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The mortality and morbidity burden estimation of diarrheal diseases (DD), and Shigella and Enterotoxigenic E. Coli (ETEC) varies among different studies and by the models used for producing these estimates. Understanding the real burden of these important pathogens will guide public health and policy makers to prioritize resources for accelerating interventions against these enteric infections. In addition, long term effects, in the form of growth faltering, cognitive impairment and decreased school performance are important aspects of burden that has not been well captured. Efforts to incorporate these effects and refine their estimation, in the form of Disability Adjusted Life years (DALYs) are very important to inform the burden of diarrheal diseases and Shigella and ETEC specifically. The Institute for Health Metrics and Evaluation (IHME) at the University of Washington conducted a workshop at the VASE 2018 meeting to discuss IHME Global Burden of Diseases (GBD) modelling methods for diarrheal diseases, with a focus on ETEC and Shigella estimates in relation to other pathogens, including limitations, areas of improvements, and IHME plans for future GBD iterations., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Catalyzing and sustaining momentum for long-term research investments can be a challenge, especially for enteric pathogens like ETEC andShigella that are most threatening to the health of children in low-resource areas, and whose vaccines would not be for global use. The 2018 Vaccines Against Shigella and ETEC (VASE) Conference included a workshop focused on building the capacity of scientists to communicate about their own research and advocate for additional attention and funding for enteric disease and vaccines research. Workshop presenters shared best practices and examples of advocacy, communications, and messaging tactics that have been used successfully during early stages of vaccine development research for other pathogens. The presentations were followed by an interactive, hands-on training for real-life communication opportunities for scientists that could result in increased research funding, including developing resonant messaging for relevant audiences and practicing interviews., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the absence of good animal models, Controlled Human Infection Models (CHIMs) are useful to assess efficacy of new vaccine candidates against Enterotoxic Escherichia coli (ETEC), as well as other preventive or therapeutic interventions. At the 2018 Vaccines Against Shigella and ETEC (VASE) conference, a workshop was held to further review and discuss new challenge model developments and key issues related to further model standardization. During the workshop, invited speakers briefly summarized for attendees recent developments and main agenda issues before workshop participants were divided into four groups for more focused discussions. The main issues discussed were: (1) whether there is a need for more ETEC strains to test a diversity of vaccine candidates, and if so, what criteria/qualities are desirable in strain selection; (2) how ETEC CHIMs could be more standardized to better support ETEC vaccine development; (3) how volunteer selection criteria and screening should be performed, and; (4) how an expanded sample collection schema and collaborative analysis plan may facilitate a more in-depth assessment of the role of antigen-specific humoral and cellular immune responses in ETEC infection, and provide better insights into ETEC pathogenesis and correlates of protection. The workshop concluded that additional challenge strains may need to be developed to better support new vaccines and therapeutics that are advancing in the development pipeline. In this regard, the need for a well characterized ST-only expressing ETEC strain was highlighted as a priority given that promising new heat stable toxoid based vaccine candidates are on the horizon. In addition, further standardization of the ETEC CHIMs was strongly encouraged, noting that it may not be realistic to standardize across all strains. Also, intensified volunteer screening may result in higher attack rates, although more stringent eligibility criteria may contribute to a more limited application of the model and diminish its representativeness. Finally, a sampling schedule and priority list for minimum set of samples was also proposed. Future workshops could be held to further refine standards for ETEC CHIMS and to facilitate more collaborative work on stored sample sets from previous and future ETEC CHIMs to maximize the contribution of these trials to our understanding of ETEC pathogenesis and our development of better prevention and control measures for this important pathogen., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Well-established, validated and clinically meaningful primary and secondary endpoints are critical in advancing vaccines through proof of principal studies, licensure and pre-qualification. To that end, the field of vaccine development for Shigella, enterotoxigenic Escherichia coli (ETEC) as well as other enteric pathogens would benefit greatly from a focused review of clinical endpoints and the use of common endpoints across the field to enable study-to-study comparisons as well as comparative assessments between vaccine candidates. A workshop was conducted to review clinical endpoints from controlled human challenge studies, field studies in naïve adult travelers and pediatric studies in low-middle income countries and to develop a consensus on clinical endpoints for future vaccine trials. Following sequential presentations on different study designs (CHIM, travelers' efficacy and pediatric efficacy), workshop participants broke into three simultaneous workgroups focused on those study designs to discuss a number of topics key to clinical endpoints specific to each study design. Previously utilized endpoints were reviewed with an eye towards potentially novel endpoints for future studies and consideration of the disease parameters and spectrum of disease targeted for prevention. The strength of support among workshop participants for the use of various endpoints is summarized as are recommendations for additional endpoints to be considered in future studies. It is anticipated that this report will facilitate endpoint determination in future efficacy trials of vaccine candidates., (Published by Elsevier Ltd.)

Diarrhea remains one of the top five causes of disease and death among young children in developing nations. Fortunately, scientists are making progress developing vaccines against enterotoxigenic E. coli (ETEC) and Shigella, two of the leading diarrhea pathogens. As vaccine developers start to consider field efficacy trials of these vaccines, they should be aware of the importance of evaluating not only vaccine direct effects on the immunized, but also the herd effects that vaccination can afford to the unimmunized in a community. In a workshop held at the conference titled "Vaccines against Shigella and ETEC (VASE)", we described to participants what herd effects are and we presented on methods used in cholera and rotavirus studies that could be useful for future ETEC and Shigella vaccine trials conducted in low and middle-income nations. We also presented evidence on the effects of vaccine herd effects for estimates of vaccine cost-effectiveness., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Development of an oral enteric vaccine for infants is important for Shigella and enterotoxigenic Escherichia coli (ETEC) vaccine development. At a recent workshop titled "Technical Product Attributes in Development of an Oral Enteric Vaccine for Infants," at the 2nd International Vaccines Against Shigella and ETEC Conference (VASE Conference), the preferred product attributes for development were discussed for these vaccines. The aims of this workshop were to identify gaps and gather opinions from key experts from preclinical, process development, manufacturing, regulatory, and clinical areas to fine-tune and refine key target product attributes for infant oral vaccine development. The workshop used some examples of marketed oral infant vaccines to discuss potential improvements that can be made, such as inclusion of preservatives, multidose vials, and antacid buffer presentation (liquid or lyophilized) in novel oral enteric vaccine development., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

PATH hosted the second Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Mexico City in June 2018, again providing experts from around the world an opportunity to participate in a highly collaborative forum to discuss progress in the development of new enteric vaccines. Through a combination of plenary sessions and posters, keynote presentations, and workshops, the 2018 VASE Conference aimed to accelerate communication and progress among those working to achieve the goal of licensed vaccines against these two bacterial pathogens. Many presentations recognized the importance of diarrheal disease and long-term sequelae caused by infections with Shigella and enterotoxigenic E. coli (ETEC). Other presentations explored new strategies for vaccine development, including the search for novel, possibly conserved, antigens for more effective vaccines. Much progress is being made as some vaccine candidates are now moving through clinical trials. Research presented in oral and poster presentations at the VASE Conference covered a range of topics, including: the global burden of disease, epidemiology, and health economics; host parameters and genomics that predict responses to infection and disease; preclinical evaluations of vaccine antigens and models of enteric diseases; and vaccine candidates in clinical trials and human challenge studies. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2018 VASE Conference., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Thanks to the modern sequencing era, the extent to which infectious disease imposes selective pressures on the worldwide human population is being revealed. This is aiding our understanding of the underlying immunological and host mechanistic defenses against these pathogens, as well as potentially assisting in the development of vaccines and therapeutics to control them. As a consequence, the workshop "How genomics can be used to understand host susceptibility to enteric infection, aiding in the development of vaccines and immunotherapeutic interventions" at the VASE 2018 meeting, aimed to discuss how genomics and related tools could be used to assist Shigella and ETEC vaccine development. The workshop featured four short presentations which highlighted how genomic applications can be used to assist in the identification of genetic patterns related to the virulence of disease, or host genetic factors that could contribute to immunity or successful vaccine responses. Following the presentations, there was an open debate with workshop attendees to discuss the best ways to utilise such genomic studies, to improve or accelerate the process of both Shigella and ETEC vaccine development. The workshop concluded by making specific recommendations on how genomic research methods could be strengthened and harmonised within the ETEC and Shigella research communities., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The generation of robust systemic and mucosal antibody and cell-mediated immune (CMI) responses that are protective, long-lasting, and can quickly be recalled upon subsequent re-exposure to the cognate antigen is the key to the development of effective vaccine candidates. These responses, whether they represent mechanistic or non-mechanistic immunological correlates of protection, usually entail the activation of T cell memory and effector subsets (T-CMI) and induction of long-lasting memory B cells. However, for ETEC and Shigella, the precise role of these key immune cells in primary and secondary (anamnestic) immune responses remains ill-defined. A workshop to address immune correlates for ETEC and Shigella, in general, and to elucidate the mechanistic role of T-cell subsets and B-cells, both systemically and in the mucosal microenvironment, in the development of durable protective immunity against ETEC and Shigella was held at the recent 2nd Vaccines against Shigella and ETEC (VASE) conference in June 2018. This report is a summary of the presentations and the discussion that ensued at the workshop., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aim of this study was to develop a candidate vaccine against enterohemorrhagic Escherichia coli O157:H7. A ler deletion mutant derived from wild-type EHEC O157:H7 86-24 was constructed by use of suicide vector pCVD442. The bacteriophage encoding Shiga toxin (Stx) was excised by serial passage to produce a ler/stx deletion mutant, F25. Stx1 and Stx2 mutants were constructed by site-directed mutagenesis within the active center and membrane-spanning region of the toxin A subunit. Mutants stx1 and stx2 were then introduced into F25 to construct live attenuated candidate vaccine F105. The cytotoxicity of F25 was inactivated and that of F105 was significantly reduced in comparison with wild-type E. coli strain EDL933. Mice injected with candidate vaccine strains F25 and F105 gained weight and showed no clinical signs of disease. F25 and F105 reduced the colonization of wild-type O157:H7 in mouse intestine. Immunized pregnant mice were able to protect their suckling newborns from intragastric challenge with wild-type O157:H7. Immunized mice were protected against infection with wild-type O157:H7 and exhibited normal weight gain. Such attenuated vaccine strains may therefore have potential use as oral vaccines against O157:H7.