This is a multicentre Phase II trial evaluating different booster strategies in individuals already vaccinated against SARS-CoV-2. This trial allows testing of different booster strategies for comparative assessment of their immune responses and safety against SARS-CoV-2 and its variants. This study tests whether a 4th vaccination dose is needed and determines the optimal booster vaccination schedule for further evaluation in a phase III trial

INTERVENTION: Trade Name: Comirnaty Pharmaceutical Form: Concentrate for dispersion for injection CONDITION: Severe Acute Respiratory Syndrome Coronavirus 19 (COVID‐19/SARS‐CoV‐2) ; MedDRA version: 23.1 Level: PT Classification code 10084457 Term: COVID‐19 immunisation System Organ Class: 10042613 ‐ Surgical and medical procedures ; MedDRA version: 23.0 Level: LLT Classification code 10084462 Term: SARS‐CoV‐2 vaccination System Organ Class: 10042613 ‐ Surgical and medical procedures Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] PRIMARY OUTCOME: Main Objective: To determine the need for, optimal timing of, and immunogenicity of administering a 4th homologous vaccination dose against SARS‐CoV‐2 in the general population (18+ years) already vaccinated with the BNT162b2 vaccine. Primary end point(s): The primary endpoint comprises a composite endpoint of either an increase in anti‐RBD antibody titre to =500 IU/mL at day 14 post 4th dose booster vaccine in those with anti‐RBD antibody titre of =500 IU/mL immediately before 4th dose booster vaccination or a 2‐fold increase in anti‐RBD antibody titre at day 14 following 4th dose vaccination in those with anti‐RBD titre of =500 IU/mL immediately before 4th dose booster vaccination, as measured by quantitative immunoassay targeting the anti‐RBD antibody. Secondary Objective: • To determine the change in cellular immune response measured by a direct from blood qPCR based T‐cell activation (dq‐TACT) assay at 14 days after 4th dose vaccine in comparison to prior to 4th dose vaccination.; • To correlate humoral immune response, cellular immune responses and viral neutralising capacity against wild type SARS‐CoV‐2; • To determine the durability of humoral and cellular immune responses after 3rd dose of initial vaccination and 4th dose vaccination; • To determine rates of, and maximum disease severity associated with confirmed SARS‐CoV‐2 infections occurring after enrolment in study participants before and after 4th dose vaccine; • To explore primary and secondary endpoints stratified by incident infection pre‐4th dose vaccine or by any modification of vaccine epitope.; Timepoint(s) of evaluation of this end point: 14 days after 3rd dose vaccine INCLUSION CRITERIA: • Adults aged 18 years or above at baseline • Be at least three but no more than 6 months (+/‐ 4 weeks) from the date of 3rd dose of BNT162b2 vaccine at the time of consent • Have received three homologous doses as primary vaccination against SARS‐CoV‐2 with BNT162b2 vaccine (vaccination status should be documented). • Written informed consent from the subject has been obtained. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 400 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 100 SECONDARY OUTCOME: Secondary end point(s): • The proportion of subjects reporting positive tests (PCR and/or antigen tests) for SARS‐CoV‐2 at each reporting time point after enrolment; • The proportion of subjects who receive 4th dose vaccination at each specific timepoint that achieve a 2‐fold increase in RBD antibody titre 14 days after the 4th dose vaccine; • The proportion of subjects who receive 4th dose vaccination at each specific timepoint that achieve an anti‐RBD antibody titre =500 IU/mL 14 days after the 4th dose vaccine; • Rate of 2‐fold RBD antibody titre increase following 4th dose vaccination measured by quantitative immunoassay targeting the spike 1 (S1) and nucleocapsid (NC) antibodies at 14 days after 4th dose vaccine as compared to immediately before vaccination; • Analysis stratified by incident pre‐4th dose SARS‐CoV‐2 infections and any modification of vaccine epitope; ; Safety/tolerability:; • Solicited AEs for 7 days after 4th dose ; • Unsolicited/Spontaneous AEs until the end of trial; • Rate of serious adverse events (SAEs) Grade =3 according to the National Cancer Institute Common Toxicity Criteria until up to three months after 4th dose or subject completes the study, whichever occurs first. ; ; Laboratory:; • T‐cell activation as measured by a whole blood dq‐TACT assay before and 14 days after 4th dose vaccine; • Neutralising activity against SARS‐CoV‐2 wild‐type and variants of concern as measured by a standardised viral neutralisation assay (sub‐group analysis); ; Exploratory endpoints:; • Detailed immunophenotyping of immune responses, including metabolomics, proteomics and transcriptomics where relevant (sub‐group analysis) ; • Whole genome sequencing of isolated SARS‐CoV‐2 viral strains detected in breakthrough infections; • Haemagglutination assay as a surrogate of neutralising capacity; Timepoint(s) of evaluation of this end point: 7 and 14 days after 3rd dose vaccine