Open Randomized Trial Evaluating Four Anti-pneumococcal Vaccine Strategies With Fractionated Doses of Non Conjugate Polysaccharide Vaccine to Prevent Hyporesponse in Healthy Volunteers (HYPOPNEUMO)

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.