Antibody cross-reactivity among alphaviruses in clinical practice

Alphaviruses are mosquito-borne pathogens causing rheumatological disease and encephalomyelitis. Their spread, enhanced by climate change, presents a growing global health threat. To date, no specific treatments and, except for chikungunya virus, no preventive vaccines exist. Alphavirus infection induces cross-reactive antibodies targeting conserved epitopes in glycoprotein E1 and E2. While cross-reactivity can facilitate the development of broad-spectrum vaccines, it complicates serological diagnosis in regions with multiple co-circulating alphaviruses. This review examines how antibody cross-reactivity can foster development of cross-protective vaccines and therapeutics but also how it may present challenges such as antibody-dependent enhancement of disease and diagnostic misinterpretation. Understanding the conservation of epitopes is crucial for designing effective therapies, vaccines, and precise diagnostics to mitigate the alphavirus disease burden globally.