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Serum bactericidal assays to evaluate typhoidal and nontyphoidal Salmonella vaccines.

ABSTRACT: Invasive Salmonella infections for which improved or new vaccines are being developed include enteric fever caused by Salmonella enterica serovars Typhi, Paratyphi A, and Paratyphi B and sepsis and meningitis in young children in sub-Saharan Africa caused by nontyphoidal Salmonella (NTS) serovars, particularly S. enterica serovars Typhimurium and Enteritidis. Assays are needed to measure functional antibodies elicited by the new vaccines to assess their immunogenicities and potential protective capacities. We developed in vitro assays to quantify serum bactericidal antibody (SBA) activity induced by S. Typhi, S. Paratyphi A, S. Typhimurium, and S. Enteritidis vaccines in preclinical studies. Complement from various sources was tested in assays designed to measure antibody-dependent complement-mediated killing. Serum from rabbits 3 to 4 weeks of age provided the best complement source compared to serum from pigs, goats, horses, bovine calves, or rabbits 8 to 12 weeks of age. For S. Enteritidis, S. Typhimurium, and S. Typhi SBA assays to be effective, bacteria had to be harvested at log phase. In contrast, S. Paratyphi A was equally susceptible to killing whether it was grown to the stationary or log phase. The typhoidal serovars were more susceptible to complement-mediated killing than were the nontyphoidal serovars. Lastly, the SBA endpoint titers correlated with serum IgG anti-lipopolysaccharide (LPS) titers in mice immunized with mucosally administered S. Typhimurium, S. Enteritidis, and S. Paratyphi A but not S. Typhi live attenuated vaccines. The SBA assay described here is a useful tool for measuring functional antibodies elicited by Salmonella vaccine candidates.

SUBMITTER: Boyd MA

PROVIDER: S-EPMC4018884 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Serum bactericidal assays to evaluate typhoidal and nontyphoidal Salmonella vaccines.

Boyd Mary Adetinuke MA Tennant Sharon M SM Saague Venant A VA Simon Raphael R Muhsen Khitam K Ramachandran Girish G Cross Alan S AS Galen James E JE Pasetti Marcela F MF Levine Myron M MM

Clinical and vaccine immunology : CVI 20140312 5

Invasive Salmonella infections for which improved or new vaccines are being developed include enteric fever caused by Salmonella enterica serovars Typhi, Paratyphi A, and Paratyphi B and sepsis and meningitis in young children in sub-Saharan Africa caused by nontyphoidal Salmonella (NTS) serovars, particularly S. enterica serovars Typhimurium and Enteritidis. Assays are needed to measure functional antibodies elicited by the new vaccines to assess their immunogenicities and potential protective ...[more]

PMID: 24623629

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Project description:BackgroundNon-typhoidal Salmonella (NTS) commonly causes diarrhoea, and is usually self-limiting, although sometimes people become ill with sepsis and dehydration. Routine antibiotic use for this infection could result in persistent colonization and the spread of resistant bacterial strains.ObjectivesTo assess the efficacy and safety of giving antibiotics to people with NTS diarrhoea.Search methodsWe searched the Cochrane Infectious Diseases Group trials register (up to August 2012), the Cochrane Controlled Trials Register (CENTRAL) published in The Cochrane Library (up to Issue 8 2012); and MEDLINE, African Index Medicus, CINAHL, EMBASE, LILACS, and the Science Citation Index, all up to 6 August 2012. We also searched the metaRegister of Controlled Trials (mRCT) for both completed and on going trials and reference lists of relevant articles.Selection criteriaRandomized controlled trials (RCTs) comparing any antibiotic treatment for diarrhoea caused by NTS species with placebo or no antibiotic treatment. We selected trials that included people of all ages who were symptomatic for NTS infection. Examples of symptoms included fever, abdominal pain, vomiting and diarrhoea. We excluded trials where the outcomes were not reported separately for the NTS subgroup of patients. Two review authors independently applied eligibility criteria prior to study inclusion.Data collection and analysisTwo review authors independently extracted data on pre-specified outcomes and independently assessed the risk of bias of included studies. The primary outcome was the presence of diarrhoea between two to four days after treatment. The quality of evidence was assessed using the GRADE methods.Main resultsTwelve trials involving 767 participants were included. No differences were detected between the antibiotic and placebo/no treatment arms for people with diarrhoea at two to four days after treatment (risk ratio (RR) 1.75, 95% confidence interval (CI) 0.42 to 7.21; one trial, 46 participants; very low quality evidence). No difference was detected for the presence of diarrhoea at five to seven days after treatment (RR 0.83, 95% CI 0.62 to 1.12; two trials, 192 participants; very low quality evidence), clinical failure (RR 0.88, 95% CI 0.62 to 1.25; seven trials, 440 participants; very low quality evidence). The mean difference for diarrhoea was 0 days (95% CI -0.54 to 0.54; 202 participants, four studies; low quality evidence);for fever was 0.27 days (95% CI -0.11 to 0.65; 107 participants, two studies; very low quality evidence); and for duration of illness was 0 days (95% CI -0.68 to 0.68; 116 participants, two studies; very low quality evidence). Quinolone antibiotic treatment resulted in a significantly higher number of negative stool cultures for NTS during the first week of treatment (microbiological failure: RR 0.33, 95% CI 0.20 to 0.56; 166 participants, four trials).Antibiotic treatment meant passage of the same Salmonella serovar one month after treatment was almost twice as likely (RR 1.96, 95% CI 1.29 to 2.98; 112 participants, three trials), which was statistically significant. Non-severe adverse drug reactions were more common among the patients who received antibiotic treatment.Authors' conclusionsThere is no evidence of benefit for antibiotics in NTS diarrhoea in otherwise healthy people. We are uncertain of the effects in very young people, very old people, and in people with severe and extraintestinal disease. A slightly higher number of adverse events were noted in people who received antibiotic treatment for NTS.

Project description:BackgroundNon-typhoidal Salmonella (NTS) and Salmonella enterica serovar Typhi bacteremia are the causes of significant morbidity and mortality worldwide. There is a paucity of data regarding NTS bacteremia in South Asia, a region with a high incidence of typhoidal bacteremia. We sought to determine clinical predictors and outcomes associated with NTS bacteremia compared with typhoidal bacteremia.MethodologyWe performed a retrospective age-matched case-control study of patients admitted to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh, between February 2009 and March 2013. We compared demographic, clinical, microbiological, and outcome variables of NTS bacteremic patients with age-matched S. Typhi bacteremic patients, and a separate comparison of patients with NTS bacteremia and patients with NTS gastroenteritis.Principal findingsOf 20 patients with NTS bacteremia, 5 died (25% case fatality), compared to none of 60 age-matched cases of S. Typhi bacteremia. In univariate analysis, we found that compared with S. Typhi bacteremia, cases of NTS bacteremia had more severe acute malnutrition (SAM) in children under five years of age, less often presented with a duration of fever ≥ 5 days, and were more likely to have co-morbidities on admission such as pneumonia and clinical signs of sepsis (p<0.05 in all cases). In multivariable logistic regression, SAM, clinical sepsis, and pneumonia were independent risk factors for NTS bacteremia compared with S. Typhi bacteremia (p<0.05 in all cases). Notably, we found marked differences in antibiotic susceptibilities, including NTS strains resistant to antibiotics commonly used for empiric therapy of patients suspected to have typhoid fever.Conclusions/significanceDiarrheal patients with NTS bacteremia more often presented with co-morbidities and had a higher case fatality rate compared to those with typhoidal bacteremia. Clinicians in regions where both typhoid and NTS bacteremia are prevalent need to be vigilant about the possibility of both entities, especially given notable differences in antibiotic susceptibility patterns.

Dataset Information

Serum bactericidal assays to evaluate typhoidal and nontyphoidal Salmonella vaccines.

Publications

Serum bactericidal assays to evaluate typhoidal and nontyphoidal Salmonella vaccines.

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