Optimizing Vaccine Trials for Enteric Diseases: The Enterics for Global Health (EFGH) Shigella Surveillance Study.

In this introductory article, we describe the rationale for the Enterics for Global Health (EFGH) Shigella surveillance study, which is largely to optimize the design and implementation of pivotal Shigella vaccine trials in the target population of infants and young children living in low- and middle-income countries. Such optimization will ideally lead to a shorter time to vaccine availability in the target population. We also provide a brief description of the articles included in the supplement.

Salmonella Combination Vaccines: Moving Beyond Typhoid.

There is now a robust pipeline of licensed and World Health Organization (WHO)-prequalified typhoid conjugate vaccines with a steady progression of national introductions. However, typhoid fever is responsible for less than half the total global burden of Salmonella disease, and even less among children aged <5 years. Invasive nontyphoidal Salmonella disease is the dominant clinical presentation of Salmonella in Africa, and over a quarter of enteric fever in Asia is due to paratyphoid A. In this article, we explore the case for combination Salmonella vaccines, review the current pipeline of these vaccines, and discuss key considerations for their development, including geographies of use, age of administration, and pathways to licensure. While a trivalent typhoid/nontyphoidal Salmonella vaccine is attractive for Africa, and a bivalent enteric fever vaccine for Asia, a quadrivalent vaccine covering the 4 main disease-causing serovars of Salmonella enterica would provide a single vaccine option for global Salmonella coverage.

Taking on Typhoid: Eliminating Typhoid Fever as a Global Health Problem.

Typhoid fever is a significant global health problem that impacts people living in areas without access to clean water and sanitation. However, collaborative international partnerships and new research have improved both knowledge of the burden in countries with endemic disease and the tools for improved surveillance, including environmental surveillance. Two typhoid conjugate vaccines (TCVs) have achieved World Health Organization prequalification, with several more in the development pipeline. Despite hurdles posed by the coronavirus disease 2019 pandemic, multiple TCV efficacy trials have been conducted in high-burden countries, and data indicate that TCVs provide a high degree of protection from typhoid fever, are safe to use in young children, provide lasting protection, and have the potential to combat typhoid antimicrobial resistance. Now is the time to double down on typhoid control and elimination by sustaining progress made through water, sanitation, and hygiene improvements and accelerating TCV introduction in high-burden locations.

Systematic review of global hepatitis E outbreaks to inform response and coordination initiatives.

INTRODUCTION: Hepatitis E virus (HEV) is the most common cause of acute hepatitis. While symptoms are generally mild and resolve within weeks, some populations (e.g., pregnant women, immunocompromised adults) are at high-risk of severe HEV-related morbidity and mortality. There has not been a recent comprehensive review of contemporary HEV outbreaks, which limits the validity of current disease burden estimates. Therefore, we aimed to characterize global HEV outbreaks and describe data gaps to inform HEV outbreak prevention and response initiatives. METHODS: We performed a systematic review of peer-reviewed (PubMed, Embase) and gray literature (ProMED) to identify reports of outbreaks published between 2011 and 2022. We included (1) reports with ≥ 5 cases of HEV, and/or (2) reports with 1.5 times the baseline incidence of HEV in a specific population, and (3) all reports with suspected (e.g., clinical case definition) or confirmed (e.g., ELISA or PCR test) cases if they met criterium 1 and/or 2. We describe key outbreak epidemiological, prevention and response characteristics and major data gaps. RESULTS: We identified 907 records from PubMed, 468 from Embase, and 247 from ProMED. We screened 1,362 potentially relevant records after deduplication. Seventy-one reports were synthesized, representing 44 HEV outbreaks in 19 countries. The populations at risk, case fatalities, and outbreak durations were not reported in 66% of outbreak reports. No reports described using HEV vaccines. Reported intervention efforts included improving sanitation and hygiene, contact tracing/case surveillance, chlorinating boreholes, and advising residents to boil water. Commonly missing data elements included specific case definitions used, testing strategy and methods, seroprevalence, impacts of interventions, and outbreak response costs. Approximately 20% of HEV outbreaks we found were not published in the peer-reviewed literature. CONCLUSION: HEV represents a significant public health problem. Unfortunately, extensive data shortages and a lack of standardized reporting make it difficult to estimate the HEV disease burden accurately and to implement effective prevention and response activities. Our study has identified major gaps to guide future studies and outbreak reporting systems. Our results support the development of standardized reporting procedures/platforms for HEV outbreaks to ensure accurate and timely data distribution, including active and passive coordinated surveillance systems, particularly among high-risk populations.

Consequences of Shigella infection in young children: a systematic review.

OBJECTIVES: We conducted a systematic review of the longitudinal consequences of Shigella infection in children to inform the value proposition for an effective vaccine. METHODS: We searched PubMed and Embase for studies published from January 01, 1980 to December 12, 2022 and conducted in low- and middle-income countries that included longitudinal follow-up after Shigella detection among children aged <5 years, irrespective of language. We collected data on all outcomes subsequent to Shigella detection, except mortality. RESULTS: Of 2627 papers identified, 52 met inclusion criteria. The median sample size of children aged <5 years was 66 (range 5-2172). Data were collected in 20 countries; 56% (n = 29) of the publications included Bangladesh. The most common outcomes related to diarrhea (n = 20), linear growth (n = 14), and the mean total cost of a Shigella episode (n = 4; range: $ 6.22-31.10). Among children with Shigella diarrhea, 2.9-61.1% developed persistent diarrhea (≥14 days); the persistence was significantly more likely among children who were malnourished, had bloody stool, or had multidrug-resistant Shigella. Cumulative Shigella infections over the first 2 years of life contributed to the greatest loss in length-for-age z-score. CONCLUSION: We identified evidence that Shigella is associated with persistent diarrhea, linear growth faltering, and economic impact to the family.

Pivotal Shigella Vaccine Efficacy Trials-Study Design Considerations from a Shigella Vaccine Trial Design Working Group.

Vaccine candidates for Shigella are approaching phase 3 clinical trials in the target population of young children living in low- and middle-income countries. Key study design decisions will need to be made to maximize the success of such trials and minimize the time to licensure and implementation. We convened an ad hoc working group to identify the key aspects of trial design that would meet the regulatory requirements to achieve the desired indication of prevention of moderate or severe shigellosis due to strains included in the vaccine. The proposed primary endpoint of pivotal Shigella vaccine trials is the efficacy of the vaccine against the first episode of acute moderate or severe diarrhea caused by the Shigella strains contained within the vaccine. Moderate or severe shigellosis could be defined by a modified Vesikari score with dysentery and molecular detection of vaccine-preventable Shigella strains. This report summarizes the rationale and current data behind these considerations, which will evolve as new data become available and after further review and consultation by global regulators and policymakers.

The Burden of Typhoid Fever in Sub-Saharan Africa: A Perspective.

While typhoid fever has largely been eliminated in high-income regions which have developed modern water, sanitation, and hygiene facilities, it remains a significant public health burden resulting in morbidity and mortality among millions of individuals in resource-constrained settings. Prevention and control efforts are needed that integrate several high-impact interventions targeting facilities and infrastructure, including those addressing improvements in sanitation, access to safe water, and planned urbanization, together with parallel efforts directed at effective strategies for use of typhoid conjugate vaccines (TCV). The use of TCVs is a critical tool with the potential of having a rapid impact on typhoid fever disease burden; their introduction will also serve as an important strategy to combat evolving antimicrobial resistance to currently available typhoid fever treatments. Well-designed epidemiological surveillance studies play a critical role in establishing the need for, and monitoring the impact of, typhoid fever control and prevention strategies implemented by public health authorities. Here, we present a perspective based on a narrative review of the impact of typhoid fever on morbidity and mortality in sub-Saharan Africa and discuss ongoing surveillance activities and the role of vaccination in prevention and control efforts.

Accuracy of Medical Examiner's Assessment for Near-Real-Time Surveillance of Fatal Drug Overdoses, King County, Washington, March 2017-February 2018.

OBJECTIVES: Up-to-date information on the occurrence of drug overdose is critical to guide public health response. The objective of our study was to evaluate a near-real-time fatal drug overdose surveillance system to improve timeliness of drug overdose monitoring. METHODS: We analyzed data on deaths in the King County (Washington) Medical Examiner's Office (KCMEO) jurisdiction that occurred during March 1, 2017-February 28, 2018, and that had routine toxicology test results. Medical examiners (MEs) classified probable drug overdoses on the basis of information obtained through the death investigation and autopsy. We calculated sensitivity, positive predictive value, specificity, and negative predictive value of MEs' classification by using the final death certificate as the gold standard. RESULTS: KCMEO investigated 2480 deaths; 1389 underwent routine toxicology testing, and 361 were toxicologically confirmed drug overdoses from opioid, stimulant, or euphoric drugs. Sensitivity of the probable overdose classification was 83%, positive predictive value was 89%, specificity was 96%, and negative predictive value was 94%. Probable overdoses were classified a median of 1 day after the event, whereas the final death certificate confirming an overdose was received by KCMEO an average of 63 days after the event. CONCLUSIONS: King County MEs' probable overdose classification provides a near-real-time indicator of fatal drug overdoses, which can guide rapid local public health responses to the drug overdose epidemic.

Typhoid in India: An Age-old Problem With an Existing Solution.

Enteric fever continues to impact millions of people who lack adequate access to clean water and sanitation. The typhoid and paratyphoid fever burden in South Asia is broadly acknowledged, but current estimates of incidence, severity, and cost of illness from India are lacking. This supplement addresses this gap in our knowledge, presenting findings from two years of surveillance, conducted at multiple sites between October 2017 and February 2020, in the Surveillance for Enteric Fever in India (SEFI) network. Results provide contemporaneous evidence of high disease burden and cost of illness-the latter borne largely by patients in the absence of universal healthcare coverage in India. Against a backdrop of immediate priorities in the COVID-19 pandemic, these data are a reminder that typhoid, though often forgotten, remains a public health problem in India. Typhoid conjugate vaccines, produced by multiple Indian manufacturers, and recommended for use in high burden settings, ensure that the tools to tackle typhoid are an immediately available solution to this public health problem.

Streptococcus pyogenes pbp2x Mutation Confers Reduced Susceptibility to ß-Lactam Antibiotics.

Two near-identical clinical Streptococcus pyogenes isolates of emm subtype emm43.4 with a pbp2x missense mutation (T553K) were detected. Minimum inhibitory concentrations (MICs) for ampicillin and amoxicillin were 8-fold higher, and the MIC for cefotaxime was 3-fold higher than for near-isogenic control isolates, consistent with a first step in developing ß-lactam resistance.

Demonstrating vaccine effectiveness during a waning epidemic: A WHO/NIH meeting report on approaches to development and licensure of Zika vaccine candidates.

Since its peak in early 2016, the incidence of Zika virus (ZIKV) cases has declined to such low levels that Phase 3 field efficacy trials may be infeasible. While great progress was made to rapidly advance several vaccine candidates into Phase 1 and 2 clinical trials, in the absence of sustained viral transmission it may be difficult to evaluate the effectiveness of ZIKV vaccine candidates by conducting traditional clinical disease endpoint efficacy studies. However, ZIKV is still circulating at low levels in some areas and is likely to re-emerge in naïve populations or in sites of prior epidemics once population immunity wanes. Therefore, the public health need for a ZIKV vaccine remains. To facilitate continued ZIKV vaccine development efforts, the World Health Organization's Initiative for Vaccine Research and the National Institutes of Health's National Institute of Allergy and Infectious Diseases co-hosted a meeting of experts in March 2018 to identify strategies to demonstrate vaccine effectiveness in view of waning ZIKV disease incidence. This paper outlines points for consideration for developers, regulators, and other stakeholders working towards a licensed ZIKV vaccine. These deliberations may also be applicable to development of vaccines for other emerging infections where the size, unpredictability, and ephemeral nature of outbreaks makes clinical disease endpoint efficacy trials to demonstrate vaccine effectiveness infeasible.

Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine.

The Strategic Advisory Group of Experts (SAGE) on Immunization advises WHO on global policies for vaccines. In April, 2016, SAGE issued recommendations on the use of the first licenced dengue vaccine, CYD-TDV. In November, 2017, a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, showed that although in high seroprevalence settings the vaccine provides overall population benefit, there was an excess risk of severe dengue in seronegative vaccinees. SAGE's working group on dengue vaccines met to discuss the new data and mainly considered two vaccination strategies: vaccination of populations with dengue seroprevalence rates above 80% or screening of individuals before vaccination, and vaccinating only seropositive individuals. We report on the deliberations that informed the recommendation of the pre-vaccination screening strategy, in April, 2018. Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses.

Zika vaccines and therapeutics: landscape analysis and challenges ahead.

BACKGROUND: Various Zika virus (ZIKV) vaccine candidates are currently in development. Nevertheless, unique challenges in clinical development and regulatory pathways may hinder the licensure of high-quality, safe, and effective ZIKV vaccines. DISCUSSION: Implementing phase 3 efficacy trials will be difficult given the challenges of the spatio-temporal heterogeneity of ZIKV transmission, the unpredictability of ZIKV epidemics, the broad spectrum of clinical manifestations making a single definite endpoint difficult, a lack of sensitive and specific diagnostic assays, and the need for inclusion of vulnerable target populations. In addition to a vaccine, drugs for primary prophylaxis, post-exposure prophylaxis, or treatment should also be developed to prevent or mitigate the severity of congenital Zika syndrome. CONCLUSION: Establishing the feasibility of immune correlates and/or surrogates are a priority. Given the challenges in conducting phase 3 trials at a time of waning incidence, human challenge trials should be considered to evaluate efficacy. Continued financial support and engagement of industry partners will be essential to the successful development, licensure, and accessibility of Zika vaccines or therapeutics.

Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.

Live-attenuated tetravalent dengue vaccines: The needs and challenges of post-licensure evaluation of vaccine safety and effectiveness.

Since December 2015, the first dengue vaccine has been licensed in several Asian and Latin American countries for protection against disease from all four dengue virus serotypes. While the vaccine demonstrated an overall good safety and efficacy profile in clinical trials, some key research questions remain which make risk-benefit-assessment for some populations difficult. As for any new vaccine, several questions, such as very rare adverse events following immunization, duration of vaccine-induced protection and effectiveness when used in public health programs, will be addressed by post-licensure studies and by data from national surveillance systems after the vaccine has been introduced. However, the complexity of dengue epidemiology, pathogenesis and population immunity, as well as some characteristics of the currently licensed vaccine, and potentially also future, live-attenuated dengue vaccines, poses a challenge for evaluation through existing monitoring systems, especially in low and middle-income countries. Most notable are the different efficacies of the currently licensed vaccine by dengue serostatus at time of first vaccination and by dengue virus serotype, as well as the increased risk of dengue hospitalization among young vaccinated children observed three years after the start of vaccination in one of the trials. Currently, it is unknown if the last phenomenon is restricted to younger ages or could affect also seronegative individuals aged 9years and older, who are included in the group for whom the vaccine has been licensed. In this paper, we summarize scientific and methodological considerations for public health surveillance and targeted post-licensure studies to address some key research questions related to live-attenuated dengue vaccines. Countries intending to introduce a dengue vaccine should assess their capacities to monitor and evaluate the vaccine's effectiveness and safety and, where appropriate and possible, enhance their surveillance systems accordingly. Targeted studies are needed, especially to better understand the effects of vaccinating seronegative individuals.