Safety and Immunogenicity of Peru-15 Vaccine When Given With Measles Vaccine in Healthy Indian and Bangladeshi Infants

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Brief Title

Safety and Immunogenicity of Peru-15 Vaccine When Given With Measles Vaccine in Healthy Indian and Bangladeshi Infants

Official Title

A Multi-site, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Immunogenicity of Trehalose-reformulated Peru-15 (Choleragarde)Vaccine Given Simultaneously With Measles Vaccine in Healthy Indian and Bangladeshi Infants

Brief Summary

      The purpose of this study is to confirm the safety and immunogenicity of Peru-15 vaccine in
      infants when given simultaneously with measles vaccine.
    

Detailed Description

      Cholera is an important public health problem worldwide, remaining endemic in most of the
      developing world at the same time causing outbreaks in areas where lapses in sanitation
      occur. In 2005, 131 943 cholera cases and 2272 deaths were reported to the World Health
      Organization (WHO) with more countries reporting cholera outbreaks. Overall, this represents
      a 30% increase in the number of cases reported compared to 2004. The cholera case fatality
      rate during that year was 1.72%; however, recent outbreaks in West Africa resulted in
      case-fatality rates of as high as 12% [1, 2]. These figures are believed to be underestimates
      and that as much as 120 000 deaths due to cholera are estimated to occur each year [3]. Aside
      from this high mortality, cholera outbreaks cause economic and social disruptions.

      The states of West Bengal in India together with neighboring Bangladesh have been considered
      by many as the "homeland of cholera". In India, 4695 cases of cholera were reported to the
      WHO [1] with states such as West Bengal, Maharashtra, Andra Pradesh, Tamil Nadu, Karnataka
      and Delhi long been reporting outbreaks [4]. Although no country-wide data is available from
      Bangladesh, a 4 - year surveillance in 4 different geographical areas in Bangladesh reveal
      that cholera is widely distributed even in an area with no reported outbreaks for 10 years
      [5]. Cholera in these 2 countries affects all age groups, with the youngest age group being
      the most affected. In Kolkata, children <5 years of age had a 30% higher risk of having
      cholera compared to older individuals [6] and in Bangladesh, 53% of 5670 cholera-infected
      patients in the 4-year surveillance were children <5 years of age [5]. Further analysis of a
      3 year prospective surveillance of cholera in Kolkata shows that infants less than 2 years of
      age had a cholera incidence rate of 4.20 per 1000 person-years whereas the over-all rate in
      the study population was 1.41 per 1000 person-years (Data on file).

      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
      [7].

      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 impeded its use in
      public health settings. A live oral vaccine, CVD-103 HgR (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 [8], in a field trial of this vaccine in an
      endemic area in Indonesia, no protective efficacy was detected during the period of
      observation [9].

      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 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 expanded programme on immunization (EPI). In the Diseases of the
      Most Impoverished Programme (DOMI) of the IVI, Peru-15 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 [10]. This has the
      advantage of being given in a single dose and of having the same biotype as the current
      pandemic strain (biotype El tor), unlike CVD-103 HgR which is a classical biotype. 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 and by insertion of the cholera toxin B gene to the
      recA gene, it enabled the strain to produce cholera toxin B. This insertion has inactivated
      the recA gene, and this together with the deletion of the attRS1 sequences, has decreased the
      ability of the strain to integrate exogenous DNA making it non-recombinational. Lastly, by
      the absence of the potentially inflammatory flagella it has been rendered non-motile [10,
      11]. In addition, Phase I and II studies have been performed in North American volunteers
      where it was found to be safe and immunogenic [11-12]. 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 [13].

      This vaccine underwent phase I and II studies in a cholera-endemic area in Dhaka, Bangladesh
      in three age groups: adults aged 18 - 45 years, children aged 2 - 5 years and infants aged 9
      - 23 months [14, 15]. In these studies, a 2 x108 CFU dose of the vaccine was shown to be safe
      and able to elicit vibriocidal responses among all age groups. 75% of adults, 84% of children
      aged 2-5 years and 70% of infants aged 9-23 months developed a 4-fold rise from baseline in
      their vibriocidal titres. Only 1 of 20 adults and 8 of 140 children who received vaccine
      excreted the vaccine strain up to 4 days after vaccination. Analysis of the strains isolated
      revealed that the strains remained unchanged in phenotypic and genotypic properties after
      passage in the stool.

      To date, the vaccine has been tested on more than 400 volunteers. The freshly harvested
      product, tested on 23 volunteers and the frozen lyophilized preparation, tested on 381
      volunteers were both shown to be safe and immunogenic in all age groups. The most frequently
      reported adverse events were gastrointestinal symptoms (diarrhea, nausea, abdominal cramping,
      gas, decreased appetite) and headache and in controlled studies were reported in similar
      frequencies in subjects who received Peru-15 and placebo. The optimal dose for healthy adult
      travelers was a single, oral dose of 1 x 108 CFU. The study in Bangladesh further confirmed
      that a 108 dose was safe and immunogenic in all age groups including infants among residents
      of a cholera endemic area.

      Avant Immunotherapeutics Inc., manufacturers of Peru-15, are in the process of reformulating
      the vaccine with the long-term stabilizing ability of trehalose in order to make Peru-15 more
      thermostable at elevated temperatures, i.e. 2-8ºC. If this reformulation is proven as safe
      and at least as immunogenic as the previous version, then this will make vaccine storage
      easier and more easily deployable in field conditions in Africa, in refugee settings and in
      endemic countries in South Asia.

      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 allow clinical trials on this reformulated vaccine to be
      performed in 2 cholera-endemic countries - India and Bangladesh. 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. Furthermore, this vaccine
      may potentially be used in infants and young children who have the highest risk of cholera,
      potentially being included as part of the EPI in endemic areas.

      The previous formulations of the vaccine were shown to be safe and immunogenic in all age
      groups, including infants, in a cholera endemic area [12 - 15] and efficacious in preventing
      cholera diarrhea in healthy adult volunteers [13]. In view of this, the current dose of up to
      109 of the current formulation will be directly tested among infants.Data regarding the
      safety and immunogenicity of the trehalose-reformulated Peru-15 vaccine among infants need to
      be confirmed in order to pave the way for the possible use of this vaccine in cholera-endemic
      areas where infants and children are most at risk. Furthermore, if this vaccine will be used
      in the context of the EPI to be given together with measles vaccine, it would be important to
      determine if immune interference exists between these 2 live attenuated vaccines.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

proportion of subjects with the following adverse events: headache, vomiting, nausea, abdominal pain/cramps, gas, diarrhea, loss of appetite, myalgias, general ill feeling

Secondary Outcome

 evaluate fecal excretion and genetic stability of the vaccine strain

Condition

Cholera

Intervention

Peru-15 Vaccine

Study Arms / Comparison Groups

 Vaccine
Description:  

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

74

Start Date

November 2008

Completion Date

July 2012

Primary Completion Date

July 2012

Eligibility Criteria

        Inclusion Criteria:

        Healthy male and female infants aged 9 - 12 months will be recruited from Vellore, India
        and Dhaka, Bangladesh.

        All subjects must satisfy the following criteria at study entry:

          1. Male or female infants aged 9 - 12 months whose parents or primary caretaker have
             given the written informed consent prior to study entry

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

          3. Healthy subjects as determined by:

               -  Medical history

               -  Physical examination

               -  Clinical judgment of the investigator

        Exclusion Criteria:

          1. Parents or primary caregiver are unwilling or unable to give written informed consent
             to participate in the study

          2. Ongoing serious chronic disease

          3. Immunocompromising condition or therapy

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

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

          6. Acute disease one week prior to enrollment, with or without fever. Temperature ≥38ºC
             (oral) or axillary temperature ≥ 37.5ºC 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. Diarrhea (3 or more loose stools within a 24-hour period) 6 weeks prior to enrollment

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

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

         12. Receipt of killed oral cholera vaccine

         13. Have previously received a dose of a measles-containing vaccine (MCV)

         14. Have previously presented with a disease potentially related to measles

         15. Receipt of blood, blood products or a parenteral immunoglobulin preparation in the
             previous 3 months

         16. History of anaphylaxis, any serious vaccine reaction, allergy to eggs, egg products or
             to any measles vaccine component

         17. any condition which in the opinion of the investigator, might interfere with the
             evaluation of the study objectives
      

Gender

All

Ages

9 Months - 12 Months

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

John Clemens, MD, , 

Location Countries

Bangladesh

Location Countries

Bangladesh

Administrative Informations


NCT ID

NCT00624975

Organization ID

CHPR-01


Responsible Party

Sponsor

Study Sponsor

International Vaccine Institute

Collaborators

 International Centre for Diarrhoeal Disease Research, Bangladesh

Study Sponsor

John Clemens, MD, Principal Investigator, International Vaccine Insititute


Verification Date

July 2012