Immunogenicity and Reactogenicity Following a Booster Dose of COVID-19 mRNA Vaccine (Pfizer-BioNtech) and Two Adjuvanted Sub-unit Vaccines (SP/GSK) Administered in Adults Who Received 2 Doses of Pfizer-BioNTech mRNA Vaccine as a Primary Vaccination

Study Overview
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Brief Summary
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The vaccination campaign in France began in early 2021 and was declared mandatory for all French people in July 2021. The efficacy of COVID-19 vaccines has since been widely demonstrated, as well as their safety, and now 60% of the adult population in France has received a first dose, most of them with Pfizer-BioNTech's mRNA vaccine. However, despite the increasing coverage, new data highlight the need for a booster dose for the most vulnerable people, including patients with immune deficiency. This makes it likely that a booster dose will also be needed in the general population, especially among healthcare workers, due to the active circulation of new variants since the beginning of summer 2021 and evidence of reduced protection against them. On the other hand, in addition to evaluating the potential benefit of a booster vaccination, it appears interesting to also evaluate a heterologous vaccination regimen, i.e. a booster with a different vaccine than the one used for the primary vaccination. Some studies have already evaluated a two-dose heterologous regimen and the results have shown stronger protection against SARS-CoV-2. In addition, this alternative could provide a real benefit in terms of accessibility, cost, and acceptability. The vaccine developed by Sanofi-Pasteur is based on a traditional recombinant protein approach using GSK's AS03 adjuvant. Two formulations of this vaccine are currently under development, the first targeting the S protein of the D614 strain (Wuhan strain), the second targeting the B.1.351 variant. Their value as a booster needs to be evaluated. The objective of this trial is therefore to evaluate the immunological response and safety induced by a homologous vaccine booster (Pfizer-BioNTech vaccine booster) and a heterologous vaccine booster (one of the two experimental Sanofi/GSK vaccines booster), on the D614 (Wuhan) strain and on the SARS-CoV-2 variants.

Detailed Description
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The efficacy of COVID 19 vaccines for reducing the risk of severe COVID-19 infection has now been demonstrated in real life. In France, the vaccination campaign started on December 27th, 2020 and was launched rapidly for healthcare professionals and for individuals at risk of severe COVID on January 2021. On August 5th 30th, 2021, approximately 60% of the population (> 12 years) had already received complete vaccination. Out of approximately 74,3 million doses of vaccine administered, 58 million doses are Pfizer BioNTech vaccine (78%). Data currently available on the persistence of immunity on the one hand and the appearance of viral variants with reduced sensitivity to vaccine immunity on the other, raise the need to administer further additional dose at an interval from the primary vaccination that remains to be defined, possibly different according to age and co-existing diseases. Currently, the only data published are related to the administration of a third dose (booster) of the same vaccine as the one used for primary vaccination. However, some vaccines developed more recently could be an interesting alternative for booster dose in terms of reactogenicity, availability, cost and acceptance. Moreover heterologous vaccination could be more immunogenic than homologous scheme. The vaccine developed by Sanofi Pasteur is based on a conventional adjuvanted recombinant protein approach. Two prototype vaccines are under development, one based on the Spike protein of the SARS CoV-2 D614 strain, the other on the B.1.351 strain. Their interest as booster vaccines needs to be investigated. The objective of this trial is to assess the response induced by a booster dose of either recombinant protein-based subunit vaccine (targeting D614 strain or B.1.351 strain) or by a booster dose of Pfizer-BioNTech mRNA vaccine (targeting Wuhan strain) in individuals previously vaccinated with 2 doses of Pfizer-BioNTech mRNA vaccine. These results will provide important information for booster vaccination recommendations. Participants enrolled will be healthy adults with no medical history of COVID-19; they will be recruited in 10(15?) centers in mainland France, via the COVIREIVAC network. The study will be a randomized, single-blinded, multicentre trial with three parallel arms: ARM 1 receiving Pfizer-BioNTech vaccine Group 1.A: 18-64 years old Group 1.B: 65 years and older ARM 2 receiving SP/GSK subunit D614 vaccine Group 2.A: 18-64 years old Group 2.B: 65 years and older ARM 3 receiving SP/GSK subunit B.1.351 vaccine Group 3.A: 18-64 years old Group 3.B: 65 years and older Participants will undergo 5 visits : V1 (D0): inclusion, randomization, pregnancy test, PCR test, blood draw and administration of the booster dose V2 (D28): follow-up visit with a review of solicited and unsolicited local and systemic reactions that occurred since the last visit, and blood draw V3 (D90): follow-up visit with review of potential adverse events and blood draw V4 (D180): follow-up visit with review of potential adverse events and blood draw V5 (D365): follow-up visit with review of potential adverse events and blood draw Blood samples will be used to conduct immunological analyses, and cellular analyses for a sub-category of 26 participants per group.

Official Title
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Immunogenicity and Reactogenicity Following a 3rd Dose of COVID-19 mRNA Vaccine (Pfizer-BioNtech) and Two Adjuvanted Sub-unit Vaccines (SP/GSK) Administered as a Booster in Adults Who Received 2 Doses of Pfizer-BioNTech mRNA Vaccine as a Primary Vaccination: A Randomized, Single-blinded Multicenter Clinical Trial

Conditions
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COVID-19, Vaccine Reaction

Intervention / Treatment
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* Biological: BNT162b2
* Biological: CoV2 preS dTM adjuvanted vaccine (D614), Sanofi/GSK
* Biological: CoV2 preS dTM adjuvanted vaccine (B.1.351), Sanofi/GSK


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Adult in a healthy condition or with a stable health status if pre-existing medical history. Stable health status is defined as an existing disease that has not required a significant change in treatment of hospitalization for worsening in the 3 months before enrollment, and for which neither a significant change in treatment or hospitalization for worsening is expected in the near future For women of childbearing age: a negative highly sensitive pregnancy urinary test during the inclusion visit AND use of an effective contraceptive method prior to vaccination and until at least 12 weeks after the vaccination Who has received 2 doses of mRNA vaccine (Pfizer-BioNTech) with an interval of 3 to 6 weeks Second dose of mRNA vaccine (Pfizer-BioNTech) administered 6 months +/- 1 month before the booster dose Understands and agrees to comply with the study procedures Written informed consent signed by both the participant and the investigator Subject affiliated to the French Social Security System. Exclusion Criteria: Acute febrile infection (body temperature ≥ 38.0°C) within the previous 72 hours and/or presenting symptoms suggestive of COVID-19 within the previous 28 days, or having been in contact with an infected individual for the last 10 days before the inclusion visit; Virologically documented history of COVID-19 (PCR or serology); Immunosuppressive therapy such as corticosteroids > 10 mg prednisone equivalent/day (excluding topical preparations and inhalers) within 3 months prior to inclusion or within 6 months for chemotherapies; Treatment with immunoglobulins or other blood derivatives within 3 months prior to inclusion or scheduled administration of immunoglobulins or blood derivatives before the end of the study; Known HIV, HCV or HBV infection; Any medical condition, such as cancer, that might impair the immune response; Use of experimental immunoglobulins, experimental monoclonal antibodies or convalescent plasma is not permitted during the study; Pregnancy or breastfeeding currently ongoing; History of severe adverse events following vaccine administration including anaphylactic reaction and associated symptoms such as rash, breathing problems, angioedema, and abdominal pain, or a history of allergic reaction that could be triggered by a component of the SARS-COV-2 vaccine at the time of the first vaccine injection; Participant who has received BCG (tuberculosis) vaccine within the previous year; Has received a vaccine within 4 weeks prior to the boost injection or is scheduled to receive a registered vaccine 4 weeks after the boost injection Any bleeding disorder considered as a contraindication to an intramuscular injection, previous phlebotomy, or receipt of anticoagulants Participation in other research involving humans (French classification Jarde 1 or Jarde 2) within 4 weeks prior to the inclusion visit, or participation in any other vaccine trial Subject under legal protection (e.g. guardianship, tutorship)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Comirnaty® (Pfizer-BioNTech)<br>Length of use : 1 day | Biological: BNT162b2<br>* ARM 1 receiving Pfizer-BioNTech vaccine Group 1.A: 18-64 years old Group 1.B: 65 years and older<br>* Other names: pfzer/BioNTech, mARN vaccine,;|
| Experimental: CoV2 preS dTM adjuvanted vaccine (D614), Sanofi/GSK<br>Length of use : 1 day | Biological: CoV2 preS dTM adjuvanted vaccine (D614), Sanofi/GSK<br>* ARM 2 receiving SP/GSK subunit D614 vaccine Group 2.A: 18-64 years old Group 2.B: 65 years and older<br>|
| Experimental: CoV2 preS dTM adjuvanted vaccine (B.1.351), Sanofi/GSK<br>Length of use : 1 day | Biological: CoV2 preS dTM adjuvanted vaccine (B.1.351), Sanofi/GSK<br>* ARM 3 receiving SP/GSK subunit B.1.351 vaccine Group 3.A: 18-64 years old Group 3.B: 65 years and older<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rate of neutralizing antibody titers against SARS-CoV-2 D614 and B.1.351 viral strains | Increased rate of at least 10 fold between D0 and D15 after the booster dose in neutralizing antibody titers against SARS-CoV-2 D614 and B.1.351 viral strains, measured by a microneutralisation technique in each group to assess the immunogenicity of a booster dose of an adjuvanted subunit vaccine (SP vaccine) as between D614 or B.1.351 and a mRNA vaccine (Pfizer BioNTech) in adults who were primarily vaccinated with 2 doses of mRNA vaccine (Pfizer BioNTech) with the 2nd dose of vaccine received at least 6 months +/- 1 month prior to the booster dose. | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of increase in neutralizing antibody titers against SARS-CoV-2 D614 and B.1.351 viral strains | Rate of increase in neutralizing antibody titers against SARS-CoV-2 D614 and B.1.351 viral strains, measured by a microneutralisation technique between 0 and 28 days after the booster dose in each group | 28 days | 
| Quantity and intensity of unsolicited local and systemic events up to 7 days | Quantity and intensity of local and systemic events of any grade occurring up to 7 days after boost injection (assessed from the list of solicited adverse events) | 7 days | 
| Quantity and intensity of unsolicited local and systemic events up to 28 days | Quantity and intensity of local and systemic events of any grade occurring up to 28 days after boost injection (assessed from the list of solicited adverse events) | 28 days | 
| Anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels | Anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels, expressed in BAU/ml, according to WHO recommendations D28 after the booster dose mRNA or adjuvanted subunit vaccine | between Month 3 and Day 0 | 
| Difference in anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels at 3 months | Difference in anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels between M3 and D0 | Between Month 6 and Day 0 | 
| Difference in anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels at 12 months | Difference in anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels between M12 and D0 | between Month 12 and Day 0 | 
| Neutralizing antibody titers against D614, alpha, gamma and delta variants at 3 months | Neutralizing antibody titers against D614, alpha, gamma and delta variants at 3 months | 3 months | 
| Neutralizing antibody titers against D614, alpha, gamma and delta variants at 3 months | Neutralizing antibody titers against D614, alpha, gamma and delta variants at 3 months | 6 months | 
| Neutralizing antibody titers against D614, alpha, gamma and delta variants at 12 months | Neutralizing antibody titers against D614, alpha, gamma and delta variants at 12 months | 12 months | 
| ELISpot IFN CD4 and CD8 response at 28 days | ELISpot IFN CD4 and CD8 response at 28 days | 28 days | 
| ELISpot IFN CD4 and CD8 response at 3 months | ELISpot IFN CD4 and CD8 response at 3 months | 3 months | 
| ELISpot IFN CD4 and CD8 response at 12 months | ELISpot IFN CD4 and CD8 response at 12 months | 12 months | 
| Anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels | Anti-Spike (D614) and anti-RBD (D614 and B.1.351) IgG levels, expressed in BAU/ml, according to WHO recommendations D3 after the booster dose mRNA or adjuvanted subunit vaccine (ancillary analysis) to assess the early humoral response by ELISA of a booster dose of mRNA vaccine or subunit adjuvanted vaccine | Day 3 | 
| ELISpot IFN CD4 and CD8 response | ELISpot IFN CD4 and CD8 response (ancillary analysis); to explore CD4 and CD8 cellular response induced by a booster dose of mRNA vaccine or adjuvanted subunit vaccine (ancillary analysis) | 28 days, 3 months and 12 months | 
| Activated (CD71+) spike Beta specific B cells will also be sorted and cultured in single cells for further analysis of their BCR and their relationship with the early CSA response. | To explore B cells (CD71) functionality Ancillary study endpoints: Cf. Coviboost ancillary study protocol. | Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Booster, COVID 19, mRNA vaccines, Immunology, Sub-unit vaccine