Background: Millions of children in sub-Saharan Africa remain incompletely vaccinated, yet coverage estimates inadequately document where along the immunisation schedule they are lost. Entry-point (never starting) and follow-up (not completing) failures call for different policy responses. We reconstructed the cascade, separated the two failure types, and quantified between-country heterogeneity at each transition. Methods: We pooled 163 of 210 sub-Saharan African Demographic and Health Surveys (1989–2024) with a complete vaccination module, analysing children aged 12–23 months (GATHER-compliant). We computed survey-weighted marginal coverage and conditional dose-completion probabilities for BCG, DPT/Pentavalent doses 1,2,3, and the first-dose measles-containing vaccine (MCV1) and assigned countries to four quadrants by entry-point (zero-dose ≥10%) and follow-up failure (≥20%) thresholds. A five-transition Markov chain was fitted DerSimonian–Laird random-effects meta-analysis with empirical-Bayes shrinkage on the logit scale; between-country variance (τ²) and Higgins’ I² were estimated. Sensitivity analyses tested card-confirmed restriction, threshold perturbation, and a Bayesian re-implementation. Findings: 263,385 children across 38 countries were analysed. Continental coverage fell from BCG 88·1% to DPT/Penta3 74·2% and MCV1 74·7% (14 percentage-point cumulative attrition). Bayes-shrunk transition probabilities ranged from 95·5% (BCG→DPT/Penta1) to 88·5% (DPT/Penta3→MCV1); the largest mid-cascade leak was DPT/Penta2→ DPT/Penta3 (89·2%, 95% CI 85·8–91·9). 21 countries were both-low, six entry-point dominant (Nigeria 54% zero-dose), four follow-up dominant, and seven both-high. Between-country variance fell roughly tenfold along the cascade (τ² 0·96 to 0·11; I²>97% throughout). The predicted continental average was 59·0% completed and 13·7% zero-dose. Findings were robust to all sensitivity analyses. Interpretation: The cascade leaks gradually rather than at a single bottleneck, and countries differ roughly tenfold more in schedule entry than in completion. Closing the entry-point gap offers the greatest scope for narrowing continental inequity. Each country’s quadrant predicts the most appropriate intervention package — outreach and zero-dose mapping, reminders and defaulter tracing, or integrated EPI strengthening.

While a growing number of invasive non-typhoidal Salmonella (iNTS) vaccine candidates, including trivalent formulations with typhoid conjugate vaccine (TCV), are in early development, the market demand and commercial potential remain unclear. This study presents a novel demand and financial forecast model for a hypothetical trivalent iNTS-typhoid vaccine, designed for introduction in sub-Saharan Africa (sSA). The model includes projected vaccine demand, revenue and profit forecasts, and net present value (NPV) analysis of return on investments required for development, licensure and manufacturing of the trivalent vaccine. By year 12 after forecasted introduction, annual demand for the trivalent vaccine is projected to reach 47 million doses for a 1-dose regimen and 96 million doses for a 2-dose regimen (Scenario 2), generating annual revenues of $94 million USD and $191 million USD, respectively. Despite these projections, the risk-adjusted NPV is negative, suggesting that the market is not commercially viable for industry investment without global health funding to de-risk the investment. This model assumes a significant demand for a trivalent vaccine in sSA and highlights the need for innovative financing to ensure commercial viability of investment in the vaccine’s development and manufacturing, toward addressing a significant public health issue.

Invasive non-typhoidal Salmonella (iNTS) disease typically presents as a non-specific febrile illness that can progress to bloodstream infections and carries a high case fatality rate. Early detection improves patient outcomes, however, in resource-constrained settings, limited diagnostic capacity leads to underdiagnosis, insufficient incidence data, and incomplete epidemiological and socio-economic research on iNTS. Although no licensed vaccines currently exist, several candidates are in pre-clinical and clinical development. In the early stages of vaccine development, it is essential to consider country-level perspectives and priorities to guide the development of novel vaccines. To support this, the World Health Organization's Vaccine Innovation Framework was applied to conduct a consultation with 40 stakeholders representing the national immunization programmes in Burkina Faso, Ghana the Gambia, the Democratic Republic of the Congo (DRC), Kenya, Malawi and Mozambique. The consultation aimed to assess the stakeholder perceptions on the need for an iNTS vaccine and to evaluate its desirability, suitability, and evidence requirements from a low- and middle-income country (LMIC) perspective. Stakeholders argued that although an iNTS vaccines is desirable, the lack of nationally available epidemiological data is a barrier to accurately understanding the disease burden. A novel vaccine would be more desirable if it aligns with the preferred product characteristics specified, and helps mitigate, rather than exacerbate, current immunization programme challenges. They also expressed a preference for combination vaccines that align programmatically, including formulations combining iNTS with typhoid conjugate vaccine (TCV), to reduce the number of injections and simplify delivery logistics. To make evidence-based decisions on potential introduction, stakeholders emphasized the need for robust data on the value and impact of iNTS vaccines.

Invasive non-typhoidal Salmonella disease represents a major public health challenge, particularly in sub-Saharan Africa, where it is a leading cause of community-acquired bloodstream infections. Despite its significant morbidity and mortality, no licensed vaccines exist. Recognizing this unmet need, multiple global health initiatives and targeted investments have advanced iNTS vaccine development. These efforts have advanced several promising candidates employing diverse platform technologies, including the first iNTS vaccine candidate to enter clinical trials in more than 15 years in 2019. To date, three additional candidates have entered clinical development-two progressing through Phase 2 trials and one currently in a Phase 1/2 study-while many more remain in preclinical development. Several candidates also incorporate antigens targeting Salmonella Typhi or Salmonella Paratyphi A alongside iNTS components to broaden coverage and expand market potential. Despite this progress, scientific, regulatory and commercial challenges persist. In response, global health organizations have intensified efforts to support vaccine development, clarify regulatory pathways and foster engagement with key decision-makers, including through the development of Preferred Product Characteristics and a Full Value of Vaccines Assessment. These coordinated efforts mark a significant step toward enabling and accelerating iNTS vaccine development, ultimately aiming to prevent iNTS disease and its associated health burden.

This study, grounded in the key stakeholders’ perspectives, highlights the critical and immediate need for the development of a new iNTS vaccine. An online survey was conducted among government officials and healthcare providers across eight African countries: Burkina Faso, the Democratic Republic of Congo, Ethiopia, Ghana, Kenya, Malawi, Mozambique, and Nigeria. The framework was built on Spring Boot and Java 8, enabling access via personal computers or mobile phones. A total of 74 out of 84 participants completed the survey. Over 50% indicated that iNTS is both a prevalent and serious disease in their respective countries. The majority (n = 70, 94.6%) identified antibiotics as the most effective treatment for iNTS disease, while 55 (67.6%) participants chose vaccination as the preferred preventive option. Respondents ranked the iNTS vaccine third. Notably, 75.7% (n = 56) emphasized the urgent need for an iNTS vaccine. Barriers to vaccine introduction were identified as insufficient funding (n = 61, 81.4%), limited awareness (n = 49, 79.7%), and challenges related to community acceptance (n = 49, 79.7%). The stakeholders’ perspectives highlight an urgent need for iNTS vaccine development. Accelerated and focused efforts are essential to address the reported pressing challenges and to pursue innovative and promising pathways for advancing iNTS vaccine development.

The era of highly effective pre-exposure prophylaxis (PrEP) has transformed HIV prevention, yet global HIV incidence remains unacceptably high, particularly in sub-Saharan Africa. While antiretroviral-based prevention is critical, persistent structural barriers to access and adherence highlight the urgent need for a complementary preventive HIV vaccine. In this narrative review and perspective, we argue that scientific progress toward an HIV vaccine must be matched by equally ambitious preparedness investments across three domains: manufacturing and supply chains, clinical trial and regulatory infrastructure, and delivery systems and community engagement. Drawing on lessons from the global rollout of PrEP, post-exposure prophylaxis (PEP), and the COVID-19 pandemic response, we outline a five-pillar strategic roadmap. This roadmap focuses on ensuring that a future HIV vaccine reaches the people who need it most from the moment of regulatory authorization, calling for co-investment in diverse platforms, binding advance market commitments, logistical simulation, and proactive planning for post-licensure effectiveness trials. Preparedness is not secondary to science; it is its essential partner.

Cholera remains a significant public health concern globally. To address this, the World Health Organization and Gavi have coordinated an oral cholera vaccine (OCV) stockpile since 2013, enabling timely vaccine access for countries experiencing outbreaks. Using comprehensive shipment data and a transmission model, the current study assessed the impact of vaccination campaigns across all recipient nations over time. The analysis estimated health outcomes under both real-world conditions—with observed delays and supply shortages—and ideal scenarios where these constraints were eliminated. Under actual shipments, vaccination campaigns prevented approximately 8.1 million cholera cases and 146,013 deaths, averting 6.7 million disability-adjusted life years (DALYs) and reducing the economic burden by US$1.05 billion. In scenarios without delays or supply limitations, the benefits were even greater, with an estimated 17.4 million cases, 321,730 deaths, and 15.1 million DALYs averted. Enhanced timeliness and sufficient vaccine supply are key to maximizing public health impact.

Since the inception of the World Health Organization (WHO) Extended Programme on Immunization in 1974, vaccines have saved the lives of approximately 150 million children, and they continue to save 2-5 million lives each year, according to WHO estimates. The consensus around the benefit and funding of childhood vaccination in low- and middle-income countries has unraveled, and the hard-won gains of the past quarter century are at risk. At the same time, in some high-income countries, vaccine hesitancy-sometimes enabled by government policy pronouncements-has led to reductions in vaccination, resulting in outbreaks of measles in countries that had eliminated this disease. Despite these setbacks, advances in vaccine platform technologies, new immunogens, and new and expanding target populations have the potential to extend the direct and indirect effects of vaccination across the life course. In this Perspective, we discuss how each of these advances could shape the future vaccine landscape. We also highlight cross-cutting issues, including those related to equity, manufacturing, funding and vaccine hesitancy, which make successful implementation more complex.

Invasive disease caused by non-typhoidal Salmonella serovars (iNTS) occurs with increased risk in the presence of other comorbidities such as malaria, HIV, malnutrition, anaemia and sickle cell disease. While infection with non-typhoidal (NTS) serovars often results in self-limited enterocolitis in high-income settings, in sub-Saharan Africa (SSA) where these risk-comorbidities are common, an invasive (iNTS) disease phenotype is seen, associated with up to 20 % case-fatality ratio, and antimicrobial resistance is both significant and growing. The need to evaluate the potential public health value of vaccines against iNTS disease is increasingly being recognized, and several candidate vaccines are in early development. A better understanding of the global burden and epidemiology of iNTS disease, as well as the potential public health and socio-economic benefits that iNTS vaccines may offer is fundamental to support and justify the investments in vaccine development. In addition, the pathways for licensure, policy recommendations and eventual vaccine prioritization and use in low- and middle-income countries (LMICs) need to be defined. Here, we report on the proceedings of an expert consultation held on 29 November - 1 December 2021 as part of an overall project to develop a Full Value of Vaccines Assessment (FVVA) for iNTS vaccines and in addition to more recent iNTS vaccine developments. Experts at the consultation reviewed the current evidence on iNTS disease and discussed knowledge gaps to be addressed to accelerate vaccine development, licensure and introduction, as well as LMIC perspectives on potential iNTS vaccine use and demand. The learnings from this consultation are critical inputs to inform remaining work under the iNTS FVVA project.

Vaccines are vital for global health, and despite bearing the highest burden of infectious diseases, Africa manufactures less than 1% of its vaccine needs. This Health Policy paper offers an overview of Africa's vaccine ecosystem, examining research and development funding, clinical trials, regulatory maturity, and manufacturing readiness with publicly available data. Funding for research and development (2007-23) was analysed with data from the G-FINDER database, which focuses on diseases disproportionately affecting low-income and middle-income countries. Clinical trial activity (2007-24) was assessed with data from multiple sources. Disease burden context was provided by the Global Burden of Disease Study 2021, and regulatory maturity levels were obtained from WHO's list of National Regulatory Authorities. Findings show that Africa received less than 2% of global vaccine research and development funding, with 95% of that funding channelled through high-income countries. Only 8% of global vaccine clinical trials included sites in Africa. Progress in regulatory and manufacturing capacity is emerging, with eight countries reaching WHO maturity level 3 and several countries planning vaccine production facilities. Our findings highlight the need for better vaccine data in Africa and the opportunity to build on existing strengths to reach enhanced sovereignty and resilient health systems.

Invasive non-typhoidal serovars of Salmonella enterica,S. Typhimurium and S. Enteritidis, (iNTS) are estimated to cause over 500,000 cases of disease leading to more than 79,000 deaths with a high case fatality ratio of 14.5 %. Most infections occur in infants and young children in LMICs in sub-Saharan Africa where host risk factors for iNTS disease such as malaria, malnutrition, HIV infection, and anemia are common. iNTS disease is observed from birth, with a peak incidence early in the second year of life, declining before the age of 3 years. The prevalence of multiple drug resistance of iNTS has increased markedly by decade, emphasizing the need for effective vaccines. A clinical development plan and regulatory pathway for licensure of iNTS vaccines has been shaped following the development of Preferred Product Characteristics and R&D Roadmap through a series of expert consultations. Several iNTS alone or combined with Typhoid Conjugate Vaccine platforms are in early clinical development. Encouraging safety and immunogenicity data have prompted developers and manufacturers to plan efficacy trials, aligned with regulatory expectations. It is critical to clearly communicate iNTS disease burden in endemic countries and to discuss complexities related to iNTS single component or combination vaccine clinical development with regulators. An essential component is the disease burden in infants less than 6 months of age, which will inform the optimal age of first vaccination (less than or from 6 months), compatibility across national expanded programme on immunization schedules, and whether a booster dose would be needed. Early regulatory guidance is essential to make informed regulatory decisions and to guide the clinical development plan and licensure pathway. Continued communication with public health stakeholders and end-user representatives will effectively contribute to better awareness and education about iNTS disease and protection afforded by vaccination.

The COVID-19 pandemic has underscored the need for a global agreement to strengthen international health regulations. However, progress towards such an agreement has been deferred to a future World Health Assembly and is likely to be further hampered by an increasingly uncertain global geopolitical context, a delay which we cannot afford. In the interim, urgent immediate action to intensify regional cooperation on pandemic preparedness and vaccine equity is needed. The three key aspects of intensified regional cooperation are: financial and economic sustainability, regulatory systems strengthening and legal frameworks that facilitate cooperation. While there is still momentum, the global community must act swiftly and cohesively, intensifying regional cooperation to strengthen governance on pandemic prevention, preparedness and response.

BACKGROUND:Patients with cholera have been shown to be protected against subsequent cholera for 3 years after their initial episode. We aimed to assess protection at 10 years of follow-up. METHODS:In this retrospective cohort study, cohorts of patients treated for cholera (index patients) and contemporaneously selected age-matched individuals without cholera (controls), randomly selected from the population of Matlab, Bangladesh, were assembled between 1990 and 2009 and followed for up to 10 years. Selection of participants who had no history of cholera in the 5 years before selection proceeded in secular sequence, and selection was done without replacement. Protection against subsequent treated cholera was assessed in proportional hazards models and waning of protection was assessed non-parametrically with use of smoothing of protection curves. FINDINGS:We included 3925 index patients and 23 550 matched controls. Patients with El Tor cholera (26 subsequent episodes among 3619 index patients) had a 48·6% (95% CI 23·1 to 65·7; p=0·0012) lower risk of El Tor cholera than controls, with no evidence of waning during up to 10 years of follow-up (p=0·87). Index patients aged 5 years and older with El Tor cholera (nine subsequent episodes among 2279 index patients) were at a 61·7% (23·6 to 80·8; p=0·0065) lower risk of El Tor cholera, whereas index patients younger than 5 years with El Tor cholera (17 subsequent episodes among 1340 index patients) had a 36·2% (-5·0 to 61·3; p=0·077) lower risk (p=0·26 for the difference by age). INTERPRETATION:Protection against El Tor cholera associated with previous El Tor cholera was moderate in magnitude and sustained over 10 years of follow-up. These findings suggest the potential for sustained, long-term protection by oral cholera vaccines in populations with endemic cholera and help inform models of cholera in endemic settings. FUNDING:Bill & Melinda Gates Foundation.

Invasive nontyphoidal Salmonella (iNTS) infections, primarily caused by Salmonella enterica serovars Typhimurium (S. Typhimurium) and Enteritidis (S. Enteritidis), represent a significant public health concern, particularly in sub-Saharan Africa, where multidrug-resistant (MDR) strains are increasingly prevalent. Despite the substantial disease burden, no vaccines are currently licensed for iNTS. This study aimed to develop an iNTS conjugate vaccine by conjugating O-specific polysaccharide (OSP) antigens to carrier proteins using chemical conjugation, a proven method known for its efficiency and scalability in licensed glycoconjugate vaccines. Various carrier proteins and chemical conjugation processes were evaluated to optimize the iNTS OSP conjugate vaccine candidates. Through this optimization, diphtheria toxoid (DT) was identified as the carrier protein that significantly enhances the anti-OSP immunogenicity of the iNTS conjugates. Key properties, such as the molecular weight and OSP:DT ratio in the iNTS OSP conjugate were found to be controllable by adjusting the ratios of CDAP conjugate reagent and DT to iNTS OSP. Optimal conjugation process parameters were identified by evaluating the relationship between these property and immunogenicity through tests in mice. The optimized iNTS conjugates for S. Typhimurium and S. Enteritidis were further developed into a bivalent formulation. This formulation was selected based on a dose-dependent immunogenicity study and included alum as an adjuvant to enhance immune response. Ultimately, a trivalent drug product formulation was developed by combining the bivalent iNTS conjugate vaccine with a typhoid conjugate vaccine. Our findings demonstrated that the iNTS OSP-DT conjugates, at the optimal conjugation ratios, induced robust immune responses with high anti-OSP IgG titers for both iNTS serovars, comparable to or exceeding those of other formulations. The inclusion of alum further enhanced immunogenicity across all formulations. Notably, the trivalent vaccine formulation showed promising results, maintaining robust immunogenic responses against all iNTS OSP antigens and the Vi polysaccharide antigen of Salmonella Typhi, without compromising the immunogenicity of any individual antigens. This study suggests that a bivalent iNTS vaccine combined with a typhoid conjugate vaccine could provide broad protection against both iNTS infections and typhoid fever, addressing a critical unmet need in regions with limited resources.

INTRODUCTION:Invasive non-typhoidal Salmonella (iNTS) disease is a global health concern, particularly for sub-Saharan Africa. Despite high case fatality risks, there is no vaccine available against the disease. An obstacle to vaccine development is a lack of data on the economic burden of iNTS disease in many parts of the world. The main aim of the current study is to estimate the economic burden of iNTS disease in 123 countries. METHODS:Several multivariate regression models were parameterised with the data obtained from an existing systematic literature review on the economic burden of iNTS disease and all forms of NTS disease. Various model diagnostics were performed to validate the statistical significance of each model outcome, and the most suitable model was selected to predict costs in countries where no data points were available. RESULTS:A generalised linear model with gamma distribution with log link was chosen based on model diagnostics. While the average economic burden per iNTS disease episode ranged from US$341 in Africa to US$2194 in Europe, the total economic burden of iNTS disease was the highest in Africa due to the high burden of the disease in the region. CONCLUSION:The current study indicates that the economic burden of iNTS disease is substantial. Given the scarcity of field-based iNTS disease economic burden estimates, cost extrapolation through an econometric framework can be helpful for understanding the associated cost implications in a resource-limited setting and for informing the cost-effectiveness of public health interventions including future vaccination strategies.

INTRODUCTION:Hepatitis E virus (HEV) is a significant public health concern, particularly in resource-limited and conflict-affected settings. While often self-limiting, HEV infection poses severe risks for pregnant women contracted with genotype 1 or 2, leading to high maternal mortality, and can cause chronic infection in immunocompromised individuals. AREAS COVERED:This review examines the epidemiology, clinical manifestations, and vaccine landscape of HEV, highlighting licensed and investigational candidates. We discuss HEV 239 vaccine the only licensed HEV vaccine which has shown high efficacy and cross-genotype protection, leading to approval in China and Pakistan. However, data gaps remain regarding its safety in pregnant women, children, and immunocompromised populations. WHO prequalification is needed for broader global access. We also review the current status of HEV vaccine development, and explore challenges, opportunities, and global policies, including efforts to improve outbreak response in high-risk settings. EXPERT OPINION:HEV vaccines are essential for disease control, but unresolved issues limit broader use. Conflicting data on miscarriage risk require further investigation. Ongoing trials in Pakistan and South Africa will offer key data on safety in pregnancy, immunogenicity in children, and use in people with HIV. WHO prequalification of HEV 239 vaccine is critical to expand access globally.