Open Randomized Trial Evaluating Four Anti-pneumococcal Vaccine Strategies With Fractionated Doses of Non Conjugate Polysaccharide Vaccine to Prevent Hyporesponse in Healthy Volunteers
Condition: Pneumococcal Infection
MeSH terms: Pneumococcal Infections
Study type: Interventional
Phase: Phase 2

Summary: 
      Immune response analysis after the combination of PCV13 and PPV23 will lead to evaluate if a
      prime with PCV13 help to obtain a good response to repeated dose of PPV23.The
      hyporesponsiveness following the unconjugated vaccine is associated with high polysaccharide
      antigen concentration. Several issues limit the development and recommendation of
      anti-pneumococcal vaccine in adult's patients at risk. Reduced doses of unconjugated
      polysaccharide antigens would bypass the hyporesponsiveness and maintain the expanded
      coverage serotype.

      A better knowledge of immune response following the combination of two vaccines in adults is
      essential. In addition, adults are required to be exposed to repeated doses of polysaccharide
      antigens by vaccine or by natural exposure, it is important to determine the extend and
      duration of any hyporesponsiveness.

      The main objective is to evaluate if non conjugate polysaccharidique fractionated doses
      administered after a conjugate vaccine help to avoid hyporesponse in a schedule with repeated
      injections of pneumococcal polysaccharidique vaccine
    

Detailed description: 
      Immune response analysis after the combination of PCV13 and PPV23 will lead to evaluate if a
      prime with PCV13 help to obtain a good response to repeated dose of PPV23.The
      hyporesponsiveness following the unconjugated vaccine is associated with high polysaccharide
      antigen concentration. Several issues limit the development and recommendation of
      anti-pneumococcal vaccine in adult's patients at risk. Reduced doses of unconjugated
      polysaccharide antigens would bypass the hyporesponsiveness and maintain the expanded
      coverage serotype.

      A better knowledge of immune response following the combination of two vaccines in adults is
      essential. In addition, adults are required to be exposed to repeated doses of polysaccharide
      antigens by vaccine or by natural exposure, it is important to determine the extend and
      duration of any hyporesponsiveness.

      The main objective is to evaluate if non conjugate polysaccharidique fractionated doses
      administered after a conjugate vaccine help to avoid hyporesponse in a schedule with repeated
      injections of pneumococcal polysaccharidique vaccine

      The projects aims are :

      - Primary is to evaluate if non conjugate polysaccharidique fractionated doses administered
      after a conjugate vaccine help to avoid hyporesponse in a schedule with repeated injections
      of pneumococcal polysaccharidique vaccine.

      Secondary objectives are :

        -  To study the immune response involved when combining conjugate vaccine (PCV13) and
           non-conjugate polysaccharide vaccine (PPV23 full dose or fractionated booster dose) and
           assesses an eventual prime-boost effect.

        -  To study the impact of fractioned PPV23 on the immune response to PPV23 serotypes,
           measured as the extension of the serotype coverage.

        -  To assess the sustainability and evolution of the immune response over time

        -  To investigate the clinical tolerance to an initial dose of PCV13 followed by repeated
           doses of PPV23 vaccines

        -  To describe any invasive infections pneumococcal and community acquired pneumonia
           occurring during the time course of the study.

      Study duration Recruitment: 6 months Participation: 36 months Total duration of the study: 42
      month

      Study Design Vaccine trial Open randomized 1:1:1:1 phase II comparing the immunogenicity of
      four pneumococcal vaccination strategies administered by intramuscular route in healthy
      volunteer's adults aged 18 to 49 years.

      Four dose combination of two vaccines will be assessed, Pneumo23® and Prevenar13®. Volunteers
      will receive three vaccine injections during the study.

      Sixty (60) healthy volunteers will be enrolled and randomized into the four following groups:

        -  Group A: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 one dose of
           Pneumo23® and at M12, 1/5 dose of Pneumo23®

        -  Group B: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 1/5 dose of
           Pneumo23® and at M12, 1/5 dose of Pneumo23®

        -  Group C: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 1/5 dose of
           Pneumo23® and at M12, one dose of Pneumo23®

        -  Group D: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 one dose of
           Pneumo23® and at M12, one dose of Pneumo23®

      Number of visits per volunteer: 9 visits

        -  3 vaccination visits: M0, M2, M12

        -  6 follow-up visits: M1, M3, M13, M18, M24, M36.

        -  Unscheduled visit if suspected invasive pneumococcal infection (meningitis, bacteraemia,
           pneumonia, pleural-pneumonia)

      Total number of scheduled subjects :

      60 healthy volunteers will be recruited at the CIC 1417: 15 volunteers per group There was no
      statistical determination of sample size. Data from this trial will identify one or more
      vaccine strategies that could be tested in clinical trials on population at risk for invasive
      pneumococcal diseases.

      Data from published studies don't give homogeneous references about geometric means titers in
      OPA with fractional of polysaccharidique vaccine. This is the first study evaluating combined
      vaccination strategies with a schedule with one initial dose of PCV13 and complete or
      fractional doses of PPV23.

      Expected patient or public health benefit A better assessment of the immunogenicity induced
      by the combination of Prevenar13® and Pneumo23® will allow to adapt pneumococcal vaccine
      recommendations for adults. The Pneumo23® has been for a long time the only vaccine
      recommended in adults with a condition that places them at high risk of invasive pneumococcal
      infection: splenectomy or functional asplenia, homozygous sickle cell disease, HIV infection
      (regardless of the immunovirological status), nephrotic syndrome, respiratory failure, heart
      failure, patients with chronic liver disease, with a history of pulmonary infection or
      invasive pneumococcal disease. It has to be repeated every 5 years (BEH-vaccination schedule
      and vaccine recommendations), given the absence of an immune memory. But its immunogenicity
      is limited and repeated doses may induce hyporesponsiveness. The recent availability of
      Prevenar13®, polysaccharide conjugate vaccine, in adults led to reassess recommendations for
      adults advising the combination of two vaccines: PCV13 and PPV23 2 months apart (then
      repeated doses of PPV23 at 5 years), to induce a response called "prime-boost", that is to
      say PPV23stimulation of memory response initiated by PCV13 (Advisory Committee on
      Immunization Practices (ACIP) Recommended Immunization Schedule for Adults Aged 19 Years and
      Older - United States, 2013 --MMWR/January 28 2013/Vol. 62). These recommendations need to
      rely on more solid immunological substrate, including more data in adults whose immune status
      differs from children. To our knowledge, there is no data examining the various mechanisms of
      the immune response in the combination of these two vaccines, and taking into account the
      effect of dose of polysaccharide antigens in the same study, with such immunological
      monitoring in adults. Data from this clinical trial will therefore support these
      recommendations, either on the induction of immunological memory response by the PCV13, or on
      the impact of repeated doses of PPV23. Preventing pneumococcal infections would decrease
      morbidity; extend life expectancy and quality of life in patients at risk. In a public health
      perspective, by reducing the number and duration of hospitalization, it would reduce
      dramatically the vaccine cost.

      Study duration Recruitment: 6 months Participation: 36 months Total duration of the study: 42
      month

      Study Design Vaccine trial Open randomized 1:1:1:1 phase II comparing the immunogenicity of
      four pneumococcal vaccination strategies administered by intramuscular route in healthy
      volunteer's adults aged 18 to 49 years.

      Four dose combination of two vaccines will be assessed, Pneumo23® and Prevenar13®. Volunteers
      will receive three vaccine injections during the study.

      Sixty (60) healthy volunteers will be enrolled and randomized into the four following groups:

        -  Group A: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 one dose of
           Pneumo23® and at M12, 1/5 dose of Pneumo23®

        -  Group B: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 1/5 dose of
           Pneumo23® and at M12, 1/5 dose of Pneumo23®

        -  Group C: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 1/5 dose of
           Pneumo23® and at M12, one dose of Pneumo23®

        -  Group D: 15 subjects receiving at M0 one dose of Prevenar13®, at M2 one dose of
           Pneumo23® and at M12, one dose of Pneumo23®

      Number of visits per volunteer: 9 visits

        -  3 vaccination visits: M0, M2, M12

        -  6 follow-up visits: M1, M3, M13, M18, M24, M36.

        -  Unscheduled visit if suspected invasive pneumococcal infection

      Total number of scheduled subjects :

      60 healthy volunteers will be recruited at the CIC 1417: 15 volunteers per group There was no
      statistical determination of sample size. Data from this trial will identify one or more
      vaccine strategies that could be tested in clinical trials on population at risk for invasive
      pneumococcal diseases.

      Data from published studies don't give homogeneous references about geometric means titers in
      OPA with fractional of polysaccharidic vaccine. This is the first study evaluating combined
      vaccination strategies with a schedule with one initial dose of PCV13 and complete or
      fractional doses of PPV23.

      Expected patient or public health benefit A better assessment of the immunogenicity induced
      by the combination of Prevenar13® and Pneumo23® will allow to adapt pneumococcal vaccine
      recommendations for adults. The Pneumo23® has been for a long time the only vaccine
      recommended in adults with a condition that places them at high risk of invasive pneumococcal
      infection: splenectomy or functional asplenia, homozygous sickle cell disease, HIV infection
      (regardless of the immunovirological status), nephrotic syndrome, respiratory failure, heart
      failure, patients with chronic liver disease, with a history of pulmonary infection or
      invasive pneumococcal disease. It has to be repeated every 5 years (BEH-vaccination schedule
      and vaccine recommendations), given the absence of an immune memory. But its immunogenicity
      is limited and repeated doses may induce hyporesponsiveness. The recent availability of
      Prevenar13®, polysaccharide conjugate vaccine, in adults led to reassess recommendations for
      adults advising the combination of two vaccines: PCV13 and PPV23 2 months apart (then
      repeated doses of PPV23 at 5 years), to induce a response called "prime-boost", that is to
      say PPV23stimulation of memory response initiated by PCV13 (Advisory Committee on
      Immunization Practices (ACIP) Recommended Immunization Schedule for Adults Aged 19 Years and
      Older - United States, 2013 --MMWR/January 28 2013/Vol. 62). These recommendations need to
      rely on more solid immunological substrate, including more data in adults whose immune status
      differs from children. To our knowledge, there is no data examining the various mechanisms of
      the immune response in the combination of these two vaccines, and taking into account the
      effect of dose of polysaccharide antigens in the same study, with such immunological
      monitoring in adults. Data from this clinical trial will therefore support these
      recommendations, either on the induction of immunological memory response by the PCV13, or on
      the impact of repeated doses of PPV23. Preventing pneumococcal infections would decrease
      morbidity; extend life expectancy and quality of life in patients at risk. In a public health
      perspective, by reducing the number and duration of hospitalization, it would reduce
      dramatically the vaccine cost.
    

Intervention name(s): Pneumo 23® 0,5; Pneumo 23® 0,1; Prevenar13® 0,5
Intervention type(s): Biological; Biological; Biological
Intervention description(s): Polysaccharide vaccine Pneumo 23® (Sanofi Pasteur MSD), containing 23 valencies Pneumococcus (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F) administered by intramuscular route. (Deltoid) at full dose. One dose contains: 0, 5 mL of 25 μg of polysaccharide of the 23 serotypes pneumococcus.; Polysaccharide vaccine Pneumo 23® (Sanofi Pasteur MSD), containing 23 valencies Pneumococcus (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F) administered by intramuscular route. (Deltoid) at a 1/5 of the dose. One dose contains: 0, 5 mL of 25 μg of polysaccharide of the 23 serotypes pneumococcus.; The conjugate vaccine Prevenar13® (Pfizer) containing 13 valencies Pneumoccocus (4, 6B, 9V, 14, 18C, 19F, 23F), conjugated with diphtheria anatoxin (CRM 197) administered by intramuscular route (deltoid).
One dose contains: 0, 5 ml of 2 - 4μg of polysaccharide of the13 serotypes pneumococcus which 12 are shared with Pneumo 23® vaccine conjugated to diphtheria toxoid (CRM 197).
Intervention MeSH terms: Heptavalent Pneumococcal Conjugate Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: hyporesponsiveness; vaccination; recommendations; improvement; schedule; fractional dose; conjugate polysaccharide vaccine