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

This study has been completed.
Sponsor:
Collaborators:
Vaccine Technologies Inc.
Siriraj Hospital, Mahidol University
Information provided by (Responsible Party):
International Vaccine Institute
ClinicalTrials.gov Identifier:
NCT00741637
First received: August 25, 2008
Last updated: March 29, 2012
Last verified: March 2012
  Purpose

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


Condition Intervention Phase
Cholera
Vibrio Infections
Diarrhea
Biological: CholeraGarde®
Biological: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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

Resource links provided by NLM:


Further study details as provided by International Vaccine Institute:

Primary Outcome Measures:
  • 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 [ Time Frame: 0,1,2,3,4,5,6,7,14,30,90 days post intervention ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 [ Time Frame: 0,1,2,3,4,5,6,7,14,30,90 days post vaccination ] [ Designated as safety issue: Yes ]
  • Proportion of subjects given CholeraGarde® or placebo with any of the following adverse events [ Time Frame: 30 minutes after adminstration and throughout the trial ] [ Designated as safety issue: Yes ]
  • Geometric mean serum vibriocidal IgG antibody titers measured at baseline and one week after a single dose of CholeraGarde® or placebo [ Time Frame: One week ] [ Designated as safety issue: Yes ]
  • Proportion of subjects given CholeraGarde® or placebo with fecal excretion of CholeraGarde® [ Time Frame: At 3, 7, 14, and 30 days post-dosing ] [ Designated as safety issue: Yes ]
  • Mean HIV viral load (copies/ml) increases, with CholeraGarde® or placebo [ Time Frame: relative to baseline, at 7, 30, and 90 days post-dosing ] [ Designated as safety issue: Yes ]
  • Mean CD4 lymphocyte count, with CholeraGarde® or placebo [ Time Frame: relative to baseline, at 90 days post-dosing ] [ Designated as safety issue: Yes ]

Enrollment: 32
Study Start Date: July 2010
Study Completion Date: June 2011
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vaccine
Live attenuated oral CholeraGarde® (5x107 to 1x109 CFU) vaccine
Biological: CholeraGarde®

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

Other Name: CholeraGarde®
Placebo Comparator: Placebo
A buffer solution containing 2.5 g sodium bicarbonate, and 1.65 g ascorbic acid.
Biological: Placebo
A buffer solution containing 2.5 g sodium bicarbonate, and 1.65 g ascorbic acid.

  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00741637

Locations
Thailand
Department of Preventive and Social Medicine Siriraj Hospital
Bangkok, Thailand, 10700
Sponsors and Collaborators
International Vaccine Institute
Vaccine Technologies Inc.
Siriraj Hospital, Mahidol University
Investigators
Principal Investigator: Winai Ratanasuwan, MD, MPH Faculty of Medicine Siriraj Hospital
  More Information

No publications provided

Responsible Party: International Vaccine Institute
ClinicalTrials.gov Identifier: NCT00741637     History of Changes
Other Study ID Numbers: CH-PR-02
Study First Received: August 25, 2008
Last Updated: March 29, 2012
Health Authority: Thailand: Ethical Committee

Keywords provided by International Vaccine Institute:
Vibrio Cholerae
Diarrhea
Live oral Vaccines
Immunogenicity
Safety
HIV

Additional relevant MeSH terms:
Cholera
Diarrhea
HIV Seropositivity
Vibrio Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Signs and Symptoms, Digestive
Signs and Symptoms
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases

ClinicalTrials.gov processed this record on July 28, 2014