Organized and led by:

• Thomas Wierzba, PhD, MPH, PATH

Scientists are making progress developing ETEC, Shigella, and other enteric vaccines. As vaccine developers prepare for field efficacy trials of these vaccines, they should be aware of the importance of herd protection (indirect effects) when assessing vaccine efficacy as well as the scientific approaches to measuring herd protection. In this workshop, we will define and describe what is meant by herd protection and present on the methods for measuring herd protection during efficacy trials and post-licensure studies in low- and middle-income nations. We will also review evidence on the effects of herd protection for estimating vaccine cost-effectiveness. Attendees should leave the workshop with an enhanced understanding of herd protection and implications for cost-effectiveness measures.
 

Organized and led by:

• Ifor R. Williams, MD, PhD, Emory University
• Timothy Hand, PhD, University of Pittsburgh

Enteric pathogens remain a major threat to human health, yet for many of these pathogens no licensed vaccine currently exists. Some candidate vaccines are subunit vaccines that may be effective in infants and children in LMICs if effective means could be devised to achieve mucosal protection via a parenteral route. This workshop will review immunologic mechanisms responsible for immunity at mucosal surfaces and present examples where the parenteral administration of a vaccine has been attempted in an effort to achieve mucosal protection. The presenters will form a panel to discuss the findings from their studies and related topics including the value of specific adjuvants for eliciting mucosal immunity via a parenteral route and the potential use of prime-boost strategies within the first year of life. It is expected that the discussion will address what regimens are most likely to be effective in the future use of parenterally-administered vaccines.
 

Organized and led by:

• Birgitte Giersing, PhD, World Health Organization
• Calman MacLennan, PhD, Bill & Melinda Gates Foundation

Shigella controlled human infection models (CHIMs) have been established at three US institutions allowing for the detailed study of diarrheal disease caused by Shigella sonnei and flexneri 2a. These models open new possibilities to investigate vaccine efficacy, the association and correlation of immune response with protection, and accelerate regulatory approval.

In spring 2018, WHO is convening global stakeholders to explore potential routes to licensure for Shigella vaccines, within the context of considerations for policy recommendation, WHO prequalification, and uptake in low- and middle-income countries (LMICs). As part of this consultation, the role of CHIM models in accelerating licensure and vaccine introduction in LMICs will be considered. This workshop will explore the proposals emanating from this consultation, through a combination of presentations and round-table breakout discussions.
 

Organized and led by:

• Ibrahim Khalil, MD, MPH, Institute of Health Metrics and Evaluation (IHME), University of Washington

The burden estimates of Shigella and ETEC vary among different studies, as well as among models used for producing these estimates. Understanding the real burden of these important pathogens will guide public health and policymakers to prioritize resources for accelerating interventions against these enteric Infections. In addition, long-term effects, in the form of growth faltering, cognitive impairment, and school performance, are important aspects of burden that have not been well captured. Efforts to incorporate these effects and refine their estimation, in the form of DALYs, are very important to inform the burden of diarrheal diseases and Shigella and ETEC specifically. This workshop will include a presentation about IHME modeling for diarrheal diseases, with a focus on Shigella and ETEC estimates in relation to other pathogens, including limitations, areas of improvement, and IHME plans for future Global Burden of Disease (GBD) iterations, followed by discussion around the following topics:

• How Shigella and ETEC burden estimates can guide vaccine development, coverage, and regimens.
• What are the areas of improvement for diarrhea burden estimates in general (e.g., estimating asymptomatic enteric infections) and for the two pathogens specifically (e.g., estimating different serotypes, ST/LT ETEC…etc.)?
• Forecasting burden and estimating cost-effectiveness of ETEC and Shigella vaccines.
• What is the best way to deliver the message about the continuously changing burden estimates, especially with the yearly GBD update? How can we avoid confusion?

Organized and led by:

• Sachin Mani, PhD
• Marcelo Sztein, MD, Center for Vaccine Development and Global Health, University of Maryland School of Medicine

The hallmark of an optimal vaccine candidate is the generation of robust systemic and mucosal antibody and cell-mediated immune responses that are long-lasting, durable, and can be recalled upon subsequent re-exposure to the antigen. This usually entails the activation of T cell memory and effector subsets and induction of long-lasting B memory (BM) cells. However, for ETEC and Shigella, the precise role of these key immune cells in primary and secondary (anamnestic) immune responses remains ill-defined. To better elucidate the mechanistic role of T-cell subset and B-cells, both systemically and in the mucosal microenvironment, in the development of durable protective immunity against ETEC and Shigella, this workshop will be comprised of a series of short talks by experts in these areas followed by a panel discussion.
 

Organized and led by:

• Kurt Hanevik, MD, PhD, University of Bergen

Several ETEC CHIMs have been performed in the United States and Norway during the last several years. This workshop will follow up on central topics raised in the 2016 VASE CHIM workshop, with a specific focus on ETEC and new data obtained and analyzed since then.

In light of recent studies with established ETEC challenge strains and new ST-only strains, we will discuss whether there is a need for more strains, and, if so, what criteria/qualities are desirable in strain selection. We will discuss how ETEC CHIMs could be more standardized to better support ETEC vaccine development, incorporating novel methods of inoculum preparation, the development and application of new immunological tools, and recent experience in dose responses, fasting times, and the evaluation of broader outcome measures.

The use of ETEC CHIMs to evaluate vaccine efficacy requires susceptible volunteers to achieve a sufficiently high attack rate. We will highlight recent experience in evaluating pre-existing immunity and volunteer susceptibility to ETEC, and discuss how these data may be used to refine subject selection criteria while ensuring a representative study population.

CHIMs can also be utilized to expand our knowledge of ETEC pathogenesis and correlates of protection. We will include a focused discussion on expanded sample collection schema and collaborative analysis plan that will 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 how the most promising ETEC vaccine candidates may impact on both acute and potentially more long-term consequences of ETEC infections.
 

Organized and led by:

• Jessica White, PhD, PATH
• Manjari Lal, PhD, PATH

Childhood vaccine schedules continue to grow more and more complex. Efforts to reduce the complexity of childhood vaccination include combining products for a single administration as well as alternative routes of administration that do not require injections. Oral vaccine administration is a particularly attractive alternative for enteric vaccine development because of this route's ability to elicit both mucosal and systemic immunity. This workshop will work to identify the key product attributes and considerations in product development from different perspectives: regulatory, manufacturing, formulation, etc.
 

Organized and led by:

• Lynda Mottram, PhD, University of Gothenburg

Thanks to the modern sequencing era, the extent to which infectious disease imposes selective pressures on different human populations, is being revealed. This is aiding our understanding of the underlying host immunological and mechanistic defenses against these pathogens, as well as potentially assisting in the development of vaccines and therapeutics to control them. Therefore, the aim of this workshop is for key speakers from the enterotoxigenic Escherichia coli (ETEC) and Shigella field, to present examples of different techniques being used to investigate the underlying immune and biological transcriptional factors (both direct and indirect) that these important diarrheal pathogens impose. These presentations could be followed by an open debate on the best way to utilize such studies, before concluding and making key recommendations on how these studies could aid ETEC and Shigella vaccine development, while supporting the production of anti-infection therapeutics.
 

Organized and led by:

• Hope Randall, PATH

Catalyzing and sustaining momentum for long-term research investments can be a challenge, especially for a neglected issue like diarrheal disease. The success of rotavirus vaccines indicates that the pathway is not impossible, but it’s certainly more difficult for enteric pathogens (like ETEC and Shigella) that are most threatening to the health of children in low-resource areas and new vaccines that wouldn’t be for global use. How do you generate excitement and interest among donors to invest in diarrheal disease prevention through vaccines, especially during the early phases of clinical trials, when they may not even be aware that this is a major child health problem?

During this workshop, PATH will share examples of advocacy tactics we’ve used during these early stages and provide hands-on training for real-life communication opportunities for scientists that could result in increased funding, including developing resonant messaging for key donor audiences and reviewing media interview best practices.
 

Organized and led by:

• Chad Porter, PhD, MPH, Naval Medical Research Center

The use of well-established, validated and clinically meaningful primary and secondary endpoints is 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 development of consensus endpoints across the field to enable study-to-study comparisons as well as comparative assessments between vaccine candidates. The objective of this workshop is 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.

Across three different study designs (CHIM, travelers’ efficacy and pediatric efficacy) there will be a review of traditional endpoints for studies of ETEC, Shigella and other enteric pathogens with a consideration of the disease parameters and spectrum of disease targeted for prevention. The implications of these endpoints on sample size requirements will also be considered. Additionally, the use of various scoring systems will be reviewed and their merits assessed as potential primary or secondary endpoints in clinical trials of vaccine efficacy. The role of subjective endpoints and individual-based assessments of disease severity in addition to (or in lieu of) objective endpoints will be considered. In addition to clinical endpoints of disease, discussions will also consider the potential for alternative endpoints focused on long-term morbidity endpoints.