Histo–Blood Group Antigen Phenotype Determines Susceptibility to Genotype-Specific Rotavirus Infections and Impacts Measures of Rotavirus Vaccine Efficacy

Abstract

BackgroundLewis and secretor histo–blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE.MethodsIn infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD.ResultsA vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36–.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort.ConclusionsHost HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status.Clinical Trials RegistrationNCT01375647.

The Impact of Human Genetic Polymorphisms on Rotavirus Susceptibility, Epidemiology, and Vaccine Take

“…Although fewer studies on P [4] are available, similar discrepancies have been reported, with some studies showing that secretor and Lewis positivity (Lewis b phenotype) are markers of susceptibility rather than only secretor positivity [15]. One study [16], reported no P [4] infections in non-secretors, but Lewis-positive non-secretors were susceptible to P [8] infections. The reduced estimate of vaccine efficacy in this study was thus mediated by the complete protection of non-secretors to P [4], and not P [8], infections.…”

“…Some discrepancies have been found between studies, mostly regarding the P [8] genotype, which most studies have investigated. While most studies have reported a strong association between positive secretor status and susceptibility, some studies have reported Lewis positivity, independent of secretor status, as a susceptibility factor [16,21], while others have reported that secretor-and Lewis-positive status (Lewis b phenotype) may be a stronger susceptibility marker than only secretor-positive status [12,15]. Although fewer studies on P [4] are available, similar discrepancies have been reported, with some studies showing that secretor and Lewis positivity (Lewis b phenotype) are markers of susceptibility rather than only secretor positivity [15].…”

“…Positive secretor status is strongly associated with P [8] and P [4] infections, but the discrepancies observed between studies warrant more investigation. The putative reasons include a strain-dependent susceptibility, methodological differences between studies, differences between mild and severe rotavirus cases [15,16], or the lack of sufficient samples for reliable statistical analysis. All studies on the P[6] genotype to date have reported a strong association with Lewis negativity independent of secretor status.…”

Molecular basis of P[6] and P[8] major human rotavirus VP8* domain interactions with histo-blood group antigens

“…The discovery that P [4], P [6], and P [8] human RVs recognize the secretor epitopes of human HBGAs appears to correlated with the predominance of these genotypes in causing the vast majority (>95%) of human infections worldwide. Epidemiological and biochemical studies suggest that non-secretors and Leindividuals may be resistant to P [4] and P [8] infections [27,28,56,57]. Nonsecretors are also possible to be susceptible to infection with prevalent human RVs as other epidemiological study demonstrated no significant correlation was found between secretor status and the susceptibility to P [6] RV infections [26].…”

“…evolutionary, dependent manner. While differential immune responses, presence of other co-receptors and variable host factors may all account for the relative distribution of RV genotypes and variable vaccine efficacy in different populations [56], achieving a more complete understanding of the specificity of glycan recognition specificity of VP8*domains may help understand the limited effectiveness of the two current RV vaccines in certain populations and provide clues for the formulation of more effective vaccines. For example, based on relative effectiveness of the two current RV vaccines, Rotarix and RotaTeq, in the developing versus developed countries and their different vaccine designs, a role of the P type (VP4/VP8*) in host immune protection against RVs has been emphasized, which has led to a hypothesis on the lack of cross-protection of the P [8] based Rotarix and RotaTeq against other RV P types that are more commonly seen in the developing countries than in the developed countries could be a major reason of the low effectiveness of both vaccines observed in many developing countries (refer to our recent review article, Jiang et al 2017), although other factors, such as malnutrition, intestinal microbiota, human maternal milk of children living in many developing countries may also play roles.…”