, and MPXV-reactive binding antibodies in historically smallpox-vaccinated and recently MVA-BN-vaccinated cohorts and to investigate if MPXV-infected individuals show rapid neutralizing antibody responses. The team used MPXV isolated from a Dutch patient to develop ELISA and neutralization assays for MPXV.

The neutralizing assays and ELISA were carried out on sera from individuals with historical smallpox vaccination, persons with positive polymerase chain reaction (PCR) tests for MPXV, individuals who received recent MVA-BN vaccinations, and an earlier clinical trial with MVA-H5 influenza vaccination. Since the Netherlands stopped smallpox vaccinations in 1974, birth before 1974 was taken as a proxy for historical smallpox vaccination, as historical vaccination records were unavailable.

The suitable serological assays were selected by comparing the neutralizing activity of serum samples from infected and vaccinated individuals against MVA, VACV, and MPXV. The antigenic similarities of the poxviruses were also assessed.

Results

The study results indicated the detection of MPXV-neutralizing antibodies in all cohorts. A recent MPXV infection boost antibody levels in individuals with previous vaccinations. Still, the same effect was not as apparent in historically vaccinated individuals who received a recent MVA-BN vaccination.

Individuals born before 1974 had antibodies that could neutralize MPXV, but individuals without historic smallpox vaccination exhibited relatively low levels of MPVX neutralizing antibody response, despite primary MVA-BN vaccination. Interestingly, in MVA-BN vaccinated individuals, MVA and MPXV neutralization were not highly correlated, indicating possible antigenic differences between the two poxviruses.

Furthermore, in persons without a pre-existing immune response against VACV, even two doses of MVA-BN elicited relatively low antibody levels with weak neutralizing capacity. The existing VACV-specific ELISA was sensitive in detecting VACV-binding antibodies in most of the serum samples, but the MPXV-specific ELISA developed in this study was less sensitive.

Additionally, assays using sera from the MVA-H5 clinical trial showed that an additional shot of MVA increased the VACV-reactive antibodies. The earlier MVA-H5 clinical trial had also determined that using a lower dose of vaccine (dose-sparing) results in a weak immune response.

Conclusions

To summarize, the authors report that in individuals immunized with the VACV smallpox vaccine, a primary MVA-BN vaccination results in lower levels of neutralizing antibodies against MPVX than an MPXV infection. The historic VACV vaccine still provides a stronger immunity against MPXV than two doses of the MVA-BN vaccination. Furthermore, MVA-BN-vaccinated individuals did not show comparable MPXV cross-reactive antibody and MVA-specific responses.

Currently, the United States employs a vaccine strategy where two subcutaneous doses of the MVA-BH vaccine are being provided to ensure widespread vaccination with a lower (one-fifth) dosage. The negative impact of dose-sparing on immunization outcomes indicates the need for better immunization approaches.

Overall, the findings of the study question the efficacy of the MVA-BN vaccine in protecting against monkeypox. The researchers believe that a third dose of the MVA-BN vaccine will improve immunity. Since the MPXV vaccines in clinical use are built on the MVA vaccine, further studies to assess the efficacy of the vaccine in generating MPXV-neutralizing antibodies are necessary.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.