Norovirus immunity at the maternal-child interface

ABSTRACT
Following the global roll-out of rotavirus vaccines, attention is now focusing on vaccination strategies against
norovirus, the next leading cause of viral gastroenteritis. Several norovirus vaccine candidates are in the pipeline,
including an oral GI.1/GII.4 vaccine that will soon be tested in lactating women. The main goal of this vaccination
strategy is to elicit norovirus-specific antibodies in breastmilk. However, very little is currently known about
norovirus immunity in breastmilk. Epidemiologic studies do not consistently find breastfeeding to protect against
norovirus. Also, no prior studies have fully characterized norovirus-specific antibodies in lactating women with
natural norovirus infections to understand what might be attainable with postpartum vaccines. A better
understanding of maternal immunity and how it protects infants against norovirus infections could guide novel
postpartum vaccination strategies. In addition, pediatric vaccines are being developed. A parenteral GI.1/GII.4
norovirus vaccine is undergoing testing in children after encouraging Phase IIb results in adults. However,
vaccine-elicited immunity in naïve infants may differ from that in adults, who have experienced multiple prior
infections. For example, our group demonstrated that the dominant response to the parenteral GI.1/GII.4 vaccine
in adults was boosting from a previous GII.4 infection. Further, we have demonstrated that natural norovirus
infections in young children elicit a narrow antibody response—typically to the infecting genotype only—
suggesting that an effective pediatric vaccine would need to include multiple norovirus genotypes. These
differences in the immune response in adults vs. children suggest that understanding the unique immune stage
of the infant is necessary to develop an effective pediatric vaccine. This project connects a robust field site with
state-of-the-art immunological approaches to inform norovirus vaccination strategies to benefit children. We will
enroll 120 Guatemalan breastfed infants with acute norovirus gastroenteritis and their mothers to determine if
there is an association between norovirus-specific antibodies in breastmilk and the duration of norovirus
infections in infants. Next, we will characterize and compare humoral immunity to norovirus in infants and
mothers infected with the same norovirus strain. Finally, we will characterize the kinetics and breadth of
norovirus-specific antibodies in breastmilk in lactating women with norovirus infections. We hypothesize that a)
infants receiving breastmilk with higher levels of genotype-specific norovirus antibodies will have shorter
norovirus infections as compared to infants receiving lower levels of these antibodies, b) infants will mount narrow
antibody responses to norovirus as compared to (previously exposed) adults, and c) in lactating women with
norovirus infections, norovirus-specific antibody responses in breastmilk will be broad and short-lived, similar to
antibody responses to norovirus in another mucosal fluid, saliva. This project responds to the pressing need to
inform norovirus vaccination strategies to benefit children, while adding to our basic understanding of immune
protection at the maternal-child interface.

Grant Number: 5R21AI180612-02
NIH Institute/Center: NIH
Principal Investigator: Sylvia Becker-Dreps