Abstract
ABSTRACTReactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 × 108 CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 × 109 CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 × 108-CFU standard dose (n = 50) or a ≥2 × 109-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 (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR (P = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, P = 0.045) and was ∼2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose (P > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.)
Highlights
Reactive immunization with a single-dose cholera vaccine that could rapidly protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control
Extensive evidence shows that the presence of serum vibriocidal antibodies following receipt of a cholera vaccine or after wild-type infection is a correlate of protection against cholera [10, 11, 13, 24]
Almost all vibriocidal antibodies can be absorbed with purified O1 polysaccharide, and the initial vibriocidal antibody response resides in the IgM fraction of serum immunoglobulin, but some long-lived IgG antibody occurs
Summary
Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. A public health problem that persists among the least privileged populations of many developing countries and can rapidly dehydrate stricken individuals, leading to hypovolemic shock and death without prompt rehydration, is devastating during virgin soil epidemics that reach immunologically naive populations, as seen in Peru in 1991 and Haiti in 2010 [1, 2] In such epidemics, the case fatality rate is often unacceptably high, as the familiarity with cholera and the infrastructure required to treat cholera are typically lacking. A single dose of Vaxchora containing Ն2 ϫ 108 CFU manufactured from the PXVX0200 master cell bank of CVD 103-HgR is highly immunogenic in stimulating serum vibriocidal antibody (a Ͼ90% seroconversion rate) and has significantly protected U.S volunteers against experimental challenge 10 days and 3 months after vaccination [9]. The demonstration in experimental challenge studies in U.S volunteers that a single Ն2 ϫ 108-CFU dose of Vaxchora provides 91% efficacy against challenge at 10 days after vaccination [9] and documentation by a World Health Organization (WHO) team of the logistical practicality of single-dose use of the previous high-dose formulation of the CVD 103-HgR vaccine (Orochol E) in reactive vaccination to control an explosive cholera epidemic in Micronesia [3] elicited enthusiasm to evaluate a high-dose PaxVax formulation of CVD 103-HgR as a potential future tool for reactive vaccination in explosive virgin soil cholera epidemics in developing countries
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