Maternal antibody interference contributes to reduced rotavirus vaccine efficacy in developing countries

Abstract

Rotavirus (RV) vaccine efficacy is significantly reduced in lower- and middle-income countries (LMICs) compared to high-income countries. This review summarizes current research into the mechanisms behind this phenomenon, with a particular focus on the evidence that maternal antibody (matAb) interference is a contributing factor to this disparity. All RV vaccines currently in use are orally administered, live-attenuated virus vaccines that replicate in the infant gut, which leaves their efficacy potentially impacted by both placentally transferred immunoglobulin G (IgG) and mucosal IgA Abs conferred via breast milk. Observational studies of cohorts in LMICs demonstrated an inverse correlation between matAb titers, both in serum and breast milk, and infant responses to RV vaccination. However, a causal link between maternal humoral immunity and reduced RV vaccine efficacy in infants has yet to be definitively established, partially due to limitations in current animal models of RV disease. The characteristics of Abs mediating interference and the mechanism(s) involved have yet to be determined, and these may differ from mechanisms of matAb interference for parenterally administered vaccines due to the contribution of mucosal immunity conferred via breast milk. Increased vaccine doses and later age of vaccine administration have been strategies applied to overcome matAb interference, but these approaches are difficult to safely implement in the setting of RV vaccination in LMICs. Ultimately, the development of relevant animal models of matAb interference is needed to determine what alternative approaches or vaccine designs can safely and effectively overcome matAb interference of infant RV vaccination.

Rotavirus A infection in pre- and post-vaccine period: Risk factors, genotypes distribution by vaccination status and age of children in Nampula Province, Northern Mozambique (2015-2019)

“…Similar results were reported in Kenya in children under 24 months, where a high proportion of positive children were exclusively breastfed than those with other types of food, with 16% and 10.3% respectively in the post-vaccine period [43]. One of the hypotheses behind this finding is related to the maternal antibodies which may interfere with the RVA vaccine efficacy in lower and middle-income countries, however, the causal link is not well described [44].…”

Protective Transfer: Maternal passive immunization with a rotavirus-neutralizing dimeric IgA protects against rotavirus disease in suckling neonates

“…Breast milk contains high levels of sIgA that act as the first line of defense against enteric infection in suckling infants (Glass and Stoll, 1989;Ruiz-Palacios et al, 1990;Torres and Cruz, 1993). Despite this, the burden of RV disease in LMIC remains high, likely due to a combination of factors including high pathogen load, malnutrition and decreased vaccine efficacy compared to high income countries (Guerrant et al, 2008;Otero et al, 2020;Velasquez et al, 2018). Neutralizing antibodies against the external RV proteins VP4 and VP7 play a role in protective immunity against RV infection (Clarke and Desselberger, 2015;Desselberger and Huppertz, 2011;Greenberg et al, 1983;Offit and Blavat, 1986).…”

“…Indeed, previous studies have demonstrated that socioeconomic status plays a role in generation of anti-RV antibodies (Ray et al, 2007;Trang et al, 2014). Additionally, maternal vaccination may lead to maternal antibody interference and decreased immunogenicity in vaccinated infants (Appaiahgari et al, 2014;Otero et al, 2020). Based on this, other therapeutic strategies for delivery of potently RV-neutralizing antibodies are needed.…”

Effect of Infant and Maternal Secretor Status on Rotavirus Vaccine Take—An Overview

“…The efficacy of the currently orally administered live-attenuated vaccines may be impacted both due to the placentally transferred IgG immunoglobulins and the mucosal IgA through breastmilk [39,40]. Several studies, mostly in low-and middle-income (LMIC) countries, have addressed these questions and observed a correlation between higher maternal antibody titers both in serum and breastmilk, and reduced rotavirus vaccine response [40][41][42]. In addition, an earlier study investigating rotavirus specific neutralization titers in mothers and children less than 2 years of age reported that low serotype-specific neutralizing antibody titers in the mother predispose the child for infection to the same serotype [43].…”