Abstract
BackgroundTo contribute to the global demand for oral cholera vaccine (OCV), the production of Euvichol® was scaled up with elimination of thimerosal. To demonstrate the equivalence of the variations, a study was carried out in the Philippines. MethodsHealthy male and female adults and children in Manila were randomized to receive two doses of Euvichol® two weeks apart from either the 100L (Comparator) or the 600L (Test) variation. Primary and secondary immunogenicity endpoints were respectively geometric mean titer (GMT) of vibriocidal antibodies (two weeks post second dose) and seroconversion rate (two weeks after each dose) against O1 Inaba, Ogawa, and O139 serogroups. The GMT of vibriocidal antibodies against O1 Inaba, Ogawa, and O139 two weeks post first dose was also measured. To show the equivalence of two variations of Euvichol®, the ratio of GMT and the difference of seroconversion rate between Test and Comparator vaccines were tested with equivalence margin of [0.5, 2.0] for GMT ratio and of 15% for seroconversion rate, respectively. Safety assessment included solicited reactogenicity within 6 days after each dose and unsolicited and serious adverse events. ResultsA total of 442 participants were enrolled. For the overall population, equivalence between Test and Comparator was demonstrated for vibriocidal antibody response against O1 Inaba and Ogawa serotypes and O139 serogroup in both modified intention-to-treat (mITT) and per protocol analysis, since the 95% confidence intervals (CI) of GMT to any serotypes were within the lower and upper boundary [0.5, 2.0]. Seroconversion rates after two doses also showed equivalence for O1 Inaba, Ogawa, and O139. The vaccine was safe and well tolerated, similarly between the two groups. ConclusionThe study results support the equivalence of the 600L Euvichol® to the 100L formulation in healthy children and adults. The 600L Euvichol® is safe and immunogenic in adults and children.ClinicalTrials.gov registration number: NCT02502331.
Highlights
With estimated 1.3–4.0 million cholera cases and 21,000– 143,000 annual deaths in endemic countries [1], the World Health Organization (WHO) recommends oral cholera vaccine (OCV) use for control of both endemic and epidemic cholera [2,3]
To assess the equivalence of Test and Comparator vaccines, we considered the immunogenicity in the overall population
The primary immunogenicity analysis was conducted in all age cohorts combined, in accordance with the study design of the previous EuvicholÒ phase 3 clinical trial in The Philippines [9], which demonstrated the non-inferiority of EuvicholÒ vs. ShancholTM and paved the way for the WHO pre-qualification of EuvicholÒ
Summary
With estimated 1.3–4.0 million cholera cases and 21,000– 143,000 annual deaths in endemic countries [1], the World Health Organization (WHO) recommends oral cholera vaccine (OCV) use for control of both endemic and epidemic cholera [2,3]. EuvicholÒ was originally developed in 100L formulation in order to be equivalent to ShancholTM in terms of quality, safety and immunogenicity, containing the same active ingredients as well as thimerosal as preservative. Both ShancholTM and EuvicholÒ are presented as single-dose vials, with two doses being administered with a 2week interval to all persons 1 year of age and older [6,7]. Equivalence between Test and Comparator was demonstrated for vibriocidal antibody response against O1 Inaba and Ogawa serotypes and O139 serogroup in both modified intention-to-treat (mITT) and per protocol analysis, since the 95% confidence intervals (CI) of GMT to any serotypes were within the lower and upper boundary [0.5, 2.0]. The vaccine was safe and well tolerated, between the two groups
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