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

Abstract

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.

Figure 1.

Selection of samples for testing from the parent ROTASIIL efficacy trial.

Figure 2.

Attributable incidence (AI) per 1,000 child-years for severe gastroenteritis by study group and overall in children less than 24 months old. BRV-PV group: AI in participants who were administered the vaccine; Overall burden: overall AI of various pathogens for severe diarrhea; Placebo group: AI in participants who were administered placebo. Dashed lines indicate the 95% confidence intervals for each estimate. C. jejuni/coli = Campylobacter jejuni/coli; ST ETEC = stable toxin enterotoxigenic Escherichia coli; V. cholerae = Vibrio cholerae.

Figure 3.

Attributable incidence per 1,000 child-years for severe gastroenteritis in children less than 24 months old stratified by age. Dashed lines indicate the 95% confidence intervals for each estimate. C. jejuni/coli = Campylobacter jejuni/coli; ST ETEC = stable toxin enterotoxigenic Escherichia coli; V. cholerae = Vibrio cholerae.

Figure 4.

(A) Clinical profile of gastroenteritis attributable to specific pathogens. (B) Association between co-infecting pathogens and the clinical profile of rotavirus gastroenteritis. OR Virus = sum of AFs for adenovirus 40/41, norovirus GII, sapovirus, and astrovirus; Bacteria = sum of AFs for Shigella/EIEC, Vibrio cholerae, ST-ETEC, Campylobacter jejuni/coli, typical enteropathogenic Escherichia coli, Aeromonas, and Salmonella; Protozoa = sum of AFs for Cryptosporidium spp. and Entamoeba histolytica. AF = attributable fraction; EIEC = enteroinvasive E. coli; OR = odds ratio; ST-ETEC = stable toxin enterotoxigenic E. coli.