Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial Comparing the Reactogenicity and Immunogenicity of a Single Standard Dose to Those of a High Dose of CVD 103-HgR Live Attenuated Oral Cholera Vaccine, with Shanchol Inactivated Oral Vaccine as an Open-Label Immunologic Comparator

Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically-naive individuals during “virgin soil” epidemics would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora™) containing ≥2x10 8 colony forming units (cfu) induces vibriocidal antibody seroconversion (correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2x10 9 cfu to elicit high seroconversion in developing country populations. We compared vibriocidal responses of Malians (18-45 years old) randomized to ingest a single ≥2x10 8 cfu standard-dose (N=50) or ≥2x10 9 cfu high-dose (N=50) of PaxVax CVD 103-HgR with buffer, or two doses (N=50) of Shanchol™ inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice, 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (≥4-fold vibriocidal titer rise) between baseline and 14 days after CVD 103-HgR, and following the first and second dose of Shanchol were the main outcomes measured. By day 14 post-vaccination, seroconversion after a single standard-dose of CVD 103-HgR was 71.7% (33/46) and 83.3% (40/48) after high-dose. Seroconversion following first-dose Shanchol 56.0% (28/50) was significantly lower compared with high-dose CVD 103-HgR (p=0.003). High-dose CVD 103-HgR vibriocidal geometric mean titer (GMT) exceeded standard-dose GMT at day 14 (214 vs 95, p=0.045) and was ∼2-fold higher than day 7 and day 14 GMT following the first Shanchol dose (p>0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess efficacy and practicality in field situations.