Biomarkers of Environmental Enteropathy are Positively Associated with Immune Responses to an Oral Cholera Vaccine in Bangladeshi Children

Abstract

Environmental enteropathy (EE) is a poorly understood condition that refers to chronic alterations in intestinal permeability, absorption, and inflammation, which mainly affects young children in resource-limited settings. Recently, EE has been linked to suboptimal oral vaccine responses in children, although immunological mechanisms are poorly defined. The objective of this study was to determine host factors associated with immune responses to an oral cholera vaccine (OCV). We measured antibody and memory T cell immune responses to cholera antigens, micronutrient markers in blood, and EE markers in blood and stool from 40 Bangladeshi children aged 3–14 years who received two doses of OCV given 14 days apart. EE markers included stool myeloperoxidase (MPO) and alpha anti-trypsin (AAT), and plasma endotoxin core antibody (EndoCab), intestinal fatty acid binding protein (i-FABP), and soluble CD14 (sCD14). We used multiple linear regression analysis with LASSO regularization to identify host factors, including EE markers, micronutrient (nutritional) status, age, and HAZ score, predictive for each response of interest. We found stool MPO to be positively associated with IgG antibody responses to the B subunit of cholera toxin (P = 0.03) and IgA responses to LPS (P = 0.02); plasma sCD14 to be positively associated with LPS IgG responses (P = 0.07); plasma i-FABP to be positively associated with LPS IgG responses (P = 0.01) and with memory T cell responses specific to cholera toxin (P = 0.01); stool AAT to be negatively associated with IL-10 (regulatory) T cell responses specific to cholera toxin (P = 0.02), and plasma EndoCab to be negatively associated with cholera toxin-specific memory T cell responses (P = 0.02). In summary, in a cohort of children 3–14 years old, we demonstrated that the majority of biomarkers of environmental enteropathy were positively associated with immune responses after vaccination with an OCV.

Pathophysiology of environmental enteric dysfunction and its impact on oral vaccine efficacy

“…In this study, fecal myeloperoxidase (MPO) and plasma sCD14 were positively associated with the development of plasma antibody responses to vaccination, whereas fecal AAT and plasma EndoCab were negatively associated with cholera toxin-specific T cell responses, including IL-10 production. 87 In a large (n = 754) trial in India of azithromycin given from 11 to 14 days before vaccination, the intervention had no effect on OPV responses. 29 It did, however, reduce fecal MPO by 26% and α 1 -antitrypsin by 19%, suggesting that enteropathy and vaccine responses can be dissociated.…”

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…Owing to the invasive nature of intestinal biopsies, studies of EED have tended to rely on serum and fecal biomarkers, such as those indicative of small bowel bacterial overgrowth (e.g., hydrogen breath test), gut inflammation (e.g., fecal calprotectin and myeloperoxidase), microbial translocation (e.g., serum EndoCab) and mucosal permeability (e.g., lactulose/mannitol test). To date, the study of these biomarkers has failed to yield any consistent associations between EED and oral vaccine performance [28,98,[170][171][172][173], as discussed in detail elsewhere [Church et al, In Preparation].…”

“…[65], [98], [108], [135], [171], [196] [67], [133][134][135], [198][199][200][201] [8], [181], [182], [201], [203], [204] [28], [92], [93], [128], [131], [137], [138], [140], [130], [131], [157], [202] [ [43][44][45], [49], [61][62][63][64][65][66][67][68][69][70], [197] [ [155][156][157] [28], [98], [170][171][172]…”

“…Several studies have documented increased immunogenicity or protective efficacy following administration of CVD 103-HgR to individuals with O versus non-O blood groups [11,[91][92][93], though a recent study in North-American adults failed to replicate these findings [94]. Meanwhile, trials of oral-killed whole-cell vaccines have yielded conflicting results when comparing immunogenicity or efficacy according to ABO blood type, including observations of either improved or impaired response in individuals with blood group O (vs non-O) [32,95,96], or no difference according to blood group [97,98]. It is worth noting that regions in which oral cholera vaccine candidates have underperformed (e.g., Thailand and Indonesia) do not differ markedly in blood group O frequency from those in which a robust vaccine response is seen (e.g., North America) [11,99].…”

The Burden of Enteropathy and “Subclinical” Infections

“…At least 40 different biomarkers or metabolites have been investigated as potential indicators for EE that is clinically significant enough to result in growth faltering (Table 1). 6,29,33–39 These include markers of disrupted intestinal barrier or absorptive function (e.g. lactulose and mannitol, rhamnose, or D-xylose absorption and excretion in the urine, alpha-1-antitrypsin in stool, tight junction components in plasma or intestinal tissue staining); translocation of microbes or their products (e.g.…”