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

Malick M Gibani, Merryn Voysey, Celina Jin, Claire Jones, Helena Thomaides-Brears, Elizabeth Jones, Philip Baker, Marcus Morgan, Alison Simmons, Melita A Gordon, Vincenzo Cerundolo, Virginia E Pitzer, Brian Angus, Myron M Levine, Thomas C Darton, Andrew J Pollard, Malick M Gibani, Merryn Voysey, Celina Jin, Claire Jones, Helena Thomaides-Brears, Elizabeth Jones, Philip Baker, Marcus Morgan, Alison Simmons, Melita A Gordon, Vincenzo Cerundolo, Virginia E Pitzer, Brian Angus, Myron M Levine, Thomas C Darton, Andrew J Pollard

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.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
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.
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.
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.

References

    1. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004; 82:346–53.
    1. Crump JA, Mintz ED. Global trends in typhoid and paratyphoid fever. Clin Infect Dis 2010; 50:241–6.
    1. Buckle GC, Walker CLF, Black RE. Typhoid fever and paratyphoid fever: systematic review to estimate global morbidity and mortality for 2010. J Glob Health 2012; 2:10401.
    1. Mogasale V, Maskery B, Ochiai RL, et al. . Burden of typhoid fever in low-income and middle-income countries: a systematic, literature-based update with risk-factor adjustment. Lancet Glob Health 2014; 2:e570–80.
    1. Antillón M, Warren JL, Crawford FW, et al. . The burden of typhoid fever in low- and middle-income countries: a meta-regression approach. PLoS Negl Trop Dis 2017; 11:e0005376.
    1. Saad NJ, Bowles CC, Grenfell BT, et al. . The impact of migration and antimicrobial resistance on the transmission dynamics of typhoid fever in Kathmandu, Nepal: a mathematical modelling study. PLoS Negl Trop Dis 2017; 11:e0005547.
    1. Karkey A, Thompson CN, Tran Vu Thieu N, et al. . Differential epidemiology of Salmonella Typhi and Paratyphi A in Kathmandu, Nepal: a matched case control investigation in a highly endemic enteric fever setting. PLoS Negl Trop Dis 2013; 7:e2391.
    1. WHO. Typhoid vaccines: WHO position paper–March 2018. Wkly Epidemiol Rec 2018; 93:477–500.
    1. Gilman RH, Hornick RB, Woodard WE, et al. . Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella Typhi as a liver oral vaccine. J Infect Dis 1977; 136:717–23.
    1. Levine MM, Ferreccio C, Black RE, Tacket CO, Germanier R. Progress in vaccines against typhoid fever. Rev Infect Dis 1989; 11(Suppl 3):S552–67.
    1. Sur D, Ochiai RL, Bhattacharya SK, et al. . A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med 2009; 361:335–44.
    1. Khan MI, Soofi SB, Ochiai RL, et al. ; DOMI Typhoid Karachi Vi Effectiveness Study Group Effectiveness of Vi capsular polysaccharide typhoid vaccine among children: a cluster randomized trial in Karachi, Pakistan. Vaccine 2012; 30:5389–95.
    1. Jin C, Gibani MM, Moore M, et al. . Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet 2017. doi: 10.1016/S0140-6736(17)32149-9.
    1. Dobinson HC, Gibani MM, Jones C, et al. . Evaluation of the clinical and microbiological response to Salmonella Paratyphi A infection in the first paratyphoid human challenge model. Clin Infect Dis 2017; 64:1066–73.
    1. Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT, Snyder MJ. Typhoid fever: pathogenesis and immunologic control. 2. N Engl J Med 1970; 283:739–46.
    1. Pitzer VE, Bowles CC, Baker S, et al. . Predicting the impact of vaccination on the transmission dynamics of typhoid in South Asia: a mathematical modeling study. PLoS Negl Trop Dis 2014; 8:e2642.
    1. Watson CH, Edmunds WJ. A review of typhoid fever transmission dynamic models and economic evaluations of vaccination. Vaccine 2015; 33(Suppl 3):C42–54.
    1. Waddington CS, Darton TC, Jones C, et al. . An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin Infect Dis 2014; 58:1230–40.
    1. Darton TC, Jones C, Blohmke CJ, et al. . Using a human challenge model of infection to measure vaccine efficacy: a randomised, controlled trial comparing the typhoid vaccines M01ZH09 with placebo and Ty21a. PLoS Negl Trop Dis 2016; 10:e0004926.
    1. Gibani M, Jin C, Thomaides-Brears H, et al. . Investigating systemic immunity to typhoid and paratyphoid fever: characterising the response to re-challenge in a controlled human infection model. Open Forum Infect Dis 2017; 4:S227–8.
    1. Identifier: NCT03067961. Investigating typhoid fever pathogenesis-full text Available at: . accessed 17 March 2017.
    1. McCullagh D, Dobinson HC, Darton T, et al. . Understanding paratyphoid infection: study protocol for the development of a human model of Salmonella enterica serovar Paratyphi A challenge in healthy adult volunteers. BMJ Open 2015; 5:e007481.
    1. Wong VK, Baker S, Connor TR, et al. ; International Typhoid Consortium An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid. Nat Commun 2016; 7:12827.
    1. Standards Unit, Microbiology Services PHE. UK standards for microbiology investigations–investigation of faecal specimens for enteric pathogens. Bacteriology 2014; B30:1–41.
    1. Micoli F, Rondini S, Gavini M, et al. . A scalable method for O-antigen purification applied to various Salmonella serovars. Anal Biochem 2013; 434:136–45.
    1. Meiring JE, Gibani M; TyVAC Consortium Meeting Group: The Typhoid Vaccine Acceleration Consortium (TyVAC): vaccine effectiveness study designs: accelerating the introduction of typhoid conjugate vaccines and reducing the global burden of enteric fever. Report from a meeting held on 26–27 October 2016, Oxford, UK. Vaccine 2017; 35:5081–8.
    1. Lin FY, Ho VA, Khiem HB, et al. . The efficacy of a Salmonella Typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med 2001; 344:1263–9.
    1. Mohan VK, Varanasi V, Singh A, et al. . Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin Infect Dis 2015; 61:393–402.
    1. Voysey M, Pollard AJ. Seroefficacy of Vi polysaccharide-tetanus toxoid typhoid conjugate vaccine (Typbar TCV). Clin Infect Dis 2018; 67:18–24.
    1. Dupont HL, Hornick RB, Snyder MJ, Dawkins AT, Heiner GG, Woodward TE. Studies of immunity in typhoid fever. Protection induced by killed oral antigens or by primary infection. Bull World Health Organ 1971; 44:667–72.
    1. Saul A, Smith T, Maire N. Stochastic simulation of endemic Salmonella enterica serovar Typhi: the importance of long lasting immunity and the carrier state. PLoS One 2013; 8:e74097.
    1. Moor K, Diard M, Sellin ME, et al. . High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 2017; 544:498–502.
    1. Baker S, Holt KE, Clements AC, et al. . Combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission. Open Biol 2011; 1:110008.
    1. Vollaard AM, Ali S, van Asten HA, et al. . Risk factors for typhoid and paratyphoid fever in Jakarta, Indonesia. JAMA 2004; 291:2607–15.
    1. Martin LB, Simon R, MacLennan CA, Tennant SM, Sahastrabuddhe S, Khan MI. Status of paratyphoid fever vaccine research and development. Vaccine 2016; 34:2900–2.
    1. Wong VK, Baker S, Pickard DJ, et al. . Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events. Nat Genet 2015; 47:632–9.
    1. Darton TC, Meiring JE, Tonks S, et al. ; STRATAA Study Consortium The STRATAA study protocol: a programme to assess the burden of enteric fever in Bangladesh, Malawi and Nepal using prospective population census, passive surveillance, serological studies and healthcare utilisation surveys. BMJ Open 2017; 7:e016283.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever