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INTRODUCTION: The leishmaniases represent a group of parasitic diseases caused by infection with one of several species of Leishmania parasites. Disease presentation varies because of differences in parasite and host genetics and may be influenced by additional factors such as host nutritional status or co-infection. Studies in experimental models of Leishmania infection, vaccination of companion animals and human epidemiological data suggest that many forms of leishmaniasis could be prevented by vaccination, but no vaccines are currently available for human use. AREAS COVERED: We describe some of the existing roadblocks to the development and implementation of an effective leishmaniasis vaccine, based on a review of recent literature found on PubMed, BioRxiv and MedRxiv. In addition to discussing scientific unknowns that hinder vaccine candidate identification and selection, we explore gaps in knowledge regarding the commercial and public health value propositions underpinning vaccine development and provide a route map for future research and advocacy. EXPERT OPINION: Despite significant progress, leishmaniasis vaccine development remains hindered by significant gaps in understanding that span the vaccine development pipeline. Increased coordination and adoption of a more holistic view to vaccine development will be required to ensure more rapid progress in the years ahead.

BACKGROUND Despite Group B streptococcus being a leading cause of maternal and infant morbidity and mortality, no vaccine is currently available to prevent this disease. To inform vaccine developers, countries, and funders, we analyse in this paper the key factors likely to influence the demand for a GBS vaccine and the long-term financial sustainability for a commercial entity considering the development of such a vaccine. METHODS By using population-based forecasting, we estimated the demand for a GBS vaccine based on the burden of disease, the strength of the maternal immunisation systems, the fiscal space, and the track record in introducing new vaccines. Furthermore, we estimated the financial viability for a vaccine developer by estimating the Net Present Value of the vaccine development project using a Discounted Cash Flow model. RESULTS Demand for this vaccine can be significant if policy recommendations for use are adopted by countries, in particular the largest ones, most of which have a burden that justifies the use of the vaccine and if financing for the vaccine will be made available either by countries themselves or by funding mechanisms such as Gavi, the Vaccine Alliance. Different administration schedules may result in even larger demand. With a widespread policy recommendation, the commercial viability of this vaccine can be achieved. The cost of clinical development - particularly the type of pivotal trial required - and the number of competitors are the factors that can strongly influence the long-term financial sustainability and hence the interest of vaccine developers. CONCLUSIONS This analysis suggests the potential for full financial and commercial viability for a manufacturer pursuing the development and commercialization of a GBS vaccine. Risks exists in relation to the clinical trial design and costs, the level of competition, countries' ability to pay, the administration schedule and the availability of policies that encourage use of the vaccine. To reduce those risks and ensure equitable access to a GBS vaccine, the role of donors or financers can prove very important; as can a coordinated operational research agenda that aims at clarifying those areas of uncertainty.

Partnerships are fundamental to progress in immunization, and this is especially true for human papillomavirus (HPV) vaccination, which must be delivered in the context of a broader immunization, sexual and reproductive health, and cervical cancer prevention programs. Starting from the discovery and development of HPV vaccines, through to implementation and improvement of the program's resilience, partnerships have played a critical role. In May 2018, the Global Strategy to Accelerate the Elimination of Cervical Cancer set a target for 90 % of girls to be fully vaccinated with HPV vaccine by age 15 years. This will require effective partnership and multisectoral collaboration among current and future partners to ensure alignment of interests, efficient execution, and the establishment of mechanisms to resolve emerging challenges and pre-empt foreseeable risks. In ramping up this partnering approach, HPV can provide a template for other health and immunization programs. ispartof: Vaccine pages:S0264-410X(22)01453-0- ispartof: location:Netherlands status: Published online

Highlights • The M&E/A framework was a critically important element of GVAP. • It was a cyclical process of monitoring, review, and recommendations for action. • Though a step in the right direction, it failed to hold all stakeholders accountable. • Several GVAP goals were aspirational and unrealistic for many countries., Introduction The Monitoring & Evaluation/Accountability (M&E/A) framework of the Global Vaccine Action Plan (GVAP) was used to report progress annually to the World Health Assembly (WHA). Methods Stakeholder feedback was obtained through five reviews consisting of surveys and semi-structured interviews conducted from 2017 to 2019. Participants consisted of individuals involved in the development and implementation of GVAP or its M&E/A process, national immunization managers, academics, representatives of non-governmental organizations, and civil society organizations. Results The feedback was mixed and contradictory for some components, though most participants reported that the M&E/A process was a highlight of GVAP and a step in the right direction. Several of the goals and targets were considered aspirational and unrealistic for many countries. There were mixed responses on whether it promoted accountability, especially at the country level. Discussion The mixed and contradictory views on the M&E/A processes and its impact suggested a failure of communication about its scope and intent. Though the process, especially the annual reporting to the WHA, kept immunization high on the global agenda, it failed to fully meet the expectations in promoting accountability. Engaging with countries to capture the local context in setting global goals and targets and promoting local M&E/A processes will be important to achieve accountability in the next decade.

Highlights • GVAP built visibility for immunization and was an improvement over prior plans. • GVAP implementation was incomplete due to limited awareness and stakeholder buy-in. • The GVAP Monitoring & Evaluation/Accountability framework gave valuable guidance. • Future strategies should build greater buy-in and communicate more effectively., Introduction The Global Vaccine Action Plan (GVAP), unanimously endorsed by the World Health Assembly in 2012, defined an ambitious strategy to improve immunization. At the end of the decade, significant progress has been made but four of the five GVAP goals are likely to be missed. This report describes a set of surveys and interviews relating to GVAP, conducted to inform the immunization strategy for the next decade. Methods Three surveys and two sets of semi-structured interviews were conducted from 2017 to 2019. Respondents consisted of immunization stakeholders at global, regional, and country levels, and included individuals who had been involved in the development and implementation of GVAP or its monitoring, evaluation and accountability (M&E/A) process; national immunization managers; academics; and personnel from non-governmental organizations and civil society organizations. Results The surveys and interviews gave consistent results. They highlighted the value of GVAP in increasing visibility for immunization and the benefits of the GVAP M&E/A framework. The main limitations of GVAP were identified as the limited ownership by countries and other stakeholders leading to incomplete implementation of the strategy and poor accountability for achieving GVAP targets. Discussion These results informed the review of GVAP and the development of its successor strategy, the Immunization Agenda 2030. In addition, these surveys and interviews identified two challenges in assessing the value of GVAP: the need to rely exclusively on stakeholder perspectives and difficulties in attributing benefits. These challenges are inherent in evaluating an over-arching strategy such as GVAP and should be factored into interpretation of the results.

The development of vaccines against one or all forms of human leishmaniasis remains hampered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 310-830 million doses for a vaccine preventing visceral leishmaniasis and 557-1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years ∼160,000 doses for prevention and ∼7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.Author SummaryThe leishmaniases are potentially vaccine-preventable diseases of global importance, yet no vaccines for human use have attained registration. This work sheds lights on the potential size of demand for a human vaccine for the prevention of visceral and cutaneous leishmaniasis as well as for the prevention and treatment of post-kala-azar dermal leishmaniasis. The analysis is grounded in the definition of vaccine use cases which, by transparently defining different applications of the vaccines in the immunisation programs, provides the basis for defining the target populations and vaccine characteristics. The output of this work, the first-of-its-kind for leishmaniasis, fills a critical information gap and will provide policy makers and vaccine developers with important insights into the public health relevance of a human leishmaniasis vaccine and the strengths of its commercial value proposition. Ultimately this research aims to inform future decisions on disease prioritization and on investments by key stakeholders, as well as to identify areas for further research.

SUMMARY Objectives : We sought to collate and summarize high-quality data on non-typhoidal Salmonella invasive disease (iNTS) incidence to provide contemporary incidence estimates by location and year. Methods : We systematically searched the databases Embase + MEDLINE, Web of Science, and PubMed for articles published on the incidence of iNTS from inception of the database through 8 May 2020 with no language, country, date, or demographic restrictions applied. A meta-analysis was performed to report pooled iNTS incidence as a rate of cases per 100,000 per year. Results : Among 13 studies eligible for analysis, there were 68 estimates of incidence. Overall pooled incidence (95% CI) was 44.8 (31.5-60.5) per 100,000 persons per year. When stratified by region, pooled incidence was significantly higher in Africa than Asia, 51.0 (36.3-68.0) compared to 1.0 (0.2-2.5), respectively. Incidence was consistently higher in children aged

BACKGROUND: Non-typhoidal salmonella can cause serious, life-threatening invasive infections involving the bloodstream and other normally sterile sites. We aimed to systematically review the prevalence of complications and case-fatality ratio (CFR) of non-typhoidal salmonella invasive disease to provide contemporary global estimates and inform the development of vaccine and non-vaccine interventions. METHODS: We did a global systematic review and meta-analysis of studies investigating the complications and mortality associated with non-typhoidal salmonella invasive disease. We searched Embase, MEDLINE, Web of Science, and PubMed for peer-reviewed, primary research articles published from database inception up to June 4, 2021, with no restrictions on language, country, date, or participant demographics. Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included. We excluded case reports, case series, policy reports, commentaries, editorials, and conference abstracts. Data on the prevalence of complications and CFR were abstracted. The primary outcomes were to estimate the prevalence of complications and CFR of non-typhoidal salmonella invasive disease. We calculated an overall pooled CFR estimate and pooled CFR stratified by UN region, subregion, age group, and by serovar when available with a random-effects meta-analysis. A risk-of-bias assessment was done, and heterogeneity was assessed with Cochran's Q Test, I2, and τ2. This study was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and is registered with PROSPERO, CRD42020202293. FINDINGS: The systematic review returned a total of 8770 records. After duplicates were removed, 5837 titles and abstracts were screened, yielding 84 studies from 35 countries after exclusions. Of these included studies, 77 (91·7%) were hospital-based and 66 (78·6%) were located in Africa or Asia. Among 55 studies reporting non-typhoidal salmonella disease-associated complications, a total of 45 different complications were reported and 1824 complication events were identified among 6974 study participants. The most prevalent complication was septicaemia, occurring in 171 (57·2%) of 299 participants, followed by anaemia in 580 (47·3%) of 1225 participants. From 81 studies reporting the CFR of non-typhoidal salmonella invasive disease, the overall pooled CFR estimate was 14·7% (95% CI 12·2-17·3). When stratified by UN region, the pooled CFR was 17·1% (13·6-21·0) in Africa, 14·0% (9·4-19·4) in Asia, 9·9% (6·4-14·0) in Europe, and 9·6% (0·0-25·1) in the Americas. Of all 84 studies, 66 (78·6%) had an overall high risk of bias, 18 (21·4%) had a moderate risk, and none had a low risk. Substantial heterogeneity (I2>80%) was observed in most (15 [65·2%] of 23) CFR estimates. INTERPRETATION: Complications were frequent among individuals with non-typhoidal salmonella invasive disease and approximately 15% of patients died. Clinicians, especially in African countries, should be aware of non-typhoidal salmonella invasive disease as a cause of severe febrile illness. Prompt diagnoses and management decisions, including empiric antimicrobial therapy, would improve patient outcomes. Additionally, investments in improving clinical microbiology facilities to identify non-typhoidal salmonella and research efforts towards vaccine development and non-vaccine prevention measures would prevent non-typhoidal salmonella invasive disease-associated illness and death. FUNDING: EU Horizon 2020 research and innovation programme. ispartof: LANCET INFECTIOUS DISEASES vol:22 issue:5 pages:692-705 ispartof: location:United States status: published

Human visceral leishmaniasis (VL) vaccines are currently under development and there is a need to understand their potential impact on population wide VL incidence. We implement four characteristics from different human VL vaccine candidates into two published VL transmission model variants to estimate the potential impact of these vaccine characteristics on population-wide anthroponotic VL incidence on the Indian subcontinent (ISC). The vaccines that are simulated in this study 1) reduce the infectiousness of infected individuals towards sand flies, 2) reduce risk of developing symptoms after infection, 3) reduce the risk of developing post-kala-azar dermal leishmaniasis (PKDL), or 4) lead to the development of transient immunity. We also compare and combine a vaccine strategy with current interventions to identify their potential role in elimination of VL as a public health problem. We show that the first two simulated vaccine characteristics can greatly reduce VL incidence. For these vaccines, an approximate 60% vaccine efficacy would lead to achieving the ISC elimination target (, Author summary Vaccines for human visceral leishmaniasis (VL) are currently under development. In this study, we simulate VL transmission dynamics using mathematical models to explore the potential impact of vaccines on population-wide incidence. We show that some vaccines have high potential to reduce VL incidence, namely those that reduce the infectiousness of infected individuals to sand flies and those that reduce the chance of developing symptoms once infected. The effect of vaccines that lead to protection from infection is potentially the greatest, but depending on the duration of immunity, individuals would require booster doses to guarantee lifelong impact. Vaccines that prevent the development of post-kala-azar dermal leishmaniasis are a promising tool to sustain low VL incidence and prevent recrudescence of infection when regular interventions are halted. Our results strongly support the continued development of VL vaccines, as their potential impact on population incidence can be substantial.

Over the past decade, several countries across all regions, income groups and procurement methods have been unable to secure sufficient BCG vaccine supply. While the frequency of stock-outs has remained rather stable, duration increased in 2014-2015 due to manufacturing issues and attracted the attention of national, regional and global immunization stakeholders. This prompted an in-depth analysis of supply and demand dynamics aiming to characterize supply risks. This analysis is unique as it provides a global picture, where previous analyses have focused on a portion of the market procuring through UN entities. Through literature review, supplier interviews, appraisal of shortages, stock-outs and historical procurement data, and through demand forecasting, this analysis shows an important increase in global capacity in 2017: supply is sufficient to meet forecasted BCG vaccine demand and possibly buffer market shocks. Nevertheless, risks remain mainly due to supply concentration and limited investment in production process improvements, as well as inflexibility in demand. Identification of these market risks will allow implementation of risk-mitigating interventions in three areas: (1) enhancing information sharing between major global health actors, countries and suppliers, (2) identifying interests and incentives to expand product registration and investment in the BCG manufacturing process, and (3) working with countries for tighter vaccine management.