Chronic Vaccine Boost Prolongs Malaria Vaccine Immunity and CD4 Effector and Memory T cells

Vaccines to persistent parasite infections have been challenging to develop, and current iterations lack long-term protection. Persistent infection generates effector and effector memory T cells (Teff, Tem), and both contribute to protection, as we recently showed for Plasmodium infection. Sterilizing immunity from live P. chabaudi vaccination lasts less than 200 days. While specific antibody levels remain stable after the acute phase of infection, the decay of T cells corresponds with loss of protection from re-infection. Chronic vaccination with CMV has been shown to generate Tem and Teff, and so we tested MCMV for the ability to prolong protection to P. chabaudi. We generated MCMV encoding P. chabaudi MSP-1 epitope B5 (MCMV-B5), and used B5 TCR Transgenic CD4 T cells to follow the MCMV-B5 response. We showed that boosting the live malaria vaccine with MCMV-B5: i) prolonged vaccine protection to heterologous infection at day 200, ii) increased parasite-specific T cells and promoted a highly-differentiated Teff phenotype, including iii) IFN-γ+ and TNF+ T cells. Importantly, chronic MCMV infection itself improved protection from P. chabaudi infection and promoted generation of a T cell phenotype similar to P. chabaudi infection. Investigating the mechanisms of MCMV in prolonged vaccine-induced protection, we found an impressive role for IFN-γ, as its neutralization in vivo during MCMV latency is associated with loss of protection to P. chabaudi challenge. Blocking IFN-γ before challenge induced fewer Teff and less plasma IL-12 upon P. chabaudi challenge. Our findings suggest a mechanism to boost CD4 T cell immunity using chronic vaccines, which may be broadly applicable to infections that require T cell based immunity. Supported by R01AI135061