A randomized, double-blinded, placebo-controlled phase 2b trial of ETVAX supplemented with 10 ug of dmLT was conducted among 729 Finnish volunteers (18-65 years old) randomized to receive two doses of either ETVAX or placebo two weeks apart (; EudraCT2016-002690-35; NCT03729219). Although the data for this trial are being prepared for initial publication elsewhere, it can be said that the safety, immunogenicity and efficacy data are encouraging for moving on to Phase 3 planning for travelers and further studies among infants and young children in low to low-middle income countries (LMICs) that will lead to Phase 3 testing for both indications. The Benin Phase 2B study was a critical step in the development of the ETVAX vaccine since it was a very stringent test of its impact on ETEC TD since the burden of co-pathogens in the field proved exceptionally high and ETEC was found in 75% of all severe diarrhea cases. These data for protection are consistent with those reported for the first generation inactivated ETEC vaccine.
As described above, ETVAX has been shown to be safe and induce strong intestinal-mucosal IgA antibody responses to CF antigens and LTB when tested among adult Swedish volunteers, healthy Bangladeshi adults and children, and in healthy Zambian children. An ongoing trial in The Gambia is a randomized, double-blind, placebo controlled (1:1) trial to measure the safety, immunogenicity, and protective efficacy of three ETVAX doses given as 1/4 of an adult dose plus 2.5 ug of dmLT. Vaccine is given on days 1, 15, and 90 to healthy Gambian children aged 6 to 18 months (; PACTR20201081021852). As of 17 November 2022, 4936 children have been enrolled and received at least one vaccine dose and 88% of these children received all three doses. Although safety data is blinded to group assignment, the investigational product appears safe. Active surveillance using home visits for solicited adverse events (i.e., diarrhea, vomiting, fever, acute allergic reactions) within seven days of any vaccine or placebo dose in a cohort of 350 children detected 89 events, only two events (1 vomiting, 1 fever) were severe and considered product related. Among all other children (n = 4115), there were 348 adverse events during dosing; three were severe (1 pneumonia, 1 measles, 1 bronchiolitis) and none were product related. For 32 serious adverse events, none were found product related. To 31 October 2022, 360 moderate to severe diarrhea cases have been detected and 94 (26%) were ETEC positive by multiplex PCR. Stool specimens are under testing for ETEC phenotypes and co-pathogens.
To date the only licensed inactivated whole cell vaccines against enteric diseases are against cholera, and most depend upon delivery of acid-resistant polysaccharide antigens. The presentation for these vaccines not requiring a buffer involves a cell suspension in a plastic tube that can be dispensed directly into the recipient's mouth. A more complex presentation may be necessary to exploit the potential of whole cell vaccines containing adjuvants and conserved protein antigens. This need has been studied extensively with ETVAX so that the number of vaccine components and their presentation for administration can be simplified (N. Carlin, personal communication). The presentations now being considered for traveler and LMIC pediatric use of ETVAX will consist of a spray dried sachet (dmLT [10 ug] + antacid buffer + LCTBA) and a liquid bottle of 10 ml of bacterial cells For adults the sachet may be reconstituted in the bacterial suspension of cells in a glass containing 150 ml of water prior to consumption. For children in LMICs, the sachet contents are anticipated to be mixed directly with the bacterial suspension for administration. The two-component, self-contained formulation is a significant advance. The need for no extraneous water overcomes a delivery issue that has been problematic for widespread use of some oral inactivated whole cell vaccines (i.e.Dukorall). At this point, ETVAX has a practical formulation designed to minimize user error. Future work may be able to further reduce the footprint of this vaccine for refrigeration.
Although ETVAX promises to be an effective vaccine with broad protection against ETEC, the value proposition for this vaccine could be greatly increased by using it as a platform to immunize against other pathogens; I. Khalil, personal communication). For example, recombinant protective antigens against other mucosal pathogens could be cloned into one or more of the strains now comprising ETVAX. Alternatively, other whole cell vaccines alone or themselves expressing heterologous antigens could be co-formulated with ETVAX. These could include the cross-protective inactivated Shigella whole cell vaccine or the Hikojima or Euvichol cholera vaccines. An advantage of a practical means of oral vaccine delivery compared to parenteral injections is that the other whole cell vaccines would not need to be mixed before administration to be acceptable. Instead, after administering the ETVAX with buffer and adjuvant, a second simpler plastic vial containing just the additional whole cell antigens in PBS could be used for further oral immunization, possibly benefitting from the buffer and adjuvant in ETVAX.