Self-amplifying mRNA vaccines protect elderly BALB/c mice against a lethal respiratory syncytial virus infection

Respiratory syncytial virus (RSV) represents a significant threat, being a primary cause of critical lower respiratory tract infections and fatalities among infants and the elderly worldwide, and poses a challenge to global public health. This urgent public health challenge necessitates the swift development of safe and effective vaccines capable of eliciting robust immune responses at low doses. Addressing this need, our study investigated five self-amplifying mRNA (sa-mRNA) candidate vaccines that encode the various pre-fusion conformations of the RSV fusion protein. When administered via low-dose intramuscular injection to 8-month-old elderly mice, these vaccines triggered potent humoral reactions and T helper type 1-biased cellular immunity. A prime-boost strategy followed by challenge with a lethal, mouse-adapted RSV strain showed that three of these sa-mRNA candidates achieved greater than 80% survival rates. An immune correlates of protection analysis contrasting immunized survivors with non-survivors suggest that the titers of IgG and neutralizing antibody are associated with vaccine-mediated protection from RSV infection. Our results highlight the usefulness of sa-mRNA vaccines to play a crucial role in forging an effective defense against RSV, addressing a critical need in protecting vulnerable populations against this virus.