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Enteric virome negatively affects seroconversion following oral rotavirus vaccination in a longitudinally sampled cohort of Ghanaian infants.

ABSTRACT: Rotavirus vaccines (RVVs) have substantially diminished mortality from severe rotavirus (RV) gastroenteritis but are significantly less effective in low- and middle-income countries (LMICs), limiting their life-saving potential. The etiology of RVV's diminished effectiveness remains incompletely understood, but the enteric microbiota has been implicated in modulating immunity to RVVs. Here, we analyze the enteric microbiota in a longitudinal cohort of 122 Ghanaian infants, evaluated over the course of 3 Rotarix vaccinations between 6 and 15 weeks of age, to assess whether bacterial and viral populations are distinct between non-seroconverted and seroconverted infants. We identify bacterial taxa including Streptococcus and a poorly classified taxon in Enterobacteriaceae as positively correlating with seroconversion. In contrast, both bacteriophage diversity and detection of Enterovirus B and multiple novel cosaviruses are negatively associated with RVV seroconversion. These findings suggest that virome-RVV interference is an underappreciated cause of poor vaccine performance in LMICs.

SUBMITTER: Kim AH

PROVIDER: S-EPMC8763403 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Enteric virome negatively affects seroconversion following oral rotavirus vaccination in a longitudinally sampled cohort of Ghanaian infants.

Kim Andrew HyoungJin AH Armah George G Dennis Francis F Wang Leran L Rodgers Rachel R Droit Lindsay L Baldridge Megan T MT Handley Scott A SA Harris Vanessa C VC

Cell host & microbe 20211220 1

Rotavirus vaccines (RVVs) have substantially diminished mortality from severe rotavirus (RV) gastroenteritis but are significantly less effective in low- and middle-income countries (LMICs), limiting their life-saving potential. The etiology of RVV's diminished effectiveness remains incompletely understood, but the enteric microbiota has been implicated in modulating immunity to RVVs. Here, we analyze the enteric microbiota in a longitudinal cohort of 122 Ghanaian infants, evaluated over the cou ...[more]

PMID: 34932985

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Project description:BackgroundThe underperformance of oral vaccines in children of low- and middle-income countries is partly attributable to underlying environmental enteric dysfunction (EED).MethodologyWe conducted a longitudinal, community-based study to evaluate the association of oral rotavirus vaccine (Rotarix®) seroconversion with growth anthropometrics, EED biomarkers and intestinal enteropathogens in Pakistani infants. Children were enrolled between three to six months of their age based on their nutritional status. We measured serum anti-rotavirus immunoglobulin A (IgA) at enrollment and nine months of age with EED biomarkers and intestinal enteropathogens.ResultsA total of 391 infants received two doses of rotavirus (RV) vaccine. 331/391 provided paired blood samples. Of these 331 children, 45% seroconverted at 9 months of age, 35% did not seroconvert and 20% were seropositive at baseline. Non-seroconverted children were more likely to be stunted, wasted and underweight at enrollment. In univariate analysis, insulin-like growth factor (IGF) concentration at 6 months were higher in seroconverters, median (25th, 75th percentile): 26.3 (16.5, 43.5) ng/ml vs. 22.5 (13.6, 36.3) ng/ml for non-seroconverters, p-value = 0.024. At nine months, fecal myeloperoxidase (MPO) concentrations were significantly lower in seroconverters, 3050(1250, 7587) ng/ml vs. 4623.3 (2189, 11650) ng/ml in non-seroconverted children, p-value = 0.017. In multivariable logistic regression analysis, alpha-1 acid glycoprotein (AGP) and IGF-1 concentrations were positively associated with seroconversion at six months. The presence of sapovirus and rotavirus in fecal samples at the time of rotavirus administration, was associated with non-seroconversion and seroconversion, respectively.ConclusionWe detected high baseline RV seropositivity and impaired RV vaccine immunogenicity in this high-risk group of children. Healthy growth, serum IGF-1 and AGP, and fecal shedding of rotavirus were positively associated with RV IgA seroconversion following immunization, whereas the presence of sapovirus was more common in non-seroconverters.Trial registrationClinical Trials ID: NCT03588013.

Project description: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.

Project description:BackgroundRotavirus gastroenteritis remains a leading cause of morbidity and mortality despite the introduction of vaccines. Research shows there are several factors contributing to the reduced efficacy of rotavirus vaccines in low- and middle-income settings. Proposed factors include environmental enteric dysfunction (EED), malnutrition, and immune dysfunction. This study aimed to assess the effect of these factors on vaccine responses using a machine learning lasso approach.MethodsSerum samples from two rotavirus clinical trials (CVIA 066 n = 99 and CVIA 061 n = 124) were assessed for 11 analytes using the novel Micronutrient and EED Assessment Tool (MEEDAT) multiplex ELISA. Immune responses to oral rotavirus vaccines (Rotarix, Rotavac, and Rotavac 5D) as well as a parenteral rotavirus vaccine (trivalent P2-VP8) were also measured and machine learning using the lasso approach was then applied to investigate any associations between immune responses and environmental enteric dysfunction, systemic inflammation, and growth hormone resistance biomarkers.ResultsBoth oral and parenteral rotavirus vaccine responses were negatively associated with retinol binding protein 4 (RBP4), albeit only weakly for oral vaccines. The parenteral vaccine responses were positively associated with thyroglobulin (Tg) and histidine-rich protein 2 (HRP2) for all three serotypes (P8, P6 and P4), whilst intestinal fatty acid binding protein (I-FABP) was negatively associated with P6 and P4, but not P8, and soluble transferrin receptor (sTfR) was positively associated with P6 only.ConclusionMEEDAT successfully measured biomarkers of growth, systemic inflammation, and EED in infants undergoing vaccination, with RBP4 being the only analyte associated with both oral and parenteral rotavirus vaccine responses. Tg and HRP2 were associated with responses to all three serotypes in the parenteral vaccine, while I-FABP and sTfR results indicated possible strain specific immune responses to parenteral immunization.

Project description:Live oral rotavirus vaccines have significantly reduced rotavirus-related diarrheal morbidity and mortality globally, but low efficacy of these vaccines is observed in low-income countries where disease burden is highest. The biological basis of rotavirus vaccine failure remains unknown but likely includes both microbial and host factors. We investigated associations between 19 candidate SNPs in the TLR3, TLR7, TLR8, DDX58 and IFIH1 genes that play a role in innate immunity, and seroconversion in Black South African infants after vaccination with Rotarix at 6 and 14 weeks of age. Rotavirus-specific IgA antibody titre was measured by ELISA before each vaccine dose and four weeks after the second dose, and seroconversion was defined as a four-fold or greater increase in IgA antibody titre at 18 weeks of age when compared to pre-vaccine titres. A total of 95/138 individuals seroconverted (68.8%) and seroconversion was significantly affected by birthweight (P = 0.010), pre-vaccine IgA and IgG titres (P = 0.0002 and P = 0.007 respectively). rs2159377 SNP in TLR8 was significantly associated with seroconversion in a univariate allelic model (P = 0.015) and was borderline significant in a multivariable logistic regression adjusted for birthweight and pre-vaccine titres (P = 0.071), although these values did not remain significant after Bonferroni correction. A haplotype of six SNPs on the X chromosome across TLR7 and TLR8, including rs179008 and rs5935438 minor alleles, was significantly associated with seroconversion in a univariate model (P = 0.042), but not in a multivariable model or after Bonferroni correction. Epistatic interaction between rs5743305 in TLR3 and rs55789327 in DDX58 was significantly associated with seroconversion (P = 0.034) but a genetic risk score constructed from all 19 minor alleles was not. Our results suggest that TLR variants may influence IgA antibody production and seroconversion to Rotarix vaccine in South Africans. Host genetic variation contributes to the varying immunogenicity of live oral rotavirus vaccines.

Dataset Information

Enteric virome negatively affects seroconversion following oral rotavirus vaccination in a longitudinally sampled cohort of Ghanaian infants.

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Enteric virome negatively affects seroconversion following oral rotavirus vaccination in a longitudinally sampled cohort of Ghanaian infants.

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