Immunological and Physiological Responses to Measles Vaccine

Measles remains one of the most important causes of child mortality with recent increases in cases exacerbated by lapses in immunization during the COVID-19 pandemic. Measles virus (MeV) is a highly infectious non-segmented negative-strand RNA virus. Studies of measles in children and a well-characterized rhesus macaque model have shown that wild type (WT) MeV infection is initiated in the respiratory tract and spreads to lymphoid tissue with profound short and long-term effects on the immune system. Measles induces intense immune activation, increases susceptibility to other infections, decreases Ab to other pathogens, can trigger autoimmune encephalomyelitis, and induces life-long immunity to MeV. Although infectious virus is cleared during the rash-associated adaptive immune response, viral RNA persists in peripheral blood mononuclear cells (PBMCs) and lymphoid tissues for months with ongoing immune stimulation and continued production of MeV-specific antibody-secreting cells, antibody maturation and multiple waves of functionally distinct T cells. The live attenuated measles vaccine (LAMV) was developed by passage of WT MeV in chicken cells, licensed in 1963 and has been remarkably successful in controlling measles. Safety and availability of reverse genetics has led to development as a vaccine vector and oncolytic agent. However, there is little knowledge of where LAMV replicates, mechanism(s) of attenuation or how the immune responses induced differ from WT MeV for protective immunity or immunosuppression except to note that Ab titers are lower and protection less durable. We have shown that a central difference between infection with LAMV and WT MeV is replication in immune cells, that antiviral treatment accelerates RNA clearance and impairs antibody production. We hypothesize that persistent viral RNA is required for stimulation of durable immunity to MeV and that immune activation in response to infection affects pre-existing immunity. We will address these gaps in knowledge of LAMV biology through the following specific aims: (1) Identify the viral determinants of inefficient LAMV replication in immune cells through construction of recombinant LAMVs with WT sequences; (2) Identify the in vivo sites of LAMV replication and dynamics of RNA clearance compared to WT MeV through study of MeV replication in rhesus macaques; (3) Define the immune responses to infection with LAMV and WT MeV and effects of antiviral therapy in rhesus macaques; and (4) Determine the mechanism(s) by which WT MeV infection decreases Ab diversity in rhesus macaques and whether this occurs after infection with LAMV.