Effect of Non-Rotavirus Enteric Infections on Vaccine Efficacy in a ROTASIIL Clinical Trial

Dilip Abraham The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India;

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Prasanna Samuel Premkumar The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India;

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James A. Platts-Mills Infectious Diseases and International Health, University of Virginia, Charlottsville, Virginia;

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Tushar Tewari Center for Vaccine Innovation and Access, PATH, New Delhi, India;

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Niranjan Bhat Center for Innovation and Access, PATH, Washington, District of Columbia

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Revathi Rajendiran The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India;

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Hemavathi Gunalan The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India;

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Gagandeep Kang The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India;

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This study examined the relative proportion of enteric pathogens associated with severe gastroenteritis (GE) among children younger than 2 years in a phase III efficacy trial of the ROTASIIL® vaccine in India, evaluated the impact of co-infections on vaccine efficacy (VE), and characterized the association between specific pathogens and the clinical profile of severe GE. Stored stool samples collected from cases of severe GE in the phase III trial were tested by quantitative polymerase chain reaction using TaqMan Array Cards. Etiology was attributed by calculating the adjusted attributable fraction (AF) for each pathogen. A test-negative design was used to estimate VE. The pathogens with the highest AFs for severe diarrhea were rotavirus (23.5%), adenovirus 40/41 (17.0%), Shigella spp./enteroinvasive Escherichia coli, norovirus GII, enterotoxigenic E. coli, and Cryptosporidium spp. A considerable proportion of the disease in these children could not be explained by the pathogens tested. Severe GE cases associated with rotavirus and Shigella spp. were more likely to have a longer duration of vomiting and diarrhea, respectively. Cases attributed to Cryptosporidium spp. were more severe and required hospitalization. In the intention-to-treat population, VE was estimated to be 43.9% before and 46.5% after adjustment for co-infections; in the per-protocol population, VE was 46.7% before and 49.1% after adjustments. Rotavirus continued to be the leading cause of severe GE in this age group. The adjusted VE estimates obtained did not support co-infections as a major cause of lower vaccine performance in low- and middle-income countries.

Author Notes

Financial support: This project was funded by PATH (contract no. GAT.1822-01664798-CRT) and was a collaboration with PATH investigators, who were involved in the planning of the study and interpretation of its results. PATH received financial support for this work from the Bill & Melinda Gates Foundation (grant no. INV-006706). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License was assigned to the author accepted manuscript version that arose from this submission. The funders had no role in study design, analysis, preparation of the manuscript, or decision to publish.

Authors’ addresses: Dilip Abraham, Revathi Rajendiran, Hemavathi Gunalan, and Gangadeep Kang, The Wellcome Trust Research Laboratory, Division of Gastrointestinal Science, Christian Medical College, Vellore, Tamil Nadu, India, E-mails: dilip.abraham@cmcvellore.ac.in, revathigangana@gmail.com, heama.vathi@gmail.com, and gkang@cmcvellore.ac.in. Prasanna Samuel Premkumar, Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India, and Department of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India, E-mail: prasanna.samuel@cmcvellore.ac.in. James A. Platts-Mills, Division of Infectious Diseases and International Health, University of Virginia, Charlottsville, VA, E-mail: jp5t@virginia.edu. Tushar Tewari, Center for Vaccine Innovation and Access at PATH, New Delhi, India, E-mail: ttewari@path.org. Niranjan Bhat, Center for Vaccine Innovation and Access, PATH, Washington DC, E-mail: nbhat@path.org.

Address correspondence to Gagandeep Kang, Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Rd., Vellore 632004, Tamil Nadu, India. E-mail: gkang@cmcvellore.ac.in
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