Association of Maternal Immunity with Rotavirus Vaccine Immunogenicity in Zambian Infants

Abstract

IntroductionLive attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV-specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with Rotarix™ (RV1).Methods420 mother-child pairs were recruited at infant age 6–12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a ≥ 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre ≥ 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion.ResultsBaseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68–0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01).ConclusionLow immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and early exposure to wild-type rotavirus infections. Potential interference of anti-RV specific IgA in breast milk and pre-vaccination serum RV specific-IgA and IgG titres with RV1 seroconversion and effectiveness requires further research.

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…If natural exposure precedes vaccination, this may induce systemic and/or local immunity that impairs vaccine immunogenicity. In the case of rotavirus, exposure to natural infection in the neonatal period is common in settings with a high transmission intensity, and appears to be greatest at times of year associated with impaired vaccine immunogenicity [23]. In a review of Rotarix trials, baseline rotavirus-specific IgA seropositivity (indicative of prior virus exposure) was rare in studies performed in Europe and North America but was observed in up to 26% of participants in higher-burden settings [174].…”

“…In a review of Rotarix trials, baseline rotavirus-specific IgA seropositivity (indicative of prior virus exposure) was rare in studies performed in Europe and North America but was observed in up to 26% of participants in higher-burden settings [174]. A reduction in vaccine immunogenicity among infants positive for rotavirus-specific IgA was recently observed during studies of Rotarix conducted in Zambia [23], Bangladesh [135] and South Africa [36], but not in India [175]. Pre-vaccination exposure seems to have a similar effect on the immunogenicity of oral cholera vaccines, including both live-attenuated [11,93,176] and inactivated vaccines [96,177,178].…”

“…This may, in turn, contribute to geographic and seasonal variation in oral vaccine performance. Rotavirus-specific IgA and neutralizing antibody titers tend to be significantly higher in breast milk obtained from mothers in low-income countries (e.g., India and Bangladesh) compared with mothers from high-income countries (e.g., the USA and Sweden) and in the rotavirus high season compared with the low season [23,55,56]. Similarly, higher levels of lactoferrin and lactadherin have been observed in breast milk obtained from Indian and South-African women compared with North-American women [57], although these innate immune factors did not correlate with RotaTeq immunogenicity in a recent study in Nicaragua [58].…”

“…OPV is less immunogenic when given during warm, humid months [21,22], while Rotarix was shown to have lower immunogenicity during the cool, dry season in Zambia [23]. Oral poliovirus and rotavirus vaccines may be less immunogenic when administered in early infancy (e.g., before 6 weeks of age) compared with later infancy, although the size of this effect is small [24][25][26][27] and may be reversed at older ages [28].…”

Contribution of Maternal Immunity to Decreased Rotavirus Vaccine Performance in Low- and Middle-Income Countries

“…However, there is consistent evidence from clinical trials that RV have lower efficacies in low-and middle-income countries (LMIC): vaccine efficacies are 80 to 90% in high-income countries (HIC) and 40 to 60% in LMIC (3-8). Indeed, there is growing evidence from vaccine effectiveness studies emerging from the field that in real-life use, vaccine effectiveness is also consistently lower in LMIC (9-12).In addition to the differences in observed vaccine efficacy and effectiveness, there are also marked differences in vaccine-elicited immunity as reported by various vaccine-elicited antibody titers following rotavirus immunization (13)(14)(15)(16)(17)(18). A number of hypotheses have been put forward to explain the differences in efficacy and vaccineelicited immunity between HIC and LMIC.…”