Use of Typhoid Vi-Polysaccharide Vaccine as a Vaccine Probe to Delineate Clinical Criteria for Typhoid Fever

Abstract

Blood cultures (BCs) detect an estimated 50% of typhoid fever cases. There is need for validated clinical criteria to define cases that are BC negative, both to help direct empiric antibiotic treatment and to better evaluate the magnitude of protection conferred by typhoid vaccines. To derive and validate a clinical rule for defining BC-negative typhoid fever, we assessed, in a cluster-randomized effectiveness trial of Vi-polysaccharide (ViPS) typhoid vaccine in Kolkata, India, 14,797 episodes of fever lasting at least 3 days during 4 years of comprehensive, BC-based surveillance of 70,865 persons. A recursive partitioning algorithm was used to develop a decision rule to predict BC-proven typhoid cases with a diagnostic specificity of 97-98%. To validate this rule as a definition for BC-negative typhoid fever, we assessed whether the rule defined culture-negative syndromes prevented by ViPS vaccine. In a training subset of individuals, we identified the following two rules: rule 1: patients aged < 15 years with prolonged fever accompanied by a measured body temperature ³ 100°F, headache, and nausea; rule 2: patients aged ³ 15 years with prolonged fever accompanied by nausea and palpable liver but without constipation. The adjusted protective efficacy of ViPS against clinical typhoid defined by these rules in persons aged ³ 2 years in a separate validation subset was 33% (95% CI: 4-53%). We have defined and validated a clinical rule for predicting BC-negative typhoid fever using a novel vaccine probe approach. If validated in other settings, this rule may be useful to guide clinical care and to enhance typhoid vaccine evaluations.

Doehlert Matrix-assisted optimization of Salmonella typhi Vi polysaccharide purification parameters

“…The live attenuated bacteria lack the galE gene, are unable to synthesize the lipopolysaccharides (LPS) O-chain, and are unable to synthesis the capsular polysaccharide (CP) Vi antigen. Both LPS and CP are considered major targets for antibodies that lack these components and in the live attenuated vaccines they elicit less immunogenicity [12]. The efficacy of Ty21a enteric capsules after three doses is noted as 42%-67% at 3 years postvaccination [13,14].…”