Understanding microbial shifts and how they affect vaccine response is central to this study. We will
determine if gut microbial communities associated with breastfeeding in the HEU infant follows the same
successional trajectory as HU controls and resolve the differences at functional level. How the continuous
conditioning of the infant gut by the microbiota from the breast milk affects the infant microbiome and
subsequent immune responses to pediatric vaccination is not known and would also be studied in this
submission. Teasing out possible humoral vaccine differences due to HLA associations will be an
important component to consider when identifying the mechanism and impact of microbial ecological
conditioning through the breast milk towards vaccine responsiveness. Our submission proposes to use
biological samples collected at regular intervals over a 12 month period from a multi-site study of well
characterized cohort of mother: infant pairs of HEU and HU controls from Nigeria and South Africa to
investigate both host and microbial genetic determinants of altered immunity in African infants and is
therefore responsive to the RFA RM16-013.
Our ongoing Canadian Institute of Health Research-funded cohort has enrolled over 500 mother: infant pairs of
HEU or HU breastfed infants in Nigeria and South Africa to study the role of innate factors and activation in HIV
infection. This has afforded us the opportunity to investigate microbial shifts and how they affect growth and
immune response to pediatric vaccines in HEU infants as compared to matched HU controls. For this
submission, we hypothesize that breast milk microbiota conditioning in newborn infants impacts
growth and immune responsiveness to pediatric vaccines in the context of inherited HLA variants.
We will test this hypothesis through the following specific aims:
Aim 1: Compare the ontogeny of microbial structure and metabolome in longitudinal breast milk and stool
samples of corresponding 200 Exclusively Breast Fed (EBF) HEU versus 100 EBF HU control, infants over the
first 12 months of life to document influence of the milk microbiota on the infant gut microbiome; and their
collective effect or association with growth.
Aim 2: Assess the relationship between infant microbial structure and humoral immune responses to pediatric
AIM 3: To associate inherited HLA gene variants with humoral immune responses to pediatric vaccines in the
two infant groups.
This proposal will interrogate both host and microbial genetic determinants of altered immunity in HEU and is
therefore highly responsive to the RFA RM16-013.