Table 3.

ETEC vaccine-related characteristics and potential endpoints for future trials.

Research area	Current assumptions	Research gaps	Recommendations to address gaps
Target population	Timing is constrained by EPI schedule and need to provide protection in the first year of life when the case fatality rate (CFR) for acute diarrheal illness is greatest	Immunogenicity as a function of age for principal candidates in infants in LMICs is a question; target age-group has proven difficult to immunize effectively	Trial size sufficient to permit age stratification of results based on age of initial dose; novel approaches to improve mucosal immunogenicity in infants need to be exploded; also explore combination approaches
Efficacy	Innate immunity is equal across populations	Histo-blood group antigens (HBGA) appear to influence rates of infection and severity of disease in children to strains expressing canonical vaccine antigens CFA/I, CS3, CS5 and CS6 (PMID: 30768135)	Efficacy studies in populations should test subject HBGA to account for heterogeneity between populations in multi-site studies and within study populations
	Epidemiologically important CFA and non-canonical antigenic determinants, like EtpA and EatA are stable over time and place and are compelling candidates for inclusion in vaccines	Combination needs to be optimized to broaden coverage and efficacy	Multi-site Phase 2/3 trials should confirm this supposition and robust nature of protection
	ETEC vaccine need to have more public health benefit than preventing mortality and MSD diarrhoea. Reduction in other negative acute or more long-term negative health outcomes need to be considered	WHO ETEC vaccine PPC has called for new pre-clinical, CHIMs and field research to evaluate vaccine impacts on disease severity beyond diarrhoea and their ability to interfere with the pathogenic pathway to stunting and poor neurodevelopment	New secondary/exploratory endpoints targeting vaccine impact on reducing intestinal inflammation; growth deficits, markers of cognitive development and disease severity scores need to be evaluated in future field trials and if validated be used future pivotal Phase 3 supporting vaccine licensure
Formulation and Presentation	Improved temperature stability and simple vaccine presentation facilitating delivery are important parameters that contribute to a favourable FVVA and increase uptake	Lead cellular and subunit ETEC vaccine candidates need additional formulation and presentation research to ensure they meet WHO PPC specifications and improve their prospect for widespread uptake following licensure	Strategies need to be explored to improve the temperature stability and cold-chain foot print of the most advanced ETEC candidates, ensuring that vaccine and antigen co-formulations are more standardized, stable and also develop presentations that facilitate use in Phase 3 trials. Use of the VTIA tool recently developed by PATH and WHO can help in optimizing vaccine presentation