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Background Estimates of the relative contribution of different pathogens to all-cause diarrhoea mortality are needed to inform global diarrhoea burden models and prioritize interventions. We aimed to investigate and estimate heterogeneity in the case fatality risk (CFR) of different diarrhoeal pathogens. Methods We conducted a systematic review and meta-analysis of studies that reported cases and deaths for 15 enteric pathogens published between 1990 and 2019. The primary outcome was the pathogen-specific CFR stratified by age group, country-specific under-5 mortality rate, setting, study year and rotavirus vaccine introduction status. We developed fixed-effects and multilevel mixed-effects logistic regression models to estimate the pooled CFR overall and for each pathogen, controlling for potential predictors of heterogeneity. Results A total of 416 studies met review criteria and were included in the analysis. The overall crude CFR for all pathogens was 0.65%, but there was considerable heterogeneity between and within studies. The overall CFR estimated from a random-effects model was 0.04% (95% CI: 0.026%–0.062%), whereas the pathogen-specific CFR estimates ranged from 0% to 2.7%. When pathogens were included as predictors of the CFR in the overall model, the highest and lowest odds ratios were found for enteropathogenic Escherichia coli (EPEC) [odds ratio (OR) = 3.0, 95% CI: 1.28–7.07] and rotavirus (OR = 0.23, 95% CI: 0.13–0.39), respectively. Conclusion We provide comprehensive estimates of the CFR across different diarrhoeal pathogens and highlight pathogens for which more studies are needed. The results motivate the need for diarrhoeal interventions and could help prioritize pathogens for vaccine development.

Diarrhoeal disease attributable to enterotoxigenic Escherichia coli (ETEC) causes substantial morbidity and mortality predominantly in paediatric populations in low- and middle-income countries. In addition to acute illness, there is an increasing appreciation of the long-term consequences of enteric infections, including ETEC, on childhood growth and development. Provision of potable water and sanitation and appropriate clinical care for acute illness are critical to reduce the ETEC burden. However, these interventions are not always practical and may not achieve equitable and sustainable coverage. Vaccination may be the most cost-effective and equitable means of primary prevention; however, additional data are needed to accelerate the investment and guide the decision-making process for ETEC vaccines. First, to understand and quantify the ETEC disease burden, additional data are needed on the association between ETEC infection and physical and cognitive stunting as well as delayed educational attainment. Furthermore, the role of inappropriate or inadequate antibiotic treatment of ETEC-attributable diarrhoea may contribute to the development of antimicrobial resistance (AMR) and needs further elucidation. An ETEC vaccine that mitigates acute diarrhoeal illness and minimizes the longer-term disease manifestations could have significant public health impact and be a cost-effective countermeasure. Herein we review the ETEC vaccine pipeline, led by candidates compatible with the general parameters of the Preferred Product Characteristics (PPC) recently developed by the World Health Organization. Additionally, we have developed an ETEC Vaccine Development Strategy to provide a framework to underpin priority activities for researchers, funders and vaccine manufacturers, with the goal of addressing globally unmet data needs in the areas of research, product development, and policy, as well as commercialization and delivery. The strategy also aims to guide prioritization and co-ordination of the priority activities needed to minimize the timeline to licensure and use of ETEC vaccines, especially in in low- and middle-income countries, where they are most urgently needed.

BackgroundProgress towards measles and rubella (MR) elimination has stagnated as countries are unable to reach the required 95% vaccine coverage. Microarray patches (MAPs) are anticipated to offer significant programmatic advantages to needle and syringe (N/S) presentation and increase MR vaccination coverage. A demand forecast analysis of the programmatic doses required (PDR) could accelerate MR-MAP development by informing the size and return of the investment required to manufacture MAPs.MethodsUnconstrained global MR-MAP demand for 2030-2040 was estimated for three scenarios, for groups of countries with similar characteristics (archetypes), and four types of uses of MR-MAPs (use cases). The base scenario 1 assumed that MR-MAPs would replace a share of MR doses delivered by N/S, and that MAPs can reach a proportion of previously unimmunised populations. Scenario 2 assumed that MR-MAPs would be piloted in selected countries in each region of the World Health Organization (WHO); and scenario 3 explored introduction of MR-MAPs earlier in countries with the lowest measles vaccine coverage and highest MR disease burden.ResultsFor the base scenario (1), the estimated global PDR for MR-MAPs was forecasted at 30 million doses in 2030 and increased to 220 million doses by 2040. Compared to scenario 1, scenario 2 resulted in an overall decrease in PDR of 18%, and scenario 3 resulted in a 21% increase in PDR between 2030-2040.ConclusionsSignificant demand is expected for MR-MAPs between 2030-2040, however, efforts are required to address remaining data quality, uncertainties and gaps that underpin the assumptions in this analysis.Key pointsthe delivery of measles and rubella vaccines with microarray patches (MR-MAPs) could disrupt the immunization landscape. We estimated the demand for MR-MAPs between 2030-2040 at 4.05 billion doses. This analysis will inform the size of investment required to manufacture MR-MAPs.

The mRNA vaccine technology platform may enable rapid response to some emerging infectious diseases (EIDs), as demonstrated through the COVID-19 pandemic. Beyond the role it could play in future EID response, mRNA technology also could have an important role in accelerating the development of, and access to, vaccines for some neglected tropical diseases (NTDs), which occur mainly in impoverished regions of the world. Despite their significant disease burden, few vaccines against NTDs have been developed, in part because of the uncertain market and return on investment. In addition, the probability of technical and regulatory success is considered to be low for developing vaccines against multicellular parasites, or organisms that have sophisticated mechanisms for evading immunological surveillance, such as many of the NTD pathogens. The global 2021-2030 road map for neglected tropical diseases sets ambitious targets for the eradication, elimination, and control of NTDs. For some, effective interventions exist but are underutilized. For others, vaccines need to be developed or their use expanded to meet global targets on control and elimination. This article discusses the application of the mRNA technology platform to the development of vaccines for NTDs as well as EIDs, highlights the challenges in bringing these products to the market, and indicates potential areas which could be explored, including leveraging investment for vaccines with a more profitable market potential and enabling local manufacturing in regions where NTDs are endemic. Such regional production could include collaborations with the mRNA vaccine technology transfer hubs that are being established with the support of WHO and COVAX partners.

BackgroundTuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low- and middle-income countries (LMICs) under alternative delivery scenarios.MethodsWe calibrated a tuberculosis model to 105 LMICs (93% of global tuberculosis incidence). Vaccine scenarios were implemented asBasecase: routine vaccination of 9-year-olds and a one-time vaccination campaign for ages ≥10 with country-specific introduction between 2028–2047 and 5-year scale-up to target coverage;Accelerated Scale-up: asBasecase, but all countries introducing in 2025 with instant scale-up; andRoutine Only: asBasecase, but routine vaccination only. Vaccines protected against disease for 10-years, with 50% efficacy.FindingsTheBasecasescenario prevented 44.0 (95% uncertainty range=37.2–51.6) million tuberculosis cases, and 5.0 (4.6–5.4) million tuberculosis deaths before 2050, including 2.2 million in the WHO South-East Asian region. TheAccelerated Scale-upscenario prevented 65.5 (55.6–76.0) million cases and 7.9 (7.3–8.5) million deaths before 2050. TheRoutine Onlyscenario prevented 8.8 (7.6–10.1) million cases and 1.1 (0.9–1.2) million deaths before 2050.InterpretationsNovel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a campaign will be crucial for rapid impact. Accelerated introduction, more similar to the pace of COVID-19 vaccines, could increase lives saved by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction and scale-up.FundingWHO (2020/985800-0)

Measles and rubella microarray patches (MR-MAPs) are critical in achieving measles and rubella eradication, a goal highly unlikely to meet with current vaccines presentations. With low commercial incentive to MAP developers, limited and uncertain funding, the need for investment in a novel manufacturing facility, and remaining questions about the source of antigen, product demand, and regulatory pathway, MR-MAPs are unlikely to be prequalified by WHO and ready for use before 2033. This article describes the current progress of MR-MAPs, highlights challenges and opportunities pertinent to MR-MAPs manufacturing, regulatory approval, creating demand, and timelines to licensure. It also describes activities that are being undertaken by multiple partners to incentivise investment in and accelerate the development of MR-MAPs.

Research and innovation have been fundamental to many of the successes in immunization thus far, and will play important roles in the future success of Immunization Agenda 2030 (IA2030). Strategic Priority 7 (SP7) of IA2030, which addresses research and innovation, is explicitly informed by country needs and priorities, and aims to strengthen the innovation ecosystem through capacity building and collaboration at country, regional, and global levels. SP7 identifies four key focus areas: (1) "needs-based innovation", (2) "new and improved products, services, and practices", (3) "evidence for implementation", and (4) "local capacity". Strategic interventions in these key focus areas apply the lessons of the Global Vaccine Action Plan and the "Decade of Vaccines" to emphasize local innovation, promote the use of research by countries to improve program performance and impact, and encourage capacity building for the development and implementation of innovations. The proposed approach will maintain a focus on the development of new vaccines and the improvement of existing vaccines, and increase attention to innovation in service delivery. Monitoring and evaluation will foster evidence-based priority setting at the country level and help to ground the global research and development (RD) agenda in the needs of communities. Together, these approaches are intended to harness the power of research and innovation more effectively, to meet the challenges of the future and achieve the ambitious goals of IA2030.

In 2014, the World Health Organization, the US National Institutes of Health, and global technical partners published a comprehensive roadmap for development of new vaccines against sexually transmitted infections (STIs). Since its publication, progress has been made in several roadmap activities: obtaining better epidemiologic data to establish the public health rationale for STI vaccines, modeling the theoretical impact of future vaccines, advancing basic science research, defining preferred product characteristics for first-generation vaccines, and encouraging investment in STI vaccine development. This article reviews these overarching roadmap activities, provides updates on research and development of individual vaccines against herpes simplex virus, Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, and discusses important next steps to advance the global roadmap for STI vaccine development.

Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed "LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10microg LSA-NRC/0.5ml AS01 (n=5), high dose (HD) LSA-NRC/AS01: 50microg LSA-NRC/0.5ml AS01 (n=13); LD LSA-NRC/AS02: 10microg LSA-NRC/0.5ml AS02 (n=5) and HD LSA-NRC/AS02: 50microg LSA-NRC/0.5ml AS02 (n=13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-gamma) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-gamma responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p=0.95). LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.

Apical Membrane Antigen 1 (AMA1) and Merozoite Surface Protein 1 (MSP1) were produced as a recombinant fusion protein and formulated with the adjuvant Montanide ISA 720 with the aim of replicating the structure present in the parasite protein. A previous trial with this construct demonstrated the vaccine was safe and immunogenic but was associated with injection site reactogenicity. This Phase 1a dose-escalating, double blind, randomized, controlled trial of PfCP2.9/Montanide ISA 720 was conducted to evaluate alternative dose levels and vaccination schedules, with a pre-formulated vaccine that had undergone more in-depth and frequent quality control and stability analysis. The trial was conducted in seventy healthy Chinese malaria-naïve volunteers between January 2006 and January 2007. The objective was to assess the safety, reactogenicity and immunogenicity of 5, 20 and 50microg of PfCP2.9/ISA 720 under 2 different schedules. The most common adverse event was injection site tenderness (53%). The frequency and severity of adverse events was similar in both vaccination schedules. Antibody responses were induced and remained elevated throughout the study in volunteers receiving vaccine (p0.001). Although high antibody titers as measured by ELISA to the PfCP2.9 immunogen were observed, biological function of these antibodies was not reflected by the in vitro inhibition of parasite growth, and there was limited recognition of fixed parasites in an immunofluorescence assay. At all three dose levels and both schedules, this formulation of PfCP2.9/ISA 720 is well tolerated, safe and immunogenic; however no functional activity against the parasite was observed.

Many licensed vaccines are composed of live, attenuated or inactivated whole-cell microorganisms, or they comprise purified components from whole-cell extracts or culture supernatants. For some diseases, pathology is fairly well understood, and there may be known correlates of protection that provide obvious parameters for assessment of vaccine potency. However, this is not always the case, and some effective vaccines are routinely used even though the mechanisms or correlates of protection are unknown. Some more modern vaccine approaches employ purified recombinant proteins, based on molecules that appear on the surface of the pathogen. This is one of the strategies that has been adopted in the quest to develop a malaria vaccine. Use of these parasite antigens as vaccine candidates is supported by substantial epidemiological data, and some have demonstrated the ability to elicit protective responses in animal models of malaria infection. However, there is as yet no immunological correlate of protection and no functional assays or animal models that have demonstrated the ability to predict efficacy in humans. There is little precedence for the most appropriate and practical method for assessing potency of vaccines based on these recombinant molecules for malaria vaccines. This is likely because the majority of malaria vaccine candidates have only recently entered clinical evaluation. The PATH Malaria Vaccine Initiative (MVI) convened a panel with expertise in potency assay design from industry, governmental institutions, and regulatory bodies to discuss and review the rationale, available methods, and best approaches for assessing the potency of recombinant proteins, specifically for their use as malarial vaccines. The aim of this meeting was to produce a discussion document on the practical potency assessment of recombinant protein malaria vaccines, focusing on early phase potency assay development.

Apical membrane antigen 1 (AMA1) has been shown to be a promising malaria vaccine candidate. The multiallelic AMA1-C1 vaccine currently in Phase 1 trials in the US and Mali contains an equal mixture of the ectodomain portion of recombinant AMA1 from the FVO and 3D7 clones of Plasmodium falciparum, formulated on Alhydrogel. It is hoped that inclusion of a human-optimized CpG oligodeoxynucleotide (ODN) (CPG 7909) with our existing AMA1-C1/Alhydrogel vaccine will lead to a higher concentration of functional AMA1-C1 antibodies. Preclinical studies were performed in mice, rats and guinea pigs to assess the safety, immunogenicity and functionality of the immune response to AMA1-C1 with Alhydrogel + CPG 7909 compared to antigen with Alhydrogel alone. Day 42 mean anti-AMA1 ELISA titer values derived from individual animals were compared between Alhydrogel and Alhydrogel + CPG 7909 groups at each antigen dose for each species. Sera from Alhydrogel + CPG 7909 groups displayed significantly higher antibody titers (P < 0.025) than their comparable Alhydrogel alone group. Mouse IgG isotype analysis showed that AMA1-C1/Alhydrogel induced a predominately Th2 type response while AMA1-C1/Alhydrogel + CPG 7909 gave a mixed Th1/Th2 type response. When tested for functional activity by in vitro inhibition of parasite invasion, IgG isolated from serum pools of AMA1-C1/Alhydrogel + CPG 7909 animals was more effective against both FVO and 3D7 parasites than an equal concentration of IgG from animals receiving vaccines adjuvanted with Alhydrogel alone. These promising preclinical results have recently led to the start of a Phase 1 trial in the US.

Apical membrane antigen 1 (AMA1), a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. A phase 1 trial was conducted with 30 malaria-naïve volunteers to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of recombinant proteins based on sequences from the FVO and 3D7 clones of Plasmodium falciparum . The proteins were expressed in Pichia pastoris and adsorbed on Alhydrogel. Ten volunteers in each of three dose groups (5 μg, 20 μg, and 80 μg) were vaccinated in an open-label study at 0, 28, and 180 days. The vaccine was well tolerated, with pain at the injection site being the most commonly observed reaction. Anti-AMA1 immunoglobulin G (IgG) was detected by enzyme-linked immunosorbent assay (ELISA) in 15/28 (54%) volunteers after the second immunization and in 23/25 (92%) after the third immunization, with equal reactivity to both AMA1-FVO and AMA1-3D7 vaccine components. A significant dose-response relationship between antigen dose and antibody response by ELISA was observed, and the antibodies were predominantly of the IgG1 isotype. Confocal microscopic evaluation of sera from vaccinated volunteers demonstrated reactivity with P. falciparum schizonts in a pattern similar to native parasite AMA1. Antigen-specific in vitro inhibition of both FVO and 3D7 parasites was achieved with IgG purified from sera of vaccinees, demonstrating biological activity of the antibodies. To our knowledge, this is the first AMA1 vaccine candidate to elicit functional immune responses in malaria-naïve humans, and our results support the further development of this vaccine.

Montanide ISA 720 is an experimental adjuvant, formulated as water-in-oil emulsions, that induces high antibody titers in several animal species. It has been used in human vaccine trials with malaria and HIV vaccines. The heightened response is likely due, in part, to the formation of a depot at the injection site. However, post-formulation modifications were seen with seven proteins tested during storage of ISA 720 formulations at 37 degrees C for 1 week and two proteins stored longer at 4 degrees C. Potency studies in mice, in which the stored vaccines were diluted into placebo emulsions for appropriate dosing, indicated that this instability could lead to loss of immunogenicity in the post-injection depot, limiting the allowable storage time of preformed vaccines. We describe point-of-injection formulation for ISA 720 vaccines that meets the requirement for in vitro stability. For preformed vaccines, addition of glycine or glycylglycine prevented antigen modification on storage at 37 degrees C, providing a potential way of stabilizing antigen/ISA 720 formulations for in vitro storage and the post-injection depot.

At least a million people, mainly African children under 5 years old, still die yearly from malaria, and the burden of disease and death has increased. Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is one of the most promising blood-stage malarial vaccine candidates. However, the allelic polymorphism observed in this protein is a potential stumbling block for vaccine development. To overcome the polymorphism- and strain-specific growth inhibition in vitro, we previously showed in a rabbit model that vaccination with a mixture of two allelic forms of PfAMA1 induced parasite growth-inhibitory antisera against both strains of P. falciparum parasites in vitro. In the present study, we have established that, in contrast to a single-allele protein, the antigen mixture elicits primarily antibodies recognizing antigenic determinants common to the two antigens, as judged by an antigen reversal growth inhibition assay (GIA). We also show that a similar reactivity pattern occurs after immunization of mice. By contrast, sera from rhesus monkeys do not distinguish the two alleles when tested by an enzyme-linked immunosorbent assay or by GIA, regardless of whether the immunogen is a single AMA1 protein or the mixture. This is the first report that a malarial vaccine candidate induced different specificities of functional antibodies depending on the animal species immunized. These observations, as well as data available on human immune responses in areas of endemicity, suggest that polymorphism in the AMA1 protein may not be as formidable a problem for vaccine development as anticipated from studies with rabbits and mice.

Forty years ago, researchers first demonstrated that immunization with irradiated sporozoites could protect against malaria infection, providing the impetus for the development of a malaria vaccine. Twenty five years ago, the circumsporozoite protein (CSP), a sporozoite surface antigen that is required to establish infection, became the first Plasmodium falciparum gene to be cloned, and a vaccine based on this antigen appeared imminent. However, today we are still without a highly effective malaria vaccine, despite considerable progress achieved during many years of research and development. This review highlights the most recent test-of-concept studies involving subunit vaccines; to illustrate this field of research, five antigens--CSP, TRAP/SSP2, LSA1, MSP1 and AMA1--are discussed. These antigens have all entered clinical trials evaluating efficacy against experimental sporozoite challenge (phase IIa) and/or exposure to natural infection (phase IIb). Challenges facing the development of subunit-based vaccines are discussed, and strategies for improving their efficacy above that observed with the current leading vaccine candidate, RTS,S, are described. In addition, recent progress in the development of whole-organism vaccines is presented.

The recent availability of significantly increased levels of funding for unmet medical needs in the developing world, made available by newly created public-private-partnerships, has proven to be a powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure. The investigators bring together important published and unpublished information that illuminates the status of malaria vaccine development. They focus their comments on those candidate vaccines that are currently in or expected to enter clinical trials in the next 12 months.