A randomized, placebo-controlled, double-blind Phase 2 trial comparing the reactogenicity and immunogenicity of a single ≥2x108 colony forming units [cfu] standard-dose versus a ≥2x109 cfu high-dose of CVD 103-HgR live attenuated oral cholera vaccine, with Shanchol inactivated oral vaccine as an open label immunologic comparator

Abstract

Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically-naïve individuals during “virgin soil” epidemics would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (VaxchoraTM) containing >2x108 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 >2x109 cfu to elicit high seroconversion in developing country populations. We compared vibriocidal responses of Malians (18-45 years old) randomized to ingest a single >2x108 cfu standard-dose (N=50) or >2x109 cfu high-dose (N=50) of PaxVax CVD 103-HgR with buffer, or two doses (N=50) of ShancholTM inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice, 2 weeks apart; CVD 103-HgR recipients ingested placebo 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. (ClinicalTrials.gov number, NCT02145377)