The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies

Abstract

Background: Shedding of Salmonella Typhi or Paratyphi in the stool or urine leads to contamination of food or water, which is a prerequisite for transmission of enteric fever. Currently, there are limited data on the effect of vaccination or prior exposure on stool shedding.

Methods: Six Salmonella Typhi or Paratyphi human challenge studies were conducted between 2011 and 2017. Participants were either unvaccinated or vaccinated with 1 of 4 vaccines: Vi-polysaccharide (Vi-PS), Vi-tetanus-toxoid conjugate vaccine (Vi-TT), live oral Ty21a vaccine, or an experimental vaccine (M01ZH09). Daily stool cultures were collected for 14 days after challenge.

Results: There were 4934 stool samples collected from 430 volunteers. Participants who received Vi-PS or Vi-TT shed less than unvaccinated participants (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.15-0.77; P = .010 and OR, 0.41; 95% CI, 0.19-0.91, P = .029 for Vi-PS and Vi-TT, respectively). Higher anti-Vi immunoglobulin G titers were associated with less shedding of S. Typhi (P < .0001). A nonsignificant reduction in shedding was associated with Ty21a vaccine (OR, 0.57; 95% CI, 0.27-1.20; P = .140). Individuals previously exposed to S. Typhi shed less than previously unexposed individuals (OR, 0.30; 95% CI, 0.1-0.8; P = .016). Shedding of S. Typhi was more common than S. Paratyphi.

Conclusions: Prior vaccination with Vi vaccines, or natural infection, reduces onward transmission of S. Typhi. Field trials of Vi-TT should be designed to detect indirect protection, reflecting the consequence of reduced stool shedding observed in the human challenge model.

Keywords: Salmonella Typhi; Vi-polysaccharide vaccine; indirect effects; stool shedding; typhoid conjugate vaccine.

Figure 1.

Probability of bacterial shedding in stool by day in controlled human infection enteric fever studies. (A) N = 331 participants challenged with Salmonella Typhi according to diagnosis status. Nondiagnosed N = 145, diagnosed N = 186. (B) Unvaccinated participants exposed to oral challenge with S. Typhi (N = 197) or S. Paratyphi (N = 109) bacteria. (C) Vaccinated and unvaccinated participants challenged with 1–5 × 10⁴ colony-forming units S. Typhi wild-type bacteria according to vaccine received. Control vaccine or no vaccine (N = 158); M01ZH09, experimental typhoid vaccine (N = 32); Ty21a, live attenuated oral typhoid vaccine (N = 30); Vi-PS, Vi-polysaccharide typhoid vaccine (Typhim Vi^®, Sanofi Pasteur; N = 35); Vi-TT, Vi-tetanus toxoid conjugate vaccine (TypbarTCV^®, Bharat Biotech; N = 37)

Figure 2.

Bacterial shedding in stool after S. Typhi or S. Paratyphi challenge, according to previous exposure. P = S. Paratyphi naive (n = 39); P-P = S. Paratyphi rechallenge after previous S. Paratyphi exposure (n = 13); P-T = S. Typhi challenge after previous S. Paratyphi exposure (n = 10); T = S. Typhi challenge in S. Typhi naive participants (n = 71); T-P = S. Paratyphi challenge after previous S. Typhi exposure (n = 27); T-T = S. Typhi rechallenge after previous S. Typhi exposure (n = 27). See Supplementary Table S1 for model outputs.

Figure 3.

Relationship between days of bacterial shedding in stool after Salmonella Typhi or S. Paratyphi challenge and antibody levels prior to challenge. (A) Anti-Vi immunoglobulin (Ig) G prior to challenge with S. Typhi. (B) Anti-Hd IgG prior to challenge with S. Typhi. (C) Anti-O:2 IgG prior to challenge with S. Paratyphi. (D) Anti-S. Typhi lipopolysaccharide IgG prior to challenge with S. Typhi. Days: y-axis represents the predicted total number of days of stool shedding (out of 14). The total number of days was determined from the logistic regression model by summing across all 14 days the predicted probability for each day for each person. Abbreviation: Ig, immunoglobulin.