Mechanism of cross-reaction and cross-protection for Mayaro virus elicited by chikungunya vaccine

Project Summary/Abstract: Arthritogenic alphaviruses are mosquito-borne viruses that can cause acute and chronic polyarthralgia in humans, impacting public health and economies worldwide. Chikungunya virus (CHIKV) is the most widespread arthritogenic alphavirus, causing 16.9 million annual cases, and nearly 2.8 billion people live in areas at risk for CHIKV infection. In Latin America and the Caribbean, CHIKV geographically co-circulates with Mayaro virus (MAYV), another arthritogenic alphavirus that is an emerging viral threat. At present, no vaccines or specific therapeutics are available to treat or prevent MAYV infection. Vimkunya is a virus-like particle (VLP) vaccine against chikungunya disease approved in the United States of America in February 2025. The protection by Vimkunya likely relies on antibodies that neutralize CHIKV, and it is hypothesized to provide cross-protection against MAYV infection. Currently, three key questions about Vimkunya and cross-protection against MAYV infection need to be addressed: 1) Do neutralizing antibodies elicited by Vimkunya vaccination prevent disease caused by MAYV infection? 2) Do Vimkunya-elicited antibodies protect against MAYV infection through effector functions? 3) Does Vimkunya vaccination elicit cross-reactive T and B cell responses that contribute to protection against Mayaro disease? To address these fundamental unknowns, we will utilize human and rhesus macaque models to investigate the immune mechanisms of Vimkunya-induced cross-reactivity and cross-protection against MAYV infection. Aim 1 will use longitudinal blood sampling of humans vaccinated with Vimkunya, coupled with systems serology, flow cytometry, and single-cell genomics (scRNA-seq) methods to define the potential mechanisms of cross-reactivity of antibody, B cell, and T cell responses for MAYV. This approach will determine the mechanisms of cross-reactivity against MAYV elicited by Vimkunya vaccination in humans. Aim 2 will employ a rhesus macaque model that recapitulates Mayaro disease in humans to investigate mechanisms of Vimkunya-mediated cross-protection for Mayaro disease. We will immunize rhesus macaques with Vimkunya and collect blood, lymph nodes, and bone marrow cells at baseline and multiple weeks post-vaccination. Subsequently, we will perform experimental MAYV infection in both the previously immunized and unimmunized rhesus macaques, coupled with passive antibody transfer and targeted lymphocyte depletion approaches. Then, we will apply immunological and genomic methods to examine the role of humoral and cellular responses in cross-protection in an experimental model that recapitulates Mayaro disease as described in humans. This aim will define the mechanisms of cross-protection against Mayaro disease generated by Vimkunya immunization. Overall, the long-term goal of this project is to elucidate the immunological mechanisms of Vimkunya-mediated cross-reaction and cross-protection against MAYV. The knowledge gained in this study will inform future Vimkunya immunization programs within CHIKV and MAYV co-endemic regions and may contribute to mitigating the emergence of MAYV in urban settings.