Immunogenicity of rotavirus vaccine (RotarixTM) in infants with environmental enteric dysfunction

Abstract

IntroductionDeployment of rotavirus vaccines has contributed to significant declines in diarrheal morbidity and mortality globally. Unfortunately, vaccine performance in low-middle income countries (LMICs) is generally lower than in developed countries. The cause for this has been associated with several host and maternal factors including poor water sanitation and hygiene (WASH) status, which are predominant in LMICs. More recently, environmental enteric dysfunction (EED) has specifically been hypothesized to contribute to poor vaccine uptake and response. The aim of this study was to examine the association between serological biomarkers of EED and seroconversion to rotavirus vaccine in Zambian infants.MethodsThis was a retrospective cohort study of 142 infants who had been fully immunized with Rotarix™, and had known seroconversion status. Seroconversion was defined as 4-fold or more increase in rotavirus-specific IgA titres between pre-vaccination and one month post-dose two vaccination. We performed ELISA assays to assess soluble CD14 (sCD14), Endotoxin Core IgG Antibodies (EndoCAb), intestinal fatty acid binding protein (i-FABP) and Zonulin according to the manufacturers protocols. Generalised linear model with family-poisson, link-log and robust standard error was used to estimate the independent effects of biomarkers on seroconversion adjusting for important cofounders.ResultsThe median concentration of Zonulin, Soluble CD14, EndoCaB, and IFABP were 209.3 (IQR = 39.7, 395.1), 21.5 (IQR = 21.5, 21.5), 0.3 (IQR = 0.3, 0.3), and 107.7 (IQR = 6.4, 1141.4) respectively. In multivariable analyses adjusting for the independent effect of other biomarkers and confounders (i.e. age of child at vaccination, breast-milk anti-rotavirus IgA, infant serum anti-rotavirus IgG, and IgA seropositivity at baseline), there was strong evidence of about 24% increase in seroconversion due to doubling Zonulin concentration (Adjusted risk ratio (aRR) = 1.24; 95% CI = 1.12 to1.37; p<0.0001). Similarly, we found about 7% increase in seroconversion due to doubling IFABP concentration (aRR = 1.07; 95% CI = 1.02 to 1.13; p = 0.006).ConclusionWe found that high levels of zonulin and IFABP played a role in seroconversion. It is plausible that increased gut permeability in EED allows greater uptake of the live virus within the vaccine, but later consequences result in deleterious local structural distortions and malabsorption syndromes.

Exploring the Relationship Between Environmental Enteric Dysfunction and Oral Vaccine Responses

“…In southern India, neither EndoCAb nor sCD14 were associated with OPV3 seroconversion or shedding [ 52 ]. The same was true in a Zambian study, where no association was seen for either EndoCAb or sCD14 and seroconversion to RVV [ 55 ].…”

“…Four of the eight studies reported overall a negative association between EED and oral vaccine responses, with elevated markers of EED associated with reduced oral vaccine performance [ 51 , 53 , 54 , 56 ]. Two studies showed no significant association [ 16 , 52 ] and two studies concluded that EED was positively correlated with immunogenicity to oral vaccine antigens [ 55 , 57 ]. The majority of studies relied on vaccine immunogenicity as a proxy for oral vaccine efficacy.…”

“…Zonulin is a protein that binds to specific receptors on intestinal epithelial cells inducing the disassembly of tight junctions and thereby increasing permeability. One study, among Zambian infants, measured zonulin levels at the time of oral vaccine administration and showed a positive association between zonulin and subsequent Rotarix seroconversion [ 55 ]. Therefore, in contrast to the other four studies showing no or negative associations, this study is the first to propose that increased intestinal permeability may actually enhance oral vaccine seroconversion.…”

“…Two studies found a positive association between levels of I-FABP and oral vaccine responses. One with cholera toxin-specific effector memory T cells in Bangladeshi children, although this association was not observed for other immunological markers of cholera response [ 57 ]; the other, with rotavirus IgA in Zambian infants [ 55 ]. Together, they suggest that gut epithelial injury can enhance immune responses to oral cholera and rotavirus vaccines, respectively.…”

Efficacy and Effectiveness of Rotavirus Vaccine on Incidence of Diarrhoea among Children: A Meta-analysis

“…Various factors have been postulated as contributing to this observed effect. Host factors such as genetics, malnutrition, enteric environmental dysfunction (EED), maternal factors such as antibodies passed onto the infant, various components of breast milk, exposure to HIV and other environmental factors including poor sanitation, concurrent infection with other pathogens have all been postulated to influence vaccine effectiveness [86][87][88][89][90][91][92][93][94][95][96][97].…”