Elsevier

Vaccine

Volume 27, Issue 47, 5 November 2009, Pages 6564-6569
Vaccine

Randomized, double-blind, placebo-controlled trial to evaluate the safety and immunogenicity of live oral cholera vaccine 638 in Cuban adults

https://doi.org/10.1016/j.vaccine.2009.08.042Get rights and content

Abstract

A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety, reactogenicity and the immunogenicity of a 2 × 109 CFU dose of the 638 lyophilized live attenuated cholera vaccine for oral administration, formulated and produced at Finlay Institute, City of Havana, Cuba. Thirty-six healthy female and male adult volunteers from 18 to 40 years old were involved, clinically examined and laboratory tested after the informed consent signature. Adverse events were monitored and seroconversion rates and geometrical mean titer (GMT) of vibriocidal antibodies were tested in volunteer's sera samples. Neither serious adverse events nor other damages to the volunteers due to vaccine or placebo feeding were reported during the clinical follow-up period of this study; none of the adverse events registered within the first 72 h after inoculation were life-threatening for volunteers. Neither severe nor moderate adverse events were reported. Sixty-one percent of subjects showed mild expected adverse events in an interval lower than 24 h up to the first 72 h, 75% of these in the vaccinated group and 18% in the placebo group. Fourteen days after inoculation the GMT of vibriocidal antibodies in the vaccine group significantly increased in comparison to the placebo group. All subjects in the vaccine group (24) seroconverted (100%). Results show that this vaccine is safe, well tolerated and immunogenic in healthy female and male volunteers.

Introduction

Vaccination against cholera continues to be a feasible strategy against this infection. It has been demonstrated that oral immunization with genetically attenuated cholera strains stimulates an efficient mucosal response [1]. Previous studies carried out with CVD 103HgR (classic biotype) and Peru-15 (El Tor biotype) vaccines, indicate that both vaccines are well tolerated, immunogenic and protective in challenge clinical trials in humans [2], [3], [4], nevertheless their effectiveness in endemic areas still remains uncertain [5].

A group of genetically attenuated Vibrio cholerae strains O1 and O139 serogroups have been obtained in Cuba [6], [7], [8]. Among them, the attenuated 638 strain V. cholerae O1 El Tor Ogawa proved to be well tolerated and immunogenic in a single dose ranging from 107 to 109 CFU [9]. With 109 CFU dose, this strain is able to provide protection against the diarrhea caused by a pathogenic strain V. cholerae O1 El Tor Ogawa [10]. In a previous challenge clinical trial, under quarantine hospitality facilities, a group of healthy volunteers were immunized with a single dose of 109 CFU of the 638 strain and others received placebo as a control group. The protection conferred by previous immunization with the 638 strain against colonization and diarrhea caused by the infection with the virulent 3008 V. cholerae strain was also demonstrated in that study [10].

Thus, these results encouraged the pharmaceutical development of a lyophilized live attenuated vaccine. This vaccine was formulated under good manufacturing practice procedures and contains the 638 strain as its active pharmaceutical ingredient [11].

A phase I–II clinical trial was carried out in healthy human volunteers to evaluate safety, reactogenicity and immunogenicity of 2 × 109 CFU single dose of the live oral cholera vaccine 638.

Section snippets

Study design

Thirty-six healthy female and male volunteers from 18 to 40 years working at Scientific Institutions of the City of Havana, Cuba, were enrolled in a randomized, double-blind, placebo-controlled inpatient clinical trial, conducted at the Unit for Isolation of Biological Risks at Tropical Medicine Institute “Pedro Kourí” (IPK), in the City of Havana, Cuba, after they gave an informed consent according to the guidelines of the State Regulatory Authority for Medicine Control from the Ministry of

Clinical response to 638 vaccine

No significant changes were seen on volunteer's Hematological and Biochemical Laboratory parameters tested after vaccine or placebo feeding. No clinical manifestations were observed or reported during the first hour after vaccine administration. Nobody had serious adverse event during the clinical follow-up time of this study. None of general adverse events registered during the entire follow-up period of 30-day treatment feeding were life-threatening for volunteers involved in this study.

Table

Discussion

In this study, the absence of serious or severe adverse events or significant changes in volunteer's Hematological and Biochemical Laboratory parameters shown that the 638 vaccine is safe and confirms data from previous studies [8], [9], [10]; where a fresh culture of the 638 strain was used as oral the inoculum. Considering all subjects were clinically examined and exhaustively selected to participate in this study, we expected a higher incidence and an earlier beginning of adverse event in

Acknowledgments

We would like to thank the performance of the infirmary staff of the isolation ward at the Institute for Tropical Medicine Pedro Kourí, in the City of Havana, Cuba, for their professional performance. We specially acknowledge the voluntary participation of all the subjects enrolled in the trial. Finally we want to warmly thank Orquidea Biart la Rosa, for her careful linguistic revision of the English language of this article.

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These authors contributed equally to the results presented in this article.

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