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.

Background Infant rotavirus vaccines have led to substantial reductions in hospital admissions and deaths due to gastroenteritis, but some studies have reported an elevated risk of intussusception, a rare bowel disorder. This analysis aimed to provide evidence on the potential mortality reduction benefits and intussusception risks of current rotavirus vaccination schedules, and to explore whether alternative schedules could have advantages.Methods All 135 low-income and middle-income countries, defined by gross national income per capita of less than US$12 236 in the 2018 fiscal year, were included in the model. Mortality reduction benefits and intussusception risks of rotavirus vaccination were modelled by use of an Excel-based static cohort model with a finely disaggregated age structure. Numbers of rotavirus gastroenteritis deaths and intussusception deaths in each week of age were calculated for all infants born in the year 2015 between birth and age 5•0 years, with and without restrictions on age at administration. Benefit-risk ratios (rotavirus gastroenteritis deaths prevented per excess intussusception death) and other indicators were calculated for two vaccination schedules currently recommended by WHO and 16 alternative schedules. Of these schedules, it was assumed that between one and three doses would be given; the first dose of the rotavirus vaccine would be co-administered with either BCG or diphtheria-tetanus-pertussis (DTP)1; and the second or third dose would be co-administered with either DTP1, DTP2, DTP3, or measles (Meas)1.Findings A three-dose schedule co-administered with DTP (without age restrictions) could prevent about 74 000 (95% uncertainty interval 59 000-100 000) rotavirus gastroenteritis deaths (38% reduction) and could lead to 201 (77-550) excess intussusception deaths (1•4% increase) compared with no vaccination, resulting in a benefit-risk ratio of 369:1 (160:1-895:1). The benefit-risk ratio was most favourable when the relative risk of intussusception was assumed to decline with the national under-5 mortality rate (2386:1) and least favourable with pessimistic assumptions about access to hospital for intussusception treatment (168:1). Schedules that involve giving the first dose with BCG and the second with DTP1 had the fewest excess intussusception deaths and most favourable benefit-risk ratios.Interpretation Rotavirus vaccines have a favourable benefit-risk profile in LMICs. Neonatal schedules have the potential to prevent more rotavirus gastroenteritis deaths and cause fewer excess intussusception deaths than the schedules currently recommended by WHO, but more efficacious rotavirus vaccines would be needed to achieve more substantial mortality reduction benefits.Funding Bill & Melinda Gates Foundation.

The growing burden of antimicrobial-resistant (AMR) microbes constitutes a significant global threat. Vaccines are effective tools to prevent infections could help to control and prevent AMR. In this Viewpoint we present an Action Framework for vaccines to contribute fully, sustainably and equitably to the prevention and control of AMR by preventing infections and reducing antimicrobial use. The document identifies a series of priority actions in three areas: expanding the use of licensed vaccines to maximize impact on AMR, developing new vaccines that contribute to the prevention and control of AMR, and expanding and sharing knowledge about the impact of vaccines on AMR. The objective of this document is to support an alignment of activities among international vaccine and AMR partners, and structure and articulate key priority actions.

Background In some countries that have introduced oral rotavirus vaccines, a small but elevated risk of intussusception—a rare bowel disorder—has been reported. Updated estimates on the global epidemiology of intussusception are needed to help predict the potential number of intussusception cases that could be caused by the vaccine in different settings. Methods We estimated incidence rates, age distributions and case-fatality ratios (CFRs) for intussusception hospital admissions among children aged <5 years, before the introduction of rotavirus vaccines. We included all articles identified in a systematic review between January 2002 and January 2018, and contacted authors for more granular unpublished data on age distributions. Results We identified 128 articles containing 227 country datasets (61 age distributions, 71 incidence rates and 95 CFRs). The median age of intussusception ranged from 29 weeks in Africa (83% of cases in the first year of life) to 70 weeks in the Western Pacific region (35% of cases in the first year of life). The median (range) annual incidence of intussusception hospital admissions per 100 000 aged <1 year ranged from 34 (13–56) in Africa to 90 (9–380) in the Western Pacific region. We found extreme differences between the CFRs in Africa (1 death in every 10 hospital admissions) and the rest of the world (fewer than 1 death in every 100–2000 hospital admissions). Conclusion Intussusception epidemiology varies by country and region. Understanding and recognizing these differences will be important when assessing the potential number of intussusception cases associated with rotavirus vaccines.