Table 4.

Summary of indicators supporting an assessment of the probability of technical and regulatory success for a norovirus vaccine candidate.

Probability of success theme	Indicator	Summary	Rating
Biological Feasibility	Most advanced vaccine candidate(s)	Four candidates have undergone clinical trials with the most advance (HilleVax Bivalent GI.1/GII.4 VLP) heading into phase III trials in 2022. Other three candidates in phase I/II.	Low-Moderate
	Existence of immunity from natural exposure	Natural exposure causes asymptomatic and symptomatic infections, both of which are associated with both humoral and cellular immune responses. Cohort studies conclude that prior infection confers protection against reinfection to the same genotype and potentially to the same serogroup/different serotype; duration is unclear. Adult volunteer study results provide conflicting results, suggesting limited infection- related protection.	Moderate
	Understanding mechanisms of immunity	Recent studies focusing on host differences (HBGA phenotypes for example) may partially explain early results of lack of protective immunity conferred by a prior infection. Long term protection, mucosal/systemic immune response induction, and cross-protection against heterogeneous epitopes is not fully understood.	Low
	Likelihood of vaccine protection against the majority of pathogenic strains	Strong evidence that protection is provided against the homologous genotype. Less evidence that protection may also be against the homologous genogroup despite different genotype (although there may be differences for given serotypes). Vaccine will need to include the most common genogroup/genotypes.	Low
Product Development Feasibility	Existence of animal models to facilitate vaccine development	Mouse model and zebra-fish model are being increasingly explored. Mouse models do not recapitulate human infection and appear to have different receptor/attachment mechanisms.	Low-Moderate
	Existence of in vitro assays to facilitate vaccine development	Several antibody tests have been developed and are under evaluation. HBGA blocking antibodies may prove most helpful for establishing correlates for future studies, but this is still under evaluation. The exact host cell receptor molecule(s) necessary for attachment and invasion are not identified.	Moderate
	Ease of Clinical Development	Clinical trials following the “rotavirus clinical trials model” are likely the norm and currently being implemented for Phase III trials. Challenges will include dealing with genotype diversity and role of coinfections.	High
	Availability or need for human challenge models	Human challenge models have been important for the “proof of concept” of vaccine associated protection. Current efforts include the development of suitable genogroup/genotype candidates for human challenge. Licensure in HIC adults/travelers through use of CHIM are reasonable given recent precedence	Moderate-High