Table 1.
Participant characteristics OVG2014/01(PATCH) study.
ST-ST Re-Challenge = Homologous re-challenge with S. Typhi following previous S. Typhi challenge. SPT-SPT Re-Challenge = Homologous re-challenge with S. Paratyphi following previous S. Paratyphi challenge. ST-SPT Re-Challenge = Heterologous re-challenge with S. Paratyphi following previous S. Typhi challenge. SPT-ST Re-Challenge = Heterologous re-challenge with S. Typhi following previous S. Typhi challenge. Prior known typhoid vaccination of any type was an exclusion criterion for enrolment into the naïve arm of the study. Participants with prior history of Vi-polysaccharide vaccination were eligible for enrolment in previous paratyphoid challenge studies. Participants with a history of Vi-polysaccharide, Vi-tetanus toxoid conjugate, Ty21a, M01ZH09 vaccination received either vaccine as part of previous human challenge studies assessing vaccine efficacy. [21, 22] Minimum interval between primary challenge and re-challenge was 12 months.
Fig 1.
Time to diagnosis after challenge with a) Salmonella Typhi and b) Salmonella Paratyphi A.
Kaplan-Meier survival cumulative incidence of participants meeting the composite diagnostic endpoint, measured from challenge agent ingestion to development of first fever ≥38°C or first positive blood culture sampling. Non-diagnosed participants censored at day 14 hours. P = log-rank test between three groups. ST = S. Typhi naïve challenge. ST-ST = Homologous Re-Challenge with S. Typhi. SPT = S. Paratyphi naïve challenge. SPT-SPT = Homologous Re-Challenge with S. Paratyphi. SPT-ST Re-Challenge = Heterologous re-challenge with S. Typhi following previous S. Paratyphi challenge. ST-SPT Re-Challenge = Heterologous re-challenge with S. Paratyphi following previous S. Typhi challenge.
Fig 2.
Clinical profile following Salmonella Typhi and Salmonella Paratyphi A challenge and re-challenge: Kaplan-Meier curves indicating time to bacteraemia following Salmonella Typhi (a) and Salmonella Paratyphi (b) challenge, in naïve and re-challenge participants; Time first fever >38oC following Salmonella Typhi (c) and Salmonella Paratyphi (d) challenge, in naïve and re-challenge participants. P = log-rank test between three groups;. Comparison of cumulative symptom severity scores (Day 0 to 21) in all participants diagnosed with Salmonella Typhi (e) or Salmonella Paratyphi (f) (median, interquartile range, p = Mann-Whitney U test); Quantitative blood culture at time of typhoid (g) or paratyphoid (h) diagnosis. Box plots represent median, interquartile range. Samples with no colonies were assigned a value corresponding to half the lower limit of detection (0.05 CFU/ml). p = Mann-Whitney U test; Maximum symptom severity score in participants diagnosed with typhoid (i) or paratyphoid (j) fever. Percentage of participants reporting one or more events. Symptoms were recorded using an electronic diary from Day 0 up to Day 21 post challenge. Stacked columns display percentage of participants reporting maximum symptom severity graded as mild (present but no interference with daily activity), moderate (some limitation of daily activity) or severe (unable to perform normal daily activity).
Table 2.
Primary and secondary outcome.
ST-ST Re-Challenge = Homologous re-challenge with S. Typhi following previous S. Typhi challenge. SPT-SPT Re-Challenge = Homologous re-challenge with S. Paratyphi following previous S. Paratyphi challenge. ST-SPT Re-Challenge = Heterologous re-challenge with S. Paratyphi following previous S. Typhi challenge. SPT-ST Re-Challenge = Heterologous re-challenge with S. Typhi following previous S. Paratyphi challenge.
Table 3.
Comparison of attack rates in re-challenge cohorts according to outcome of primary challenge (nNo previous disease/nprevious disease).
Table 4.
Multivariable log-binomial model displaying adjusted relative risk of diagnosis in re-challenged participants (n = 75).
ST = S. Typhi, SPT = S. Paratyphi.
Fig 3.
Antibody response to Salmonella Typhi and Paratyphi A challenge/re-challenge.
Serum IgG response to O9:LPS following Salmonella Typhi challenge (a) and O2:LPS following Salmonella Paratyphi challenge (b) grouped according to outcome (ED = Met criteria for enteric fever diagnosis. nED = Did not meet criteria for enteric fever diagnosis); Comparison of serum IgG response to O9:LPS (c) and O2:LPS (d) according to challenge/re-challenge group. Coloured lines connect median values for each timepoint. Grey lines connect paired samples across timepoints; p = Wilcoxon signed rank test; Magnitude of anti-O9:LPS IgG following Salmonella Typhi challenge (e) and anti-O2:LPS IgG following Salmonella Paratyphi challenge (f) expressed as log10 fold change from baseline at Day 28 and Day 90, p = Mann-Whitney U test; ST = S. Typhi naïve; ST-ST = Homologous S. Typhi re-challenge. SPT-ST = Heterologous S. Typhi re-challenge. SPT = S. Paratyphi naïve; SPT-SPT = Homologous S. Paratyphi re-challenge. ST-SPT = Heterologous S. Paratyphi re-challenge.