Identifying critical determinants of vaccine-induced cellular and humoral immunity from birth through childhood in HIV-exposed and unexposed children

Vaccination is one of the most effective tools to control the spread of infections and reduce child mortality, however the WHO estimates 1.5 million children under 5 years old die each year from vaccine preventable illnesses. Vaccine efficacy may be reduced by host immune modulating factors that impair optimal immune responses, including exposure to HIV, infection with cytomegalovirus (CMV), and other factors related to maternal or infant infections and inflammation. Regions with high prevalence of HIV, poverty, and malnutrition also often have sub-optimal vaccine coverage. Together, these factors put large populations of infants and young children at risk for preventable deaths. Several studies have reported deficits in antibody responses to routine childhood vaccines in HIV-exposed uninfected (HEU) compared to HIV-unexposed (HUU) children, but few studies have looked at cellular vaccine responses in HEU. There is also evidence that infection with CMV, which elicits profound immune activation and inflammation following infection, impacts vaccine responses, but results are not conclusive. Thus, substantial gaps remain in our understanding how exposure to maternal HIV infection and infant infection with CMV may impact humoral and cellular vaccine immune responses. Our overarching hypothesis is that early-life exposure to immune modulating infections, specifically HIV and CMV, may affect immune responses to vaccines given during infancy as well as to vaccines first administered in middle childhood. We will extend follow-up of an existing birth cohort of HEU and HUU Kenyan children previously followed from pregnancy to 4 years postpartum with longitudinal collection of specimens and clinical data, including vaccine records. We will determine the effect of HIV exposure and/or early CMV acquisition on humoral and cellular responses to infant vaccines from birth through 4 years of age (Aim 1), and on humoral and cellular responses to influenza vaccination in middle childhood at 6 years (Aim 2). Data from our existing project (virome/microbiome, enteric enteropathy, growth, child and maternal in utero inflammation, infections) will be assessed as modulators of vaccine-induced immunity in HEU and HUU children from infancy through toddlerhood, early and middle childhood (Aim 3). The proposed studies offer an unprecedented opportunity to understand how HIV, CMV, malnutrition and inflammation alter early life and long-term immune reactivity in African children. Results from this study have great potential to inform novel vaccination strategies and interventions for children in areas of high HIV prevalence, CMV and malnutrition.