The effect of a comprehensive typhoid conjugate vaccine campaign on antimicrobial prescribing in children in Harare, Zimbabwe: a mixed methods study.

BACKGROUND: Vaccines prevent infections and could subsequently reduce antimicrobial use. A 1-week mass vaccination campaign was done with Typbar-TCV (Bharat Biotech, Hyderabad, India) between Feb 25 and March 4, 2019. We investigated whether this typhoid conjugate vaccine campaign could affect antimicrobial prescribing in children presenting to primary care in Harare, Zimbabwe. METHODS: In this mixed methods study, data for acute paediatric outpatient consultations between Jan 1, 2018, and March 31, 2020, were collected from five clinics in Harare. Interrupted time series analysis was done to compare prescription data before and after the campaign. To contextualise findings, qualitative data were collected between April 20, 2021, and July 20, 2022, comprising ethnographic research (ie, workshops, surveys, observations, and interviews) in 14 clinics. Ethnographic data were used for thematic analysis. The primary outcome was monthly antimicrobial prescriptions in children aged 6 months to 15 years, normalised by the number of trauma events in all age groups. FINDINGS: In the data collection period, 27 107 paediatric consultations were recorded. 17 951 (66·2%) of 27 107 children were prescribed antimicrobials. Despite the perceived reduction in typhoid cases and a decreasing trend in the prescription of antimicrobials commonly used to treat typhoid (ie, ciprofloxacin and azithromycin), mass vaccination with Typbar-TCV did not affect the total rate of antimicrobials (adjusted rate ratio, 1·20, 95% CI 0·70-2·05, p=0·51) or the rate of typhoid antimicrobials prescribed (0·93, 0·44-1·96, p=0·85). Unsafe water sources and insufficient diagnostic services were reported to contribute to the continued disease burden and antimicrobial prescription. INTERPRETATION: Non-specific febrile illness caused by confirmed or suspected typhoid is a common cause of antimicrobial use in endemic areas. Although effective in preventing typhoid fever, we were unable to identify any effect of Typbar-TCV on antimicrobial prescribing. Ethnographic research showed the effect of contextual factors on antimicrobial prescribing, including concerns regarding safe water access, appropriate sewage disposal, health-care and diagnostic availability. To realise effects beyond disease burden reduction, holistic approaches addressing these concerns are needed so that the value of vaccines mitigating the effects of antimicrobial use as a driver of antimicrobial resistance is fully achieved. FUNDING: Wellcome Trust. TRANSLATION: For the Shona translation of the abstract see Supplementary Materials section.

Collection, compilation and analysis of bacterial vaccines.

BACKGROUND: Bacterial diseases are one of the leading causes of millions of fatalities worldwide, mainly due to antimicrobial resistance. The discovery of chicken cholera vaccine in 1879 revolutionized our fight against bacterial infections. Bacterial vaccines are proven to be highly effective in preventing many infectious diseases. Currently, various licensed vaccines are available against bacterial infections such as typhoid, diphtheria, cholera and tetanus in the market. In this study, we have attempted to compile different information regarding bacterial vaccines, their types, efficacy, mechanism of action, status, route of administration and other relevant details as a knowledgebase known as BacVacDB. METHODS: BacVacDB was implemented using Linux-Apache-MySQL-PHP. HTML, PHP, CSS and Javascript have been used to develop the front end and MySQL for the back end. The data was curated from several sources, including literature, databases and relevant web resources. RESULTS: This paper reviewed 371 vaccines against 30 human bacterial diseases maintained in BacVacDB, of which 167 are approved and 204 in clinical trials. This database provides the users an effortless search facility in the four modules, 'Search,' 'Browse,' 'External Links' and 'General Information'. In this systematic attempt, we also included the history of vaccines, their mechanism, types, route of administration and approving agencies. CONCLUSIONS: This knowledgebase has an intuitive interface that allows users to explore, search, and download information as well as to submit new bacterial vaccines (https://webs.iiitd.edu.in/raghava/bacvacdb/).

Salmonellosis Including Enteric Fever.

Salmonella is a gram-negative, motile, nonsporulating, facultative anaerobic bacillus, belongs to the family Enterobacteriaceae. The bacteria were first identified in 1884. It is transmitted through direct contact with an infected person or indirect contact by the consumption of contaminated food and water. More than 2500 serotypes of Salmonella enterica have been identified but less than 100 serotypes are known to cause infections in humans. S. enterica serovar typhi (S. typhi) and S. enterica serovar paratyphi (S. paratyphi A B C) cause enteric fever, whereas nontyphoidal Salmonella serotypes (NTS) cause diarrhea. NTS commonly presents with gastroenteritis and is a self-limiting disease. Enteric fever is a potentially life-threatening acute febrile systemic infection and is diagnosed by isolating a pathogen on culture. With the emergence of the extensive drug-resistant (XDR) S. typhi clone, limited treatment options are available. Vaccination of persons at risk, improvement of sanitation, promotion of food hygiene, and detection and control of chronic carriers are essential preventive control measures of enteric fever.

Alum and metoclopramide synergistically enhance cellular and humoral immunity after immunization with heat-killed Salmonella typhimurium vaccine.

Typically, the killed form of microorganisms in combination with alum does not produce strong cellular immune responses. A recent investigation has indicated the role of dopamine D2 receptor antagonists like metoclopramide in reducing the polarization of immune responses toward Th2 immunity. This study was performed to evaluate the effects of a combination of alum and metoclopramide on the induction of cellular and humoral immunity in response to a heat-killed preparation ofSalmonella typhimurium(HKST). Wistar rats were immunized with the HKST vaccine alone or in combination with alum, metoclopramide, or the alum-metoclopramide mixture twice with a two-week interval. Fourteen days after the last vaccination, immune responses against S. typhimurium and the protective potential of the vaccines were assessed. The combination of alum and metoclopramide as an adjuvant augmented the potential of the HKST vaccine to enhance lymphocyte proliferation, delayed-type hypersensitivity reaction, and antibody titer. These results were concurrent with the polarization of immune response towards the Th1 response and improving protective immunity against S. typhimurium. Overall, the combination of alum and metoclopramide as an adjuvant synergistically enhanced cellular and humoral immunity after immunization with the HKST vaccine.

Multi-epitope DnaK peptide vaccine accords protection against lethal S. typhimurium challenge: Elicits both cell mediated immunity and long-lasting serum-neutralizing antibody titers.

Typhoid vaccine development has been impeded by inability of currently available vaccines to induce cellular immunity along with neutralizing antibodies against all serovars of S. Typhi and S. Paratyphi. Unfortunately, antibiotic treatment has shown to be an ineffective therapy due to development of resistance against multiple antibiotics. In the present study, we have explored the immunogenicity and protective efficacy of in-silico designed multi-epitope DnaK peptides as candidate vaccine molecules against Salmonella. Immunization studies in mouse typhoid model revealed three of these peptides (DP1, DP5 and DP7) are highly efficacious, stimulating both humoral and cell mediated immunity along with long lasting antibody memory response. There was significant increase in antibody titers (IgG, IgG1, IgG2a, IgA and IgM), lymphocyte proliferative responses and cytokine levels. Immunized groups showed marked reduction in organ bacterial load, fecal shedding and pronounced protection (upto 80%) as compared to unimmunized controls after challenge with S. typhimurium. Our results demonstrate the huge potential of DnaK peptide vaccine candidates (DP1, DP5 and DP7) to accord protective immunity with significant increase in survivability against Salmonella infection in mice, thus commending these molecules as promising agents to tackle typhoid.

Protection conferred by typhoid fever against recurrent typhoid fever in urban Kolkata.

We evaluated the protection conferred by a first documented visit for clinical care of typhoid fever against recurrent typhoid fever prompting a visit. This study takes advantage of multi-year follow-up of a population with endemic typhoid participating in a cluster-randomized control trial of Vi capsular polysaccharide typhoid vaccine in Kolkata, India. A population of 70,566 individuals, of whom 37,673 were vaccinated with one dose of either Vi vaccine or a control (Hepatitis A) vaccine, were observed for four years. Surveillance detected 315 first typhoid visits, among whom 4 developed subsequent typhoid, 3 due to reinfection, defined using genomic criteria and corresponding to -124% (95% CI: -599, 28) protection by the initial illness. Point estimates of protection conferred by an initial illness were negative or negligible in both vaccinated and non-vaccinated subjects, though confidence intervals around the point estimates were wide. These data provide little support for a protective immunizing effect of clinically treated typhoid illness, though modest levels of protection cannot be excluded.

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

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 ≥ 100°F, headache, and nausea; rule 2: patients aged ≥ 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 ≥ 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.

Evaluation of a standardised Vi poly-l-lysine ELISA for serology of Vi capsular polysaccharide antibodies.

Typhoid vaccines based on protein-conjugated capsular Vi polysaccharide (TCVs) prevent typhoid in infants and young children. Analysis of the serum anti-Vi IgG response following immunisation against typhoid confirms the immunogenicity of TCVs and forms an important part of the pathway to licensing. Comparative studies could expedite the licencing process, and the availability of a standardised ELISA method alongside the 1st International Standard (IS) 16/138 for anti-typhoid capsular Vi polysaccharide IgG (human) will facilitate this process. To this end, a non-commercial ELISA based on a coat of Vi and poly-l-lysine (Vi-PLL ELISA) was evaluated by 10 laboratories. Eight serum samples, including IS 16/138, were tested in the standardised Vi-PLL ELISA (n = 10), a commercial Vi ELISA (n = 3) and a biotinylated Vi ELISA (n = 1). Valid estimates of potencies relative to IS 16/138 were obtained for all samples in the Vi-PLL ELISA and the commercial ELISA, with good repeatability and reproducibility evident from the study results and concordant estimates obtained by the two ELISA methods. The study demonstrates that the Vi-PLL ELISA can be used in clinical trial studies to determine the immunogenicity of TCVs.

The need & the issues related to new-generation typhoid conjugate vaccines in India.

The low- and middle-income countries bear the highest burden of typhoid fever in the world. India, along with other South Asian countries, has a significant incidence of typhoid fever among young children though there is a paucity of published data on community burden. In spite of the availability of Vi-polysaccharide (Vi-PS) and conjugated Vi-PS vaccines, these are not adequately utilized in India and in the neighbouring countries. To address many shortcomings of the unconjugated Vi-PS vaccines, typhoid conjugate vaccines (TCVs) are developed by conjugating Vi-PS with different carrier proteins. Three such vaccines using tetanus toxoid as a carrier protein are already licensed in India. Several other Vi-PS conjugates are currently in various stages of development. The current review provides an update on the existing and upcoming new TCVs along with a detailed discussion on the various issues involved with their clinical use and limitations.

The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Efforts to quantify the global burden of enteric fever are valuable for understanding the health lost and the large-scale spatial distribution of the disease. We present the estimates of typhoid and paratyphoid fever burden from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, and the approach taken to produce them. METHODS: For this systematic analysis we broke down the relative contributions of typhoid and paratyphoid fevers by country, year, and age, and analysed trends in incidence and mortality. We modelled the combined incidence of typhoid and paratyphoid fevers and split these total cases proportionally between typhoid and paratyphoid fevers using aetiological proportion models. We estimated deaths using vital registration data for countries with sufficiently high data completeness and using a natural history approach for other locations. We also estimated disability-adjusted life-years (DALYs) for typhoid and paratyphoid fevers. FINDINGS: Globally, 14·3 million (95% uncertainty interval [UI] 12·5-16·3) cases of typhoid and paratyphoid fevers occurred in 2017, a 44·6% (42·2-47·0) decline from 25·9 million (22·0-29·9) in 1990. Age-standardised incidence rates declined by 54·9% (53·4-56·5), from 439·2 (376·7-507·7) per 100 000 person-years in 1990, to 197·8 (172·0-226·2) per 100 000 person-years in 2017. In 2017, Salmonella enterica serotype Typhi caused 76·3% (71·8-80·5) of cases of enteric fever. We estimated a global case fatality of 0·95% (0·54-1·53) in 2017, with higher case fatality estimates among children and older adults, and among those living in lower-income countries. We therefore estimated 135·9 thousand (76·9-218·9) deaths from typhoid and paratyphoid fever globally in 2017, a 41·0% (33·6-48·3) decline from 230·5 thousand (131·2-372·6) in 1990. Overall, typhoid and paratyphoid fevers were responsible for 9·8 million (5·6-15·8) DALYs in 2017, down 43·0% (35·5-50·6) from 17·2 million (9·9-27·8) DALYs in 1990. INTERPRETATION: Despite notable progress, typhoid and paratyphoid fevers remain major causes of disability and death, with billions of people likely to be exposed to the pathogens. Although improvements in water and sanitation remain essential, increased vaccine use (including with typhoid conjugate vaccines that are effective in infants and young children and protective for longer periods) and improved data and surveillance to inform vaccine rollout are likely to drive the greatest improvements in the global burden of the disease. FUNDING: Bill & Melinda Gates Foundation.

Typhoid vaccines: WHO position paper, March 2018 - Recommendations.

This article presented the World Health Organization's (WHO) recommendations on the use of Typhoid vaccines excerpted from the Typhoid vaccines: WHO position paper - March 2018 published in the Weekly Epidemiological Record (World Health Organization, 2018) [1]. This position paper replaces the 2008 WHO position paper on typhoid vaccines (WHO, 2008) [2]. It re-emphasizes the importance of vaccination to control typhoid fever and presents the WHO recommendations on the use of a new generation of typhoid conjugate vaccines. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation tables. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of cholera vaccines were discussed by the Strategic Advisory Group of Experts (SAGE) in October 2017; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/meetings/2017/October/presentations_background_docs/en/.

Burden of typhoid fever and cholera: similarities and differences. Prevention strategies for European travelers to endemic/epidemic areas.

The burden of diarrheal diseases is very high, accounting for 1.7 to 5 billion cases per year worldwide. Typhoid fever (TF) and cholera are potentially life-threatening infectious diseases, and are mainly transmitted through the consumption of food, drink or water that have been contaminated by the feces or urine of subjects excreting the pathogen. TF is mainly caused by Salmonella typhi, whereas cholera is caused by intestinal infection by the toxin-producing bacterium Vibrio cholerae. These diseases typically affect low- and middle-income countries where housing is overcrowded and water and sanitation are poor, or where conflicts or natural disasters have led to the collapse of the water, sanitation and healthcare systems. Mortality is higher in children under 5 years of age. Regarding their geographical distribution, TF has a high incidence in sub-Saharan Africa, India and south-east Asia, while cholera has a high incidence in a few African countries, particularly in the Horn of Africa and the Arabian Peninsula. In the fight against these diseases, preventive measures are fundamental. With modern air travel, transmissible diseases can spread across continents and oceans in a few days, constituting a threat to global public health. Nowadays, people travel for many reasons, such as tourism and business. Several surveys have shown that a high proportion of travelers lack adequate information on safety issues, such as timely vaccination and prophylactic medications. The main objective of this overview is to provide information to help European travelers to stay healthy while abroad, and thus also to reduce the potential importation of these diseases and their consequent implications for public health and society. The preventive measures to be implemented in the case of travel to countries where these diseases are still endemic are well known: the adoption of safe practices and vaccinations. It is important to stress that an effective preventive strategy should be based both on vaccinations and on hygiene travel guidelines. Furthermore, the emergence of multidrug-resistant strains is becoming a serious problem in the clinical treatment of these diseases. For this reason, vaccination is the main solution.

Current Clinical Trials in Non-muscle Invasive Bladder Cancer.

PURPOSE OF REVIEW: As our molecular understanding of bladder cancer continues to advance, more and more novel agents are entering clinical trials across the spectrum of bladder cancer stages. The clinical trial activity for non-muscle invasive bladder cancer (NMIBC) has been boosted further by the evolution of specific disease states that set more uniform inclusion criteria for clinical trial design. Here, we aimed to review the current clinical trials landscape in non-muscle invasive bladder cancer with respect to these disease states. RECENT FINDINGS: Most active clinical trials focus on high-risk NMIBC in either the BCG-naïve or BCG-unresponsive setting. Strict criteria to define the disease state and a clear pathway to drug registration have encouraged trials for patients with BCG-unresponsive NMIBC. The most promising potential breakthroughs for BCG-naïve patients include alternative BCG strains, immune-priming with intradermal BCG vaccination, and systemic immune checkpoint blockade. The latter therapy is also being actively investigated in multiple trials in BCG-unresponsive NMIBC, along with novel viral agents such as INSTILADRIN (nadofaragene firadenovec) and targeted agents such as oportuzumab monatox. After many years of relative stagnation, multiple new therapies currently under investigation in well-designed clinical trials appear poised for routine clinical implementation in the near future. These therapies should dramatically improve the outcome of patients with NMIBC. We can look forward to the challenges of biomarker-driven drug selection, optimal drug sequencing, and rational combination therapies.

Chitosan/alginate microparticles for the oral delivery of fowl typhoid vaccine: Innate and acquired immunity.

Oral fowl typhoid (FT) vaccine is necessary for improved flock vaccinations and economic growth. This study was undertaken to evaluate the immune responses of birds given oral fowl typhoid vaccine coated with chitosan/alginate microparticles and comparing it with the conventional subcutaneous route of administration. Preliminary studies were done to evaluate the particle size, encapsulation efficiency and agglutination. Sixty day-old chicks were divided into three groups of twenty birds each. This comprised a negative control group NEG 451 (non-vaccinated and non-challenged used as control for cytokine quantification), SC 634 (live 9R vaccine by the injection route) and OCV 567 (live 9R vaccine coated with chitosan/alginate microparticles). Vaccination was done at 10 weeks and 14 weeks of age followed by challenge at 16 weeks of age. IgG was measured using ELISA. mRNA fold expression of IFN-γ in spleen was calculated using qRT-PCR. Particle sizes ranged between 0.55 µm and 10 µm. Encapsulation efficiency was above 60%. ELISA showed E-values of 0.10 ±â€¯0.14, 0.07 ±â€¯0.01 and 0.02 ±â€¯0.01 for OCV 567, SC 634 and NEG 451 respectively after primary vaccination. Also E-values were 0.25 ±â€¯0.16, 0.19 ±â€¯0.04 and 0.0008 ±â€¯0.005 for SC 634, OCV 567 and NEG451 respectively after boost vaccination. The expression of IFN-γin spleen using 2-ΔΔ CT calculation was upregulated with values of 1.97 and 0.75 for OCV 567 and SC 634 respectively. After challenge with the 85-kb virulence plasmid SG9, there was 100% protection of the birds in both OCV 567 and SC 634 groups with no mortality. In conclusion, there was no significant difference at p < 0.05 of the means ±â€¯SD in immune responses between the oral fowl typhoid vaccine coated with chitosan/alginate microparticles and the subcutaneous route of administration. However, it is noteworthy to mention that the protective efficacy of the oral route is due to the chitosan/alginate biopolymers which coated the vaccine preventing destruction in the gastrointestinal tract.

Vaccines for preventing typhoid fever.

BACKGROUND: Typhoid fever and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and southeast Asia. Two typhoid vaccines are widely available, Ty21a (oral) and Vi polysaccharide (parenteral). Newer typhoid conjugate vaccines are at varying stages of development and use. The World Health Organization has recently recommended a Vi tetanus toxoid (Vi-TT) conjugate vaccine, Typbar-TCV, as the preferred vaccine for all ages. OBJECTIVES: To assess the effects of vaccines for preventing typhoid fever. SEARCH METHODS: In February 2018, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and mRCT. We also searched the reference lists of all included trials. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials (RCTs) comparing typhoid fever vaccines with other typhoid fever vaccines or with an inactive agent (placebo or vaccine for a different disease) in adults and children. Human challenge studies were not eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria and extracted data, and assessed the certainty of the evidence using the GRADE approach. We computed vaccine efficacy per year of follow-up and cumulative three-year efficacy, stratifying for vaccine type and dose. The outcome addressed was typhoid fever, defined as isolation of Salmonella enterica serovar Typhi in blood. We calculated risk ratios (RRs) and efficacy (1 - RR as a percentage) with 95% confidence intervals (CIs). MAIN RESULTS: In total, 18 RCTs contributed to the quantitative analysis in this review: 13 evaluated efficacy (Ty21a: 5 trials; Vi polysaccharide: 6 trials; Vi-rEPA: 1 trial; Vi-TT: 1 trial), and 9 reported on adverse events. All trials but one took place in typhoid-endemic countries. There was no information on vaccination in adults aged over 55 years of age, pregnant women, or travellers. Only one trial included data on children under two years of age.Ty21a vaccine (oral vaccine, three doses)A three-dose schedule of Ty21a vaccine probably prevents around half of typhoid cases during the first three years after vaccination (cumulative efficacy 2.5 to 3 years: 50%, 95% CI 35% to 61%, 4 trials, 235,239 participants, moderate-certainty evidence). These data include patients aged 3 to 44 years.Compared with placebo, this vaccine probably does not cause more vomiting, diarrhoea, nausea or abdominal pain (2 trials, 2066 participants; moderate-certainty evidence), headache, or rash (1 trial, 1190 participants; moderate-certainty evidence); however, fever (2 trials, 2066 participants; moderate-certainty evidence) is probably more common following vaccination.Vi polysaccharide vaccine (injection, one dose)A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (year 1: 69%, 95% CI 63% to 74%; 3 trials, 99,979 participants; high-certainty evidence). In year 2, trial results were more variable, with the vaccine probably preventing between 45% and 69% of typhoid cases (year 2: 59%, 95% CI 45% to 69%; 4 trials, 194,969 participants; moderate-certainty evidence). These data included participants aged 2 to 55 years of age.The three-year cumulative efficacy of the vaccine may be around 55% (95% CI 30% to 70%; 11,384 participants, 1 trial; low-certainty evidence). These data came from a single trial conducted in South Africa in the 1980s in participants aged 5 to 15 years.Compared with placebo, this vaccine probably did not increase the incidence of fever (3 trials, 132,261 participants; moderate-certainty evidence) or erythema (3 trials, 132,261 participants; low-certainty evidence); however, swelling (3 trials, 1767 participants; moderate-certainty evidence) and pain at the injection site (1 trial, 667 participants; moderate-certainty evidence) were more common in the vaccine group.Vi-rEPA vaccine (two doses)Administration of two doses of the Vi-rEPA vaccine probably prevents between 50% and 96% of typhoid cases during the first two years after vaccination (year 1: 94%, 95% CI 75% to 99%; year 2: 87%, 95% CI 56% to 96%, 1 trial, 12,008 participants; moderate-certainty evidence). These data came from a single trial with children two to five years of age conducted in Vietnam.Compared with placebo, both the first and the second dose of this vaccine increased the risk of fever (1 trial, 12,008 and 11,091 participants, low-certainty evidence) and the second dose increase the incidence of swelling at the injection site (one trial, 11,091 participants, moderate-certainty evidence).Vi-TT vaccine (two doses)We are uncertain of the efficacy of administration of two doses of Vi-TT (PedaTyph) in typhoid cases in children during the first year after vaccination (year 1: 94%, 95% CI -1% to 100%, 1 trial, 1625 participants; very low-certainty evidence). These data come from a single cluster-randomized trial in children aged six months to 12 years and conducted in India. For single dose Vi-TT (Typbar-TCV), we found no efficacy trials evaluating the vaccine with natural exposure.There were no reported serious adverse effects in RCTs of any of the vaccines studied. AUTHORS' CONCLUSIONS: The licensed Ty21a and Vi polysaccharide vaccines are efficacious in adults and children older than two years in endemic countries. The Vi-rEPA vaccine is just as efficacious, although data is only available for children. The new Vi-TT vaccine (PedaTyph) requires further evaluation to determine if it provides protection against typhoid fever. At the time of writing, there were only efficacy data from a human challenge setting in adults on the Vi-TT vaccine (Tybar), which clearly justify the ongoing field trials to evaluate vaccine efficacy.

Determining the Best Immunization Strategy for Protecting African Children Against Invasive Salmonella Disease.

Background: The World Health Organization recently prequalified a typhoid conjugate vaccine (TCV), recommending its use in persons ≥6 months to 45 years residing in typhoid fever (TF)-endemic areas. We now need to consider how TCVs can have the greatest impact in the most vulnerable populations. Methods: The Typhoid Fever Surveillance in Africa Program (TSAP) was a blood culture-based surveillance of febrile patients from defined populations presenting at healthcare facilities in 10 African countries. TF and invasive non-typhoidal Salmonella (iNTS) disease incidences were estimated for 0-10 year-olds in one-year age increments. Results: Salmonella Typhi and iNTS were the most frequently isolated pathogens; 135 and 94 cases were identified, respectively. Analysis from three countries was excluded (incomplete person-years of observation (PYO) data). Thirty-seven of 123 TF cases (30.1%) and 71/90 iNTS disease cases (78.9%) occurred in children aged <5 years. No TF and 8/90 iNTS infections (8.9%) were observed in infants aged <9 months. The TF incidences (/100 000 PYO) for children aged <1 year and 1 to <2 years were 5 and 39, respectively; the highest incidence was 304 per 100 000 PYO in 4 to <5 year-olds. The iNTS disease incidence in the defined age groups ranged between 81 and 233 per 100 000 PYO, highest in 1 to <2 year-olds. TF and iNTS disease incidences were higher in West Africa. Conclusions: High burden of TF detected in young children strengthens the need for TCV introduction. Given the concurrent iNTS disease burden, development of a trivalent vaccine against S. Typhi, S. Typhimurium, and S. Enteritidis may be timely in this region.

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.

BACKGROUND: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. METHODS: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing. FINDINGS: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). INTERPRETATION: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. FUNDING: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

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.

Typhoid fever is estimated to cause between 11.9-26.9 million infections globally each year with 129,000-216,510 deaths. Access to improved water sources have reduced disease incidence in parts of the world but the use of efficacious vaccines is seen as an important public health tool for countries with a high disease burden. A new generation of Vi typhoid conjugate vaccines (TCVs), licensed for use in young children and expected to provide longer lasting protection than previous vaccines, are now available. The WHO Strategic Advisory Group of Experts on Immunization (SAGE) has convened a working group to review the evidence on TCVs and produce an updated WHO position paper for all typhoid vaccines in 2018 that will inform Gavi, the Vaccine Alliance's future vaccine investment strategies for TCVs. The Typhoid Vaccine Acceleration Consortium (TyVAC) has been formed through a $36.9 million funding program from the Bill & Melinda Gates Foundation to accelerate the introduction of TCVs into Gavi-eligible countries. In October 2016, a meeting was held to initiate planning of TCV effectiveness studies that will provide the data required by policy makers and stakeholders to support decisions on TCV use in countries with a high typhoid burden. Discussion topics included (1) the latest evidence and data gaps in typhoid epidemiology; (2) WHO and Gavi methods and data requirements; (3) data on TCV efficacy; (4) cost effectiveness analysis for TCVs from mathematical models; (5) TCV delivery and effectiveness study design. Specifically, participants were asked to comment on study design in 3 sites for which population-based typhoid surveillance is underway. The conclusion of the meeting was that country-level decision making would best be informed by the respective selected sites in Africa and Asia vaccinating children aged from 9-months to 15-years-old, employing either an individual or cluster randomized design with design influenced by population characteristics, transmission dynamics, and statistical considerations.

Lack of evidence for post-vaccine onset of autoimmune/lymphoproliferative disorders, during a nine-month follow-up in multiply vaccinated Italian military personnel.

Anecdotal case reports, amplified by mass media and internet-based opinion groups, have recently indicated vaccinations as possibly responsible for autoimmunity/lymphoproliferation development. Multiply vaccinated Italian military personnel (group 1, operating in Italy, group 2, operating in Lebanon) were followed-up for nine months to monitor possible post-vaccine autoimmunity/lymphoproliferation onset. No serious adverse event was noticed in both groups. Multivariate analysis of intergroup differences only showed a significant association between lymphocyte increase and tetanus/diphtheria vaccine administration. A significant post-vaccine decrease in autoantibody positivity was observed. Autoantibodies were also studied by microarray analysis of self-proteins in subjects exposed to ≥4 concurrent vaccinations, without observing significant difference among baseline and one and nine months post-vaccine. Moreover, HLA-A2 subjects have been analyzed for the possible CD8T-cell response to apoptotic self-epitopes, without observing significant difference between baseline and one month post-vaccine. Multiple vaccinations in young adults are safe and not associated to autoimmunity/lymphoproliferation onset during a nine-month-long follow-up.