Clinical trial NCT02052154: Multicenter Pilot Study Evaluating the Immunogenicity of an Innovative Pneumococcal Vaccination Strategy in Splenectomized Adults
Official title: Multicenter Pilot Study Evaluating the Immunogenicity of an Innovative Pneumococcal Vaccination Strategy in Splenectomized Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Splenectomized Patients
Keywords: Pneumococcal infection
Splenectomized
vaccination
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2014-01-31
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: Evaluate the immunogenicity of an innovative pneumococcal vaccination strategy in splenectomized adults comprising 1 dose of Prevenar13® conjugate vaccine (PCV) at M0 followed by 1 dose of Pneumo23® or Pneumovax® polysaccharide vaccine (PPSV) at M2. Duration of follow-up of 36 months.

The main endpoint will be the proportion of subjects responsive to 9 of the 13 serotypes common to the PCV and PPSV vaccines, selected because of their frequency in invasive infections in adults in France and their potentially reduced susceptibility to penicillin (serotypes 1, 3, 6A, 7F, 9V, 14, 19A, 19F, 23F).

Detailed description: The splenectomized patient is more susceptible to infections because of the lack of specific response to the polysaccharide antigens that compose the capsules of certain bacteria. These very severe infections are known as Overwhelming Post Splenectomy Infections, or OPSI; they are characterized by very rapid onset with no prodrome and carry a high mortality rate. The annual incidence of OPSI is estimated at 0.23-0.42% with a lifetime risk of 5%. The role of pneumococcus in particular has been clearly established in these infections.

The most effective strategy to minimize the risk of pneumococcal infection is pneumococcal vaccination. Currently there are two types of vaccines available in France: polysaccharide and conjugate, both of which induce the production of anti-capsular IgG with both neutralizing and opsonic activity.

Since one of the consequences of asplenia is the absence of IgM production elicited by a polysaccharide challenge, due to an absence of splenic B cells, it is difficult to imagine that such patients would mount a satisfactory immune response to PPSV vaccination. And in fact, several studies have described the occurrence of pneumococcal OPSI in patients who were correctly vaccinated.

The study hypothesis is that a vaccination strategy combining PCV vaccine followed by PPSV vaccine will induce a good immune response in splenectomized patients, with good tolerability. All available data suggest that the optimum schedule consists of a primovaccination with one dose of PCV followed two months later by one dose of PPSV, in order to achieve a T-dependent memory response to the 13 serotypes common to the two vaccines.

The proposed endpoint is therefore to evaluate the immunogenicity and safety of a vaccination strategy comprising priming with one dose of Prevenar13® PCV vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F, + 1, 3, 5, 6A, 7F, 19A) to induce a T cell memory response, followed by the classical administration of one dose of Pneumo23® or Pneumovax® vaccine (serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F). Secondary endpoints will evaluate the safety of this strategy in terms of post-immunization local and systemic side effects, frequency of invasive pneumococcal infections, predictors of immunogenicity, and persistence of immunogenicity 30 months post-immunization.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years and ≤ 75 years
* Splenectomized since at least 2 weeks, with Howell-Jolly bodies on a blood smear and ultrasonographic confirmation
* No immunosppressived conditions : mainly trauma , idiopathic thrombocytopathic purpura or autoimmune hemolytic anemia, with no active treatment
* Available for 37 months of follow-up starting from the screening visit
* Contraception that the investigator judges effective for the first 2 months of the trial, with a negative pregnancy test
* Women not planning to become pregnant in the 6 months following inclusion (M0)
* Signed informed consent

Exclusion Criteria:

* Pregnancy or planned pregnancy in the 2 months following inclusion (M0)
* Pathology or conditions which modify immune response (excluding splenectomy) : HIV infection, immunosuppressive therapy ongoing or in 6 months before inclusion (M0), including corticosteroids \> 10 mg daily, topic inhaled or dermic corticoid treatments are allowed, hematopoietic stem cell allo / autograft, primary immune deficiency, nephrotic syndrome, sickle cell disease, evolutive neoplasia
* History of anaphylactic reaction following vaccination
* Known allergy to any of the ingredients of the vaccines: aluminium phosphate, phenol, Corynebacterium diphtheriae CRM-197 protein
* Previous vaccination with 7-valent or 13-valent pneumococcal conjugate vaccine (in the 5 last years)
* Previous vaccination with the pneumococcal polysaccharidic vaccine in the 3 years before inclusion (M0)
* Other vaccination in the month before inclusion (M0)
* Polyvalent immunoglobulin infusion in the 3 months before inclusion (M0) or during the planned duration of the study
* Anticoagulant treatment current or stopped less than 7 days before inclusion (M0); or clotting disorder contra-indicating intramuscular injection
* Participation to an other vaccine study in the 28 days before inclusion till the end of study
* Not covered by national health insurance (beneficiary or assignee)

Primary outcomes:
measure: Proportion of subjects responsive to 9 of the 13 serotypes common (serotypes 1, 3, 6A, 7F, 9V, 14, 19A, 19F, 23F).
timeFrame: M3
Secondary outcomes:
measure: IgG dosage
timeFrame: one month
measure: ELISA dosages
timeFrame: 4 months after PPSV vaccine
measure: ELISA dosages
timeFrame: 10 months after PPSV vaccine
measure: ELISA dosages
timeFrame: 34 months after PPSV vaccine
measure: Identification of predictive factors for immunogenicity
timeFrame: M0 to M36
measure: Percentage of patients presenting local or systemic reactions post-immunization
timeFrame: M0 to M36
measure: Evaluation of severe infectious episode
timeFrame: M0 to M36
measure: OPA dosages
timeFrame: 4 months after PPSV vaccine
measure: OPA dosages
timeFrame: 10 months after PPSV vaccine
measure: OPA dosages
timeFrame: 34 months after PPSV vaccine
Other outcomes:
Locations:
city: Paris
country: France
facility: Service des Maladies Infectieuses et Tropicales - Centre d'Infectiologie Necker-Pasteur, IHU Imagine - Hôpital Necker-Enfants
Study officials:
affiliation: Service des Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, APHP
name: Hélène COIGNARD-BIEHLER, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Service des Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, APHP
name: Olivier LORTHOLARY, MD, PhD
role: STUDY_DIRECTOR
affiliation: CIC Vaccinologie Cochin-Pasteur (CIC BT505) - Hôpital Cochin
name: Odile LAUNAY, MD, PhD
role: STUDY_DIRECTOR
affiliation: Service de médecine interne, Hôpital Henri Mondor
name: Marc MICHEL, MD, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Frédéric BATTEUX, MD, PhD
role: STUDY_CHAIR
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Claude-Agnès REYNAUD, PhD
role: STUDY_CHAIR
affiliation: INTS
name: Pierre BUFFET, MD, PhD
role: STUDY_CHAIR
References: