Evaluating Associations Between Vaccine Response and Malnutrition, Gut Function, and Enteric Infections in the MAL-ED Cohort Study: Methods and Challenges

SUPPLEMENT ARTICLE Evaluating Associations Between Vaccine Response and Malnutrition, Gut Function, and Enteric Infections in the MAL-ED Cohort Study: Methods and Challenges Christel Hoest,1 Jessica C. Seidman,1 William Pan,2 Ramya Ambikapathi,1 Gagandeep Kang,3 Margaret Kosek,4 Stacey Knobler,1 Carl J. Mason,5 Mark Miller,1 and The MAL-ED Network Investigatorsa 1 Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland; Department of Environmental Science and Policy and the Duke Global Health Institute, Duke University, Durham, North Carolina; 3Christian Medical College, Vellore, India; 4Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; and 5 Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand 2 Most vaccine assessments have occurred in well-nourished populations of higher socioeconomic status. However, vaccines are often used in populations with high incidences of malnutrition and infections, in whom the effectiveness of some vaccines is inferior for unknown reasons. The degree and extent of vaccine underperformance have not been systematically studied for most vaccines across differing epidemiologic settings. This paper outlines the methods used and challenges associated with measuring immunological responses to oral vaccines against poliovirus and rotavirus, and parenteral vaccines against pertussis, tetanus, and measles in an observational study that monitored daily illness, monthly growth, intestinal inflammation and permeability, pathogen burden, dietary intake, and micronutrient status in children in 8 countries. This evaluation of vaccine response in the context of low- and middle-income countries is intended to address the gaps in knowledge of the heterogeneity in vaccine response in diverse epidemiological settings and the interplay between infections, nutrition, and immune response. Keywords. vaccines; malnutrition; enteric infections; gut function; MAL-ED. Multiple factors are associated with immune response to vaccines administered during childhood as measured by antibody titers. Among the most important is the timing of antigen exposure(s), including age of first presentation and the interval between vaccine doses. Other factors may include infections (recent and/or frequent diarrhea, respiratory illness, other concurrent infections) [1, 2], malnutrition, particularly micronutrient deficiencies (vitamin A, iron, and zinc deficiency), stunting and wasting [3–5], intestinal dysfunction a MAL-ED Network Investigators are listed in the Supplementary Appendix. Correspondence: Mark Miller, MD, Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, 16 Center Drive Bethesda, MD 20892 (). Clinical Infectious Diseases® 2014;59(S4):S273–9 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: . DOI: 10.1093/cid/ciu611 (malabsorption, inflammation, overgrowth) [6], maternal exposures (maternal antibody level, breastfeeding) [7], and early exposures to environmental antigens influenced by high population density, sanitation, or siblings [8]. The amount of antigen presented to the immune system is also affected by the route of delivery. The quantity of antigen presented is likely to be less variable for parenteral vaccines, where a fixed dosage of antigen is injected, as compared to orally administered vaccines where the quantity of antigen presented to the immune system may be influenced by breastfeeding, diet, and enteric infection [9, 10]. Orally administered vaccines against polio (OPV), cholera, and rotavirus elicit poorer immune responses in lower socioeconomic settings [11–16]; however, the specific reasons for this lack of an adequate immune response are poorly understood. With the continued administration of OPV, and the Vaccine Response in MAL-ED Cohort Study • CID 2014:59 (Suppl 4) • S273 METHODS Vaccine Schedules The MAL-ED cohort study was observational and vaccines were not supplied or administered by study staff at the 8 study sites. Table 1 lists the national vaccine schedules followed for each of the study sites. Bacillus Calmette-Guerin (BCG), diphtheriapertussis-tetanus (DPT), hepatitis B, oral polio vaccine (OPV), Haemophilus influenzae type B (Hib), and measles vaccine were administered at all sites; whereas, rotavirus, pneumococcal conjugate (PCV), and yellow fever (YF) vaccines were administered at 2 or more sites. Hib was administered at all sites throughout the study period except INV, where it was introduced in December 2011. In South Africa, inactivated polio vaccine (IPV) was administered as part of the EPI schedule along with OPV. In India and Pakistan, national vaccination campaigns using OPV occurred frequently, permitting measurement of response to a variable number of OPV doses. Vitamin A supplementation was coadministered according to the national vaccination schedule in 7 of 8 sites (Table 1). receipt through routine immunization programs varied. Data on the frequency and timing of vaccine administration were actively collected by MAL-ED field-workers during monthly household visits, ideally within a 2-day window of the monthly birth anniversary [27]. During the monthly household visit, MAL-ED field-workers recorded the vaccines administered and dates of administration on the Monthly Form A/B (MOA/ MOB). The information was ideally obtained from the vaccine card; however, when vaccine cards were not available, clinical records were utilized where possible. If neither vaccine nor clinical records were available, field-workers asked the mother or caregiver if vaccines were administered since the previous monthly visit, and inquired about the type and the date of vaccine administration. Additionally, a quarterly assessment of vaccines administered and dates of administration using the Vaccine Information Form (VIF) functioned as a validation tool for the data collected on the monthly forms. The source of vaccine data was also collected on the VIF (ie, vaccine record, clinical record, mother or caregiver’s report) for all vaccines administered. Natural Exposure Natural exposure to a vaccine-preventable disease (VPD) could influence antibody titers. The MAL-ED study design included a twice-weekly visit and monitored for any reported or referred illness [17]. Although no environmental sampling was conducted, this active surveillance allowed for the possibility to detect whether mild or severe VPD was present in individuals or the occurrence of a VPD outbreak. Wild polioviruses were not known to be circulating in any of our study sites, with the possible exception of the Pakistan site. We were not able to ascertain whether wild viruses were circulating in Pakistan but had not received any reports of (...truncated)