Monkeypox mimics smallpox vaccine's immune response, new study reveals

A study published in the journal Nature Communications finds that monkeypox (MPOX) infection induces a similar anti-viral antibody response as smallpox vaccination.

Monkeypox virus-infected individuals mount comparable humoral immune responses as Smallpox-vaccinated individualsStudy: Monkeypox virus-infected individuals mount comparable humoral immune responses as Smallpox-vaccinated individuals. Image Credit: FOTOGRIN / Shutterstock


MPOX  is a zoonotic virus belonging to the Orthopoxvirus genus. Other members of this genus include vaccinia virus, variola virus, and cowpox virus. Variola virus is the causative pathogen of smallpox infection, and vaccinia virus is the backbone of most smallpox vaccines.

After the global eradication of the smallpox virus in 1980, routine smallpox vaccination with the vaccina virus was halted worldwide. Due to diminishing vaccine immunity over time, the world population remains at risk for poxvirus infections. The risk is even higher for those born after 1980, and thus, could not receive smallpox vaccination.

MPOX  virus was initially endemic to only central and western African countries. In early 2022, a number of MPOX  cases without previous travel history to MPOX  endemic regions have been detected in the UK. Afterward, similar cases have also been identified in other non-endemic countries, including the USA. To date, more than 80,000 cases of MPOX infection have been detected worldwide, with the majority being identified among men who have sex with men.

To control the recent outbreaks of MPOX  infection, public health agencies worldwide have offered smallpox vaccines, such as IMVANEX and ACAM2000, to high-risk populations. According to the available literature, antibodies induced by these vaccines remain detectable up to 35 years post-vaccination.

In this study, scientists have determined and compared the antibody response and antigen recognition induced by MPOX  infection and smallpox vaccination. Specifically, they have developed a comprehensive array of Enzyme-linked Immunosorbent Assays (ELISAs) to study poxvirus-induced antibodies using 24 MPOX virus and 3 Vaccinia virus recombinant antigens.

Antigen recognition  

Serum samples collected from smallpox-vaccinated or MPOX-infected individuals were tested using a set of 27 poxvirus antigens. The findings revealed that a single dose of the IMVANEX vaccine induced low antibody titers against a limited number of MPOX  antigens. However, the antibody titer against a number of MPOX  and vaccina antigens increased with further vaccine doses. Overall, both IMVANEX and ACAM2000 smallpox vaccines induced similar antibody responses against tested antigens.

Individuals with prior MPOX infections showed similar antibody responses to diverse poxvirus antigens as smallpox-vaccinated individuals. No difference in antigen recognition was observed between individuals with MPOX infections before and during the 2022 outbreaks.

To identify serological markers specific to MPOX  infection and smallpox vaccination, principal component analysis was conducted using antibody binding data to the tested antigens. MPOX  antigen A27 was identified as the most specific marker to MPOX infection and ACAM2000 vaccination. In contrast, MPOX  antigen M1 was identified as the most specific marker for IMVANEX vaccination.

Specific serological reactivity

The scientists explored the ability of individual antigens to distinguish between individuals with MPOX  infection or smallpox vaccination. A significantly higher antibody response to MPOX antigen A27 was observed for MPOX-infected and ACAM2000-vaccinated individuals compared to negative controls. In contrast, a significantly higher antibody response to the M1 antigen was observed only among IMVANEX-vaccinated individuals. Further analysis revealed that the antibody binding to MPOX  or vaccinia antigens primarily depends on the initial antigen exposure.

Antibody response to IMVANEX vaccination and MPOX infection

Serum samples collected from IMVANEX-vaccinated individuals at baseline (before vaccination) and at several time points after vaccination were analyzed to assess long-term antibody response to tested antigens.

The findings revealed that although antibody response was minimal after the first dose, antibodies generated 14 days after the second dose were able to bind nine antigens. Among tested antigens, MPOX  antigen B2 showed 91% sensitivity and 87% specificity in identifying post-vaccination samples.

MPOX  antigen A27 showed 91% sensitivity and 98% specificity in detecting MPOX-infected samples. MPOX antigen M1 showed 63% sensitivity and 98% specificity in identifying IMVANEX-vaccinated samples.

The testing of individual antigens revealed that the dominant antigens recognized by MPOX-infected and smallpox-vaccinated sera were highly similar. Further experiments conducted using a pool of these antigens revealed that the pooled antigen ELISA had 96% sensitivity and 98% specificity in detecting pan-poxvirus antibodies.

Study significance

The study demonstrates analogous humoral antigen binding between individuals with prior MPOX infection and those with smallpox vaccination. A highly sensitive and specific pooled antigen ELISA developed in the study is able to accurately measure immune responses to MPOX infection or smallpox vaccination without the need for whole-virus ELISAs or live-virus neutralization.  

Journal reference:
Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.


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