Continuous generation of effector (Teff) and effector memory (Tem) T cells with mouse cytomegalovirus (MCMV) vaccination to prolong malaria immunity

Abstract

Abstract Immunity to Plasmodium infection or vaccination decays without continuous exposure. This decay correlates with loss of malaria-specific T cells, not antibody. We recently demonstrated that Teff protect better than memory T cells, and that Ifng+ Teff are responsible for the protection provided by persistent P. chabaudi infection. Based on this data, we have reverse-engineered a vaccine strategy that first induces a long-lived antibody response, and then boosts the Teff and Tem response to prolong protection. We chose live vaccination with “infection and drug cure”, which generates protection that decays over 200 days. The boost uses MCMV as it is an excellent T cell-inducing vector with promise against SIV, tuberculosis and liver-stage malaria. First, we observed that MCMV infection strongly reduced parasite growth, as previously shown for Leishmania, suggesting a useful adjuvant effect. To promote continuous induction of specific T cells, we generated MCMV expressing the P. chabaudi T cell epitope B5. Vaccination with MCMV-B5 activated both adoptively transferred B5 TCR Tg T cells and MCMV-specific CD4 T cells, generating protective Teff and Tem phenotypes for over 2.5 months. Importantly, we show that boosting with the MCMV vector prolongs protection generated by the live vaccine, as shown by better protection from re-infection at day 200. We are currently investigating the contribution of activated Plasmodium-specific T cells in prolonging protective immunity by MCMV-B5, and mechanisms of protection. Our findings suggest that chronic vaccination can redress the problem of short-lived protection to malaria infection and vaccines, which would be beneficial for any efficacious but short-term vaccine strategy.