Rotavirus-Specific Immunoglobulin A Responses Are Impaired and Serve as a Suboptimal Correlate of Protection Among Infants in Bangladesh

Abstract

BackgroundRotavirus (RV)–specific immunoglobulin A (IgA) responses following oral RV vaccination are impaired in low-income countries, where the utility of RV-IgA as a correlate of protection (CoP) remains unclear. In a monovalent oral RV vaccine (Rotarix) efficacy trial among infants in Dhaka, Bangladesh, we identified factors associated with poor RV-IgA responses and explored the utility of RV-IgA as a CoP.MethodsInfants were randomized to receive Rotarix or no Rotarix at 10 and 17 weeks of life and followed with active diarrheal surveillance. RV-IgA concentration, seroconversion, and seropositivity were determined at 18 weeks of life and analyzed for correlation(s) with rotavirus diarrhea (RVD) and for contribution to Rotarix vaccine effect.ResultsAmong vaccinated infants, overall RV-IgA geometric mean concentration was 21 U/mL; only 27% seroconverted and 32% were seropositive after vaccination. Increased RV-specific maternal antibodies significantly impaired immunogenicity. Seroconversion was associated with reduced risk of RVD through 1 year of life, but RV-IgA seropositivity only explained 7.8% of the vaccine effect demonstrated by the clinical endpoint (RVD).ConclusionsRV-IgA responses were low among infants in Bangladesh and were significantly impaired by maternal antibodies. RV-IgA is a suboptimal CoP in this setting; an improved CoP for RV in low-income countries is needed.Clinical Trials RegistrationNCT01375647.

Maternal-infant rotavirus-specific antibody kinetics to inform timing of vaccine boosting in Malawi: An observational study

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ].…”

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ]. Those who responded to the vaccine maintained higher levels of both rotavirus-specific IgA and IgG over time, making them less likely to succumb to severe gastroenteritis if exposed to rotavirus [ 21 , 22 , 27 ].…”

“…Although this study was conducted in Malawi, the findings of elevated levels of maternal-derived rotavirus-specific IgG interfering with oral rotavirus vaccine (ORV) immunogenicity, suboptimal vaccine-induced IgA responses in early infancy, and an increase in rotavirus-associated infections and seroconversions beyond six months of age, are consistent with patterns reported in other LMICs [ 13 , 21 , 23 , 24 , 49 , 50 ]. This concordance suggests that the identified window for enhanced vaccine immunogenicity and the potential utility of a booster dose may be broadly relevant across similar high-burden settings.…”

Maternal-infant rotavirus-specific antibody kinetics to inform timing of vaccine boosting in Malawi: An observational study

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ].…”

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ]. Those who responded to the vaccine maintained higher levels of both rotavirus-specific IgA and IgG over time, making them less likely to succumb to severe gastroenteritis if exposed to rotavirus [ 21 , 22 , 27 ].…”

“…Although this study was conducted in Malawi, the findings of elevated levels of maternal-derived rotavirus-specific IgG interfering with oral rotavirus vaccine (ORV) immunogenicity, suboptimal vaccine-induced IgA responses in early infancy, and an increase in rotavirus-associated infections and seroconversions beyond six months of age, are consistent with patterns reported in other LMICs [ 13 , 21 , 23 , 24 , 49 , 50 ]. This concordance suggests that the identified window for enhanced vaccine immunogenicity and the potential utility of a booster dose may be broadly relevant across similar high-burden settings.…”

The Impact of Improved Water, Sanitation, and Hygiene on Oral Rotavirus Vaccine Immunogenicity in Zimbabwean Infants: Substudy of a Cluster-randomized Trial

“…RVV seroconversion in the WASH group was 39% at best (Supplementary Table 5), which is still far lower than in developed countries (67%–98%) [5]. It is, however, consistent with recent data from other developing countries: RVV seroconversion was 24% in Malawi [32] and 27% in Bangladesh [33]. Taken together, there are important implications of these findings.…”

Oral rotavirus vaccine shedding as a marker of mucosal immunity

“…Lack of association between post-dose 2 shedding and plasma RVA-IgA seropositivity suggests that lack of shedding may detect mucosal immunity that may not be always be reflected in plasma/serum antibody measurement. Nevertheless, inhibition of fecal shedding in our model did not appear to offer any appreciable advantage over RVA-IgA, which is currently the best available CoP for RVA, despite its limitations 3 , 20 . However, the RVA-IgA assay predominantly measures antibodies against the RVA middle capsid structural protein VP6, which is the immunodominant antigen in the humoral response to RVA.…”

Maternal-infant rotavirus-specific antibody kinetics to inform timing of vaccine boosting in Malawi: An observational study

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ].…”

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ]. Those who responded to the vaccine maintained higher levels of both rotavirus-specific IgA and IgG over time, making them less likely to succumb to severe gastroenteritis if exposed to rotavirus [ 21 , 22 , 27 ].…”

“…Although this study was conducted in Malawi, the findings of elevated levels of maternal-derived rotavirus-specific IgG interfering with oral rotavirus vaccine (ORV) immunogenicity, suboptimal vaccine-induced IgA responses in early infancy, and an increase in rotavirus-associated infections and seroconversions beyond six months of age, are consistent with patterns reported in other LMICs [ 13 , 21 , 23 , 24 , 49 , 50 ]. This concordance suggests that the identified window for enhanced vaccine immunogenicity and the potential utility of a booster dose may be broadly relevant across similar high-burden settings.…”

The Impact of Improved Water, Sanitation, and Hygiene on Oral Rotavirus Vaccine Immunogenicity in Zimbabwean Infants: Substudy of a Cluster-randomized Trial

“…RVV seroconversion in the WASH group was 39% at best (Supplementary Table 5), which is still far lower than in developed countries (67%–98%) [5]. It is, however, consistent with recent data from other developing countries: RVV seroconversion was 24% in Malawi [32] and 27% in Bangladesh [33]. Taken together, there are important implications of these findings.…”

Oral rotavirus vaccine shedding as a marker of mucosal immunity

“…Lack of association between post-dose 2 shedding and plasma RVA-IgA seropositivity suggests that lack of shedding may detect mucosal immunity that may not be always be reflected in plasma/serum antibody measurement. Nevertheless, inhibition of fecal shedding in our model did not appear to offer any appreciable advantage over RVA-IgA, which is currently the best available CoP for RVA, despite its limitations 3 , 20 . However, the RVA-IgA assay predominantly measures antibodies against the RVA middle capsid structural protein VP6, which is the immunodominant antigen in the humoral response to RVA.…”

Maternal-infant rotavirus-specific antibody kinetics to inform timing of vaccine boosting in Malawi: An observational study

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ].…”

“…The low Rotarix seroconversion rate shown in this study is consistent with other studies previously conducted in Malawi and other LMICs [ 4 , 13 , 24 , 27 , 37 , 38 ]. Similar to other studies, our findings show high maternal antibody levels at vaccination were associated with lower levels of vaccine-induced rotavirus-specific IgA antibodies in infants [ 13 , 24 ]. Those who responded to the vaccine maintained higher levels of both rotavirus-specific IgA and IgG over time, making them less likely to succumb to severe gastroenteritis if exposed to rotavirus [ 21 , 22 , 27 ].…”

“…Although this study was conducted in Malawi, the findings of elevated levels of maternal-derived rotavirus-specific IgG interfering with oral rotavirus vaccine (ORV) immunogenicity, suboptimal vaccine-induced IgA responses in early infancy, and an increase in rotavirus-associated infections and seroconversions beyond six months of age, are consistent with patterns reported in other LMICs [ 13 , 21 , 23 , 24 , 49 , 50 ]. This concordance suggests that the identified window for enhanced vaccine immunogenicity and the potential utility of a booster dose may be broadly relevant across similar high-burden settings.…”

The Impact of Improved Water, Sanitation, and Hygiene on Oral Rotavirus Vaccine Immunogenicity in Zimbabwean Infants: Substudy of a Cluster-randomized Trial

“…RVV seroconversion in the WASH group was 39% at best (Supplementary Table 5), which is still far lower than in developed countries (67%–98%) [5]. It is, however, consistent with recent data from other developing countries: RVV seroconversion was 24% in Malawi [32] and 27% in Bangladesh [33]. Taken together, there are important implications of these findings.…”

Oral rotavirus vaccine shedding as a marker of mucosal immunity

“…Lack of association between post-dose 2 shedding and plasma RVA-IgA seropositivity suggests that lack of shedding may detect mucosal immunity that may not be always be reflected in plasma/serum antibody measurement. Nevertheless, inhibition of fecal shedding in our model did not appear to offer any appreciable advantage over RVA-IgA, which is currently the best available CoP for RVA, despite its limitations 3 , 20 . However, the RVA-IgA assay predominantly measures antibodies against the RVA middle capsid structural protein VP6, which is the immunodominant antigen in the humoral response to RVA.…”