Safety and Immunogenicity of Single Dose Choleragarde® in HIV-Seropositive Adults

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Brief Title

Safety and Immunogenicity of Single Dose Choleragarde® in HIV-Seropositive Adults

Official Title

A Randomized, Placebo-Controlled Trial to Evaluate the Safety and Immunogenicity of a Single Dose Regimen of Live Attenuated Oral Cholera Vaccine (Choleragarde®) in HIV-Seropositive Adults in Thailand

Brief 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Proportion of subjects receiving CholeraGarde® or placebo with any of the following events within 7 days of dosing: Gas, headache, vomiting, abdominal cramps, myalgias, diarrhea, fever

Secondary Outcome

 Proportion of subjects exhibiting 4-fold or greater rises in titers of serum vibriocidal antibodies to 01 serogroup El Tor Inaba organisms, relative to baseline, one week after a single dose of CholeraGarde® or placebo

Condition

Cholera

Intervention

CholeraGarde®

Study Arms / Comparison Groups

 Vaccine
Description:  Live attenuated oral CholeraGarde® (5x107 to 1x109 CFU) vaccine

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

32

Start Date

July 2010

Completion Date

June 2011

Primary Completion Date

April 2011

Eligibility Criteria

        Inclusion Criteria:

        HIV-seropositive, non-pregnant adults, aged 18 - 45 years old who have been on standard
        highly active antiretroviral therapy (HAART) for at least 6 months prior to enrollment or
        who have never started HAART regimen will be recruited in the study.

        All subjects must satisfy the following criteria at study entry:

          1. Male and female HIV seropositive adults aged 18 to 45 years old who have given the
             written informed consent.

          2. Will comply with the requirements of the protocol (i.e. available for follow-up visits
             and specimen collection).

          3. CD4 T-lymphocyte count >500/mm3 for at least 6 months prior to inclusion

        Subjects that have never started HAART regimen must satisfy the following additional
        criteria at study entry.

        1. Asymptomatic HIV infection as determined by: Medical history, Physical examination,
        Laboratory tests, Clinical judgment of the investigator

        Subjects that have been on standard highly active antiretroviral therapy (HAART) for at
        least 6 months prior to enrollment must satisfy the following additional criteria at study
        entry.

          1. History of CD4 nadir >150/mm3

          2. Viral load (HIV-1 RNA levels) <200 copies/mL for at least 6 months prior to inclusion

        Exclusion Criteria:

        The following criteria should be checked at the time of study entry, if any of the
        following is present then the subject will be excluded from the study:

          1. Overt signs of immunodeficiency e.g. oral thrush, rapid weight loss, recurrent
             pneumonia (i.e. Stage 3 or 4 of the WHO clinical staging system for HIV infection and
             disease in adults and adolescents

          2. Ongoing serious chronic illness (e.g. with signs of cardiac or renal failure)

          3. Abdominal pain or cramps, loss of appetite, nausea, general ill-feeling or vomiting in
             the past 24 hours

          4. Presence of V. cholerae 01 or 0139, Shigella, or Cryptosporidium in stool at baseline

          5. Intake of any anti-diarrhoeal medicine in the past week

          6. Acute disease one week prior to enrollment, with or without fever. Temperature ≥38ºC
             (oral or otic) warrants deferral of the vaccination pending recovery of the subject

          7. Receipt of antibiotics in the past 2 weeks

          8. Receipt of live or killed enteric vaccine in the last 4 weeks

          9. Receipt of killed oral cholera vaccine in the past

         10. Diarrhea (3 or more loose stools within a 24-hour period) 6 weeks prior to enrollment

         11. One or more episodes of diarrhea lasting for more than 2 weeks in the past 6 months

         12. One or more episodes of abdominal pain lasting for more than 2 weeks in the past 6
             months

         13. Receipt of blood, blood products or a parenteral immunoglobulin preparation in the
             previous 6 months

         14. Receipt of any immunosuppressive therapy during the past 6 months

         15. A woman pregnant or planning to become pregnant during the period of subject's
             participation

         16. Any condition which in the opinion of the investigator, might interfere with the
             evaluation of the study objectives
      

Gender

All

Ages

18 Years - 45 Years

Accepts Healthy Volunteers

No

Contacts

Winai Ratanasuwan, MD, MPH, , 

Location Countries

Thailand

Location Countries

Thailand

Administrative Informations


NCT ID

NCT00741637

Organization ID

CH-PR-02


Responsible Party

Sponsor

Study Sponsor

International Vaccine Institute

Collaborators

 Vaccine Technologies Inc.

Study Sponsor

Winai Ratanasuwan, MD, MPH, Principal Investigator, Faculty of Medicine Siriraj Hospital


Verification Date

March 2012