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.
