A killed whole-cell one dose cholera vaccine

Dartmouth College, Hanover NH

Investigators

Abstract

? DESCRIPTION (provided by applicant): Vibrio cholerae (Vc), a Gram negative bacterium that has caused over 200 years of cholera that is both an ep- idemic and endemic diarrheal disease. Endemics in Pakistan (ancient home of cholera) and epidemics in Haiti (new home of cholera) underscore the unresolved issue how to control cholera. One aspect of control in the short term is a universal vaccine. The main challenges of a universal cholera vaccine are to provide fast im- munity (?7 days) with the longest duration using the minimal number of doses to immunize the Vc antigen (Ag) immunologically naïve or young children (2-5 years) living in endemic cholera areas. The current oral cholera vaccines (OCV) recommended by the WHO do not accomplish this in young children to a high or consistent degree. A novel experimental cholera vaccine formulation, based in part on the OCV inoculum will be tested for its ability to provide cholera immunity with one intranasal (i.n.) dose. The new additions to the existing OCV formulation are 3 proven, protective Vc Ags (TcpA, TcpF and CBP-1) that are critical for cholera pathogenesis. We showed that TcpA and TcpF were able to induce immunity after one dose. The addition of these proteins, as well as CBP-A (a less robust protective Ag) will add to the protective Ags that are part of the immunogen profile of OCV. These Ags will be targeted to the mucosal epithelia by chitosan nanoparticles (Chitnp) a pro- cess which should also optimize priming of B cells. We will also use the powerful mucosal adjuvant CT. A new CT-based adjuvants (CC-TD) is being tested in preclinical human immunization protocols. CT and other normative elements of a cholera infection are associated with better sero-conversion of young children to Vc LPS, so it makes sense to see if more Ag (associated with infection), provided in better quantity to the areas of mucosal priming with the correct attending co-stimulations signals can change an OCV into a one dose vac- cine. The hypothesis we will test is whether `maximal' induction of immunity by a reformulated, killed whole-cell (kW-C) cholera vaccine can stimulate enough protective antibody (Ab) to provide protection against cholera with just one dose. Cholera immunity is already in decline in the first year after vaccination and continues to essentially no immunity in year three for young children immunized with the Shanchol, the most widely used OCV. The long term goal for this novel OCV formulation that features 3 protective protein Ags is, the induction of broader B cell memory (a biomarker of protection against cholera) that will endure for at least 3years and perhaps longer in young children who are well known to respond to vaccine protein Ags better than vaccine-associated LPS Ags.