Safety and Immunogenicity of Single Dose Choleragarde® in HIV-Seropositive Adults
Condition: Cholera; Vibrio Infections; Diarrhea
MeSH terms: Cholera; HIV Seropositivity; Vibrio Infections; Diarrhea
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to assess the safety and immunogenicity of Peru-15
      (CholeraGarde®) vaccine in HIV seropositive adult population of Bangkok Thailand
    

Detailed description: 
      Cholera re-emerged in 2006 as a global threat with a 79% increase in 2006 compared to the
      previous year. The re-emergence of cholera increased with increasing numbers of displaced
      populations living in unsanitary conditions. About 99% of the reported cases were from Africa
      with most of the deaths reported also from this region. Case fatality rate has increased
      worldwide to 2.7% however, certain areas in Africa reported as much as 30% case fatality [WER
      2007]. These figures are believed to be underestimates and that as many as 120 000 deaths due
      to cholera are estimated to occur each year [WER 2001]. Underreporting is common due to
      inconsistencies in the definition of cholera and limitations of surveillance, however some
      countries do not report due to fear of international sanctions. In 2007, the International
      Health Regulation came into effect wherein trade and economic sanctions should no longer be
      imposed in countries reporting cholera but rather encourage open reporting so as to contain
      and prevent the spread of cholera epidemics [WER 2007].

      Provision of safe water and food, establishment of adequate sanitation, and implementation of
      personal and community hygiene constitute the main public health interventions against
      cholera. These measures cannot be fully implemented in the near future in most
      cholera-endemic areas. A safe, effective, and affordable vaccine would be a useful tool for
      cholera prevention and control.

      Considerable progress has been made during the last decade in the development of new
      generation oral vaccines against cholera. These have already been licensed in some countries
      and are now being considered for wider public health application. The World Health
      Organization recently recommended that the newer generation cholera vaccines be considered in
      certain endemic and epidemic situations, but indicated that demonstration projects are needed
      to provide more information about the costs, feasibility, and impact of using these vaccines
      [WHO Meeting 2002].

      A killed oral cholera vaccine (Dukoral™) has long been available internationally, however its
      2-dose schedule, the use of a buffer and the cost of the vaccine have long impeded its use in
      public health settings. A live oral vaccine (Orochol™), although internationally licensed is
      currently not available in the market. This vaccine is only available for use in children
      older than 6 years old and adults. Despite the immunogenicity and efficacy in challenge
      studies in North American volunteers [Tacket CO 1999], in a field trial of this vaccine in an
      endemic area in Indonesia, no protective efficacy was detected during the period of
      observation [Richie EE 1994].

      A need exists for an improved cholera vaccine that is more thermostable and may be used in
      endemic countries in younger age groups. This new generation live oral cholera vaccine must
      be administered in a single-dose regimen, be thermostable, confer high grade long-term
      protection and may be given to children below 2 years of age through mass immunization
      campaigns or through the EPI. In the Diseases of the Most Impoverished Programme (DOMI) of
      the IVI, Peru-15 (CholeraGarde®) was identified as the most promising of all the vaccine
      candidates. It is a live oral attenuated cholera vaccine derived from V. cholerae O1 El Tor
      Inaba strain that was first isolated in Peru in 1991 [Taylor DN 1994]. This has the advantage
      of having the same biotype as the current pandemic strain. Peru-15 has been attenuated by
      several genetic modifications and deletions. By the deletion of the ctx A and the rtxA genes,
      it has been rendered unable to encode for cholera toxin subunit A and RTX toxin making it
      non-toxigenic; by the inactivation of the recA gene and deletion of the attRS1 sequences, it
      has been made unable to integrate exogenous DNA making it non-recombination and by the
      absence of the potentially inflammatory flagella it has been rendered non-motile [Taylor DN
      1994, Kenner 1995]. Phase I and II studies have been performed in North American volunteers
      where it was found to be safe and immunogenic [Kenner 1995, Sack 1997] . Furthermore, the
      vaccine strain isolated from the stools of volunteers retained its non-motile characteristic.
      In a challenge study among North American volunteers, Peru-15 provided 100% protection
      against moderate and severe diarrhoea, and 93% against any diarrhoea [Cohen 2002].

      This vaccine underwent phase I and II studies in a cholera-endemic area in Matlab, Bangladesh
      in three age groups: adults aged 18 - 45 years, children aged 2 - 5 years and infants aged 9
      - 23 months [Qadri 2007]. In these studies, the vaccine has been shown to be safe and elicit
      vibriocidal responses among all age groups. Only 1 of 20 adults and 8 of 140 children vaccine
      recipients excreted the vaccine strain. Analysis of the strains isolated revealed that the
      strains remained unchanged in phenotypic and genotypic properties after passage in the stool.

      Although this vaccine can be given as a single dose, and appears to be immunogenic in
      infants, the vaccine requires stringent cold storage conditions at -20ºC. Avant
      Immunotherapeutics Inc., manufacturers of Peru-15, is currently reformulating the vaccine in
      order to make it more thermostable. In order to assess whether this vaccine is as safe and
      immunogenic as the previous formulation, this lyophilized formulation will need to undergo
      clinical testing in an endemic community.

      The International Vaccine Institute (IVI) through the Cholera Vaccine Initiative (CHOVI)
      together with Avant Immunotherapeutics Inc., manufacturers of the Peru-15 vaccine, have
      negotiated an agreement that allows clinical trials to be performed in cholera-endemic
      countries, including, India, Bangladesh, and Thailand. This will eventually enable licensure
      and facilitate the international use of this vaccine by obtaining a WHO recommendation for
      its global use. This single dose vaccine may easily be used in endemic countries and deployed
      at times when outbreaks are likely to occur.

      Because cholera tends to occur in areas where the seroprevalence of HIV is also high, safety
      and immunogenicity of any vaccine against cholera must be established among HIV infected
      individuals. There is limited data regarding the use of oral cholera vaccines among HIV
      seropositive individuals. A study in Beira, Mozambique, an area with a 20-30% HIV
      seroprevalence revealed that the killed oral rBS-WC vaccine may be effective against cholera
      [12]. However, specific data on HIV status and safety of the vaccine was not determined in
      the study. The live attenuated CVD 103 HgR vaccine was found to be equally safe among HIV
      seropositive and HIV seronegative individuals in Mali. The vaccine however was found to
      result in attenuated immune response among HIV seropositive individuals [Perry 1998].

      In order for the Peru-15 cholera vaccine to be used extensively in cholera outbreaks or in
      cholera endemic settings where HIV co-exists, safety and immunogenicity must first be
      established among HIV-seropositive individuals.

      To gain approval for use in the developing world, a single-dose of CholeraGarde® will have to
      confer high levels of protective efficacy for three years when given to endemic populations 9
      months and older. However, before undertaking a phase III efficacy trial, a series of phase
      II clinical studies need be conducted in order to confirm safety and immunogenicity of the
      vaccine. Since cholera and HIV co-exist in some areas of the world, safety and immunogenicity
      of the Peru-15 vaccine must be established among HIV seropositive individuals.
    

Intervention name(s): CholeraGarde®; Placebo
Intervention type(s): Biological; Biological
Intervention description(s): Live attenuated oral Cholera vaccine
Each vial of CholeraGarde® contains 5x107 to 1x109 CFU of Peru-15, 6.75 mg KH2PO4, and 300 mg trehalose as a lyophilized cake in 5 mL single-dose vials; A buffer solution containing 2.5 g sodium bicarbonate, and 1.65 g ascorbic acid.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Vibrio Cholerae; Diarrhea; Live oral Vaccines; Immunogenicity; Safety; HIV