Summary Background Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings. Methods We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com , ISRCTN11643110. Findings 41 344 children were vaccinated in April–May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI −12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed. Interpretation Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses. Funding The study was funded by the Bill & Melinda Gates Foundation.

Background. There is a need for a reliable, simple diagnostic assay for typhoid fever. Available commercial serologic assays for typhoid fever have limited sensitivity and specificity. Using high-throughput immunoscreening technologies, we previously identified several immunoreactive Salmonella Typhi antigens that seem promising for possible inclusion in a new diagnostic assay: hemolysin E (HlyE), cytolethal distending toxin, S. Typhi lipopolysaccharide (LPS), and S. Typhi membrane preparation.Methods. We assessed plasma antibody responses (immunoglobulin [Ig] M, IgA, and IgG) to these antigens by means of enzyme-linked immunosorbent assay in patients with suspected enteric fever, controls with other febrile illnesses, and healthy controls in Dhaka, Bangladesh and performed Tubex and Typhidot tests, the Widal assay, and the typhoid/paratyphoid test (TPTest) in each patient. Using machine learning methods, we identified a parsimonious serology signature to distinguish acute typhoid cases from controls and then validated our findings in an independent test cohort from Nepal of patients with culture-confirmed S. Typhi and controls with other bacteremic illnesses.Results. We demonstrated that the use of 2 antigens (HlyE and LPS) with 1 antibody isotype (IgA) could distinguish typhoid from other invasive bacterial infections (area under the receiver operating characteristic curve [AUC], 0.95; sensitivity, 90%, specificity, 92%). Use of a single antigen (HlyE) and isotype (IgA) had an AUC of 0.93. Conclusion.Our results suggest that development of a diagnostic assay for acute typhoid fever focused on detecting IgA responses against HlyE, with or without LPS, is warranted.

There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development.

Background Late-onset sepsis (LOS) in very low-birth-weight (VLBW) infants is associated with significant morbidity and mortality. Objectives To determine the incidence of LOS workup, association, and predictive value of clinical indicators leading to culture-positive versus culture-negative sepsis workup. Methods All sepsis workups performed after 7 days of life, in neonates with birth weight of < 1,500 g were included. Each case (culture-positive workup) was matched with a control (culture-negative workup) for gestational age (GA), birth weight, corrected gestational age, and chronological age, at the time of workup. The clinical indicators leading to the performance of sepsis workup were compared between cases and controls. Results The incidence of culture-positive workup was 87/345 (25.2%) and that of LOS was 84/279 (30.1%). Among various clinical indicators, hypothermia and apnea were significantly associated with culture-positive sepsis workup (p = 0.015 and 0.004, respectively), with a positive predictive value of 81.2 and 71.4%, respectively. Conclusion In VLBW infants, one-fourth of sepsis workups resulted in a positive culture. Apnea and hypothermia were the most significant predictors of culture-positive workup after matching for GA, birth weight, chronological age, and corrected GA at the time of the workup.