Comirnaty

Pharmacotherapeutic group: vaccines, viral vaccines, ATC code: J07BN01 Mechanism of action The nucleoside-modified messenger RNA in Comirnaty is encapsulated in lipid nanoparticles, which enable delivery of the non-replicating RNA into host cells to direct transient expression of the SARS-CoV-2 spike (S) antigen. The mRNA encodes the membrane-anchored, full-length S protein with two point mutations within the central helix. Substitution of these two amino acids with proline locks S in the antigenically preferred prefusion conformation. The vaccine elicits both neutralising antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID-19. Efficacy Omicron-adapted Comirnaty Immunogenicity in children 5 to 11 years of age (i.e. 5 to less than 12 years of age) – following a booster dose (fourth dose) A subgroup analysis from Study 6 showed that 103 participants 5 to 11 years of age who had previously completed a 2-dose primary series and received a booster dose of Comirnaty were given a booster (fourth) dose of Comirnaty Original/Omicron BA.4-5. Results include immunogenicity data from a comparator subgroup of participants 5 to 11 years of age in Study 3 who had received 3 doses of Comirnaty. At baseline, 57.3% of participants 5 to 11 years of age who received a fourth dose of Comirnaty Original/Omicron BA.4-5 and 58.4% of participants 5 to 11 years of age who received a third dose of Comirnaty were SARS-CoV-2 positive. The immune response 1 month after the booster (fourth) dose of Comirnaty Original/Omicron BA.4-5 generally elicited Omicron BA.4/BA.5–specific neutralising titres similar to those observed in the comparator group given 3 doses of Comirnaty. Comirnaty Original/Omicron BA.4-5 also elicited reference-strain–specific titres similar to those in the comparator group. Post-booster immunogenicity results in participants 5 to 11 years of age are presented in Table 3. Table 3. Study 6 — geometric mean ratio and geometric mean titre — participants with or without evidence of infection — 5 to 11 years of age — evaluable immunogenicity population SARS-CoV-2 neutralisation assay Sampling time point a Vaccine groups (as assigned/randomised) Study 6 Comirnaty (Original/Omicron BA.4/BA.5) 10 micrograms 4th dose at 1 month post–4th dose Study 3 Comirnaty 10 micrograms 3rd dose at 1 month post–3rd dose Study 6 Comirnaty (Original/Omicron BA.4/BA.5)/Comirnaty 10 micrograms n b GMT c (95% CI c) n b GMT c (95% CI c) GMR d (95% CI d) Omicron BA.4-5 — NT50 (titre) e Pre-vaccination: 102; 488.3 (361.9; 658.8); 112; 248.3 (187.2; 329.5); — 1 month: 102; 2,189.9 (1,742.8; 2,751.7); 113; 1,393.6 (1,175.8; 1,651.7); 1.12 (0.92; 1.37) Reference strain — NT50 (titre) e Pre-vaccination: 102; 2,904.0 (2,372.6; 3,554.5); 113; 1,323.1 (1,055.7; 1,658.2); — 1 month: 102; 8,245.9 (7,108.9; 9,564.9); 113; 7,235.1 (6,331.5; 8,267.8); — Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre; LLOQ = lower limit of quantitation; LS = least squares; N-binding = SARS-CoV-2 nucleoprotein binding; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Protocol-specified blood sampling time point. n = number of participants with valid and determinate assay results for the specified assay at the given sampling time point. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titre and corresponding CIs (based on the Student t-distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. GMRs and 2-sided 95% CIs were calculated by exponentiating the difference of the LS mean values for the assay and corresponding CIs from analyses of log-transformed assay results using a linear regression model with baseline log-transformed neutralising titre, post-baseline infection status, and vaccine group as covariates. SARS-CoV-2 NT50 values were determined using a validated 384-well titration plate (original strain [USA-WA1/2020, isolated in January 2020] and Omicron variant B.1.1.529, sublineage BA.4/BA.5). Immunogenicity in participants 12 years of age and older — following a booster dose (fourth dose) A subgroup analysis from Study 5 showed that 105 participants 12 to 17 years of age, 297 participants 18 to 55 years of age, and 286 participants 56 years of age and older who had previously completed a 2-dose primary series and received a booster dose of Comirnaty were given a booster (fourth) dose of Comirnaty Original/Omicron BA.4-5. At baseline, 75.2% of participants 12 to 17 years of age, 71.7% of participants 18 to 55 years of age, and 61.5% of participants 56 years of age and older were SARS-CoV-2 positive. Analyses of 50% neutralising antibody titres (NT50) against Omicron BA.4-5 and the reference strain in participants 56 years of age and older who received a booster (fourth) dose of Comirnaty Original/Omicron BA.4-5 in Study 5, compared with a subgroup of participants from Study 4 who received a booster (fourth) dose of Comirnaty, demonstrated, on the basis of the geometric mean ratio (GMR), superiority of Comirnaty Original/Omicron BA.4-5 over Comirnaty, non-inferiority based on the difference in seroresponse rates against Omicron BA.4-5, and non-inferiority of the immune response against the reference strain based on GMR (Table 4). Analyses of NT50 against Omicron BA.4/BA.5 in participants 18 to 55 years of age and in participants 56 years of age and older who received a booster (fourth) dose of Comirnaty Original/Omicron BA.4-5 in Study 5 demonstrated, in participants 18 to 55 years of age (compared with participants 56 years of age and older), non-inferiority of the response against Omicron BA.4-5 for both GMR and the difference in seroresponse rates (Table 4). In participants who received a booster (fourth) dose, the study also assessed NT50 against SARS-CoV-2 Omicron BA.4-5 and reference strains pre-vaccination and 1 month post-vaccination (Table 5). Table 4. SARS-CoV-2 GMTs (NT50) and difference in percentages of participants with seroresponse 1 month post-vaccination — Comirnaty Original/Omicron BA.4-5 from Study 5 and Comirnaty from a Study 4 subgroup — participants with or without evidence of SARS-CoV-2 infection — evaluable immunogenicity population SARS-CoV-2 GMTs (NT50) 1 month post-vaccination SARS-CoV-2 neutralisation assay Study 5 Comirnaty Original/Omicron BA.4-5 Study 4 subgroup Comirnaty Comparison by age group Comparison by vaccine group 18 to 55 years of age 56 years of age and older 56 years of age and older Comirnaty Original/Omicron BA.4-5 18 to 55 years/≥ 56 years ≥ 56 years Comirnaty Original/Omicron BA.4-5/Comirnaty n a; GMT c (95% CI c); n a; GMT b (95% CI b); n a; GMT b (95% CI b); GMR c (95% CI c); GMR c (95% CI c) Omicron BA.4-5 — NT50 (titre) d: 297; 4,455.9 (3,851.7; 5,154.8); 284; 4,158.1 (3,554.8; 4,863.8); 282; 938.9 (802.3; 1,098.8); 0.98 (0.83; 1.16) e; 2.91 (2.45; 3.44) f Reference strain — NT50 (titre) d: —; —; 286; 16,250.1 (14,499.2; 18,212.4); 289; 10,415.5 (9,366.7; 11,581.8); —; 1.38 (1.22; 1.56) g Difference in percentages of participants with seroresponse 1 month post-vaccination Comirnaty Original/Omicron BA.4-5 Study 4 subgroup Comirnaty Comparison by age group Comparison by vaccine group ≥ 56 years of age 18 to 55 years of age 56 years of age and older 56 years of age and older Comirnaty Original/Omicron BA.4-5 18 to 55 years/≥ 56 Comirnaty Original/Omicron BA.4-5/Comirnaty SARS-CoV-2 neutralisation assay N h; n i (%) (95% CI k); N h; n i (%) (95% CI k); N h; n i (%) (95% CI j); Difference k (95% CI l); Difference k (95% CI l) Omicron BA.4-5 — NT50 (titre) d: 294; 180 (61.2) (55.4; 66.8); 282; 188 (66.7) (60.8; 72.1); 273; 127 (46.5) (40.5; 52.6); -3.03 (-9.68; 3.63) m; 26.77 (19.59; 33.95) n Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre; LLOQ = lower limit of quantitation; LS = least squares; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Note: Seroresponse is defined as a ≥ 4-fold rise from baseline. If the baseline value is below the LLOQ, a post-vaccination assay result of ≥ 4 × LLOQ is regarded as a seroresponse. n = number of participants with valid and determinate assay results for the specified assay at the given sampling time point. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titre and corresponding CIs (based on the Student t-distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. GMRs and 2-sided 95% CIs were calculated by exponentiating the difference between LS mean values and corresponding CIs from analyses of log-transformed neutralising titres using a linear regression model, with baseline neutralising titre (log scale) and age or vaccine group as covariates. SARS-CoV-2 NT50 values were determined using a validated 384-well titration plate (original strain [USA-WA1/2020, isolated in January 2020] and Omicron variant B.1.1.529, sublineage BA.4/BA.5). Non-inferiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67. Superiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 1. Non-inferiority is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67 and the GMR point estimate is ≥ 0.8. N = number of participants with valid and determinate assay results for the specified assay both at the pre-vaccination time point and at the given sampling time point. This value is the denominator for the percentage calculation. n = number of participants with seroresponse to the specified assay at the given sampling time point. Exact 2-sided CI based on the Clopper–Pearson method. Difference in proportions, expressed as a percentage. 2-sided CI based on the Miettinen and Nurminen method for the difference in proportions, stratified by baseline neutralising titre category (< median, ≥ median). The median baseline neutralising titre was calculated using pooled data from the 2 comparator groups. Non-inferiority is declared if the lower bound of the 2-sided 95% CI for the difference in seroresponse percentages is > -10%. Non-inferiority is declared if the lower bound of the 2-sided 95% CI for the difference in seroresponse percentages is > -5%. Table 5. Geometric mean titres — Study 5 subgroups receiving Comirnaty Original/Omicron BA.4-5 — before the booster (fourth) dose and 1 month post-vaccination — participants 12 years of age and older — with or without evidence of infection — evaluable immunogenicity population SARS-CoV-2 neutralisation assay Sampling time point a Comirnaty Original/Omicron BA.4-5 12 to 17 years of age 18 to 55 years of age 56 years of age and older n b; GMT c (95% CI c); n b; GMT c (95% CI c); n b; GMT c (95% CI c) Omicron BA.4-5 — NT50 (titre) d Pre-vaccination: 104; 1,105.8 (835.1; 1,464.3); 294; 569.6 (471.4; 688.2); 284; 458.2 (365.2; 574.8) 1 month: 105; 8,212.8 (6,807.3; 9,908.7); 297; 4,455.9 (3,851.7; 5,154.8); 284; 4,158.1 (3,554.8; 4,863.8) Reference strain — NT50 (titre) d Pre-vaccination: 105; 6,863.3 (5,587.8; 8,430.1); 296; 4,017.3 (3,430.7; 4,704.1); 284; 3,690.6 (3,082.2; 4,419.0) 1 month: 105; 23,641.3 (20,473.1; 27,299.8); 296; 16,323.3 (14,686.5; 18,142.6); 286; 16,250.1 (14,499.2; 18,212.4) Abbreviations: CI = confidence interval; GMT = geometric mean titre; LLOQ = lower limit of quantitation; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Protocol-specified blood sampling time point. n = number of participants with valid and determinate assay results for the specified assay at the given sampling time point. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titre and corresponding CIs (based on the Student t-distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. SARS-CoV-2 NT50 values were determined using a validated 384-well titration plate (original strain [USA-WA1/2020, isolated in January 2020] and Omicron variant B.1.1.529, sublineage BA.4-5). Originally authorised Comirnaty Study 2 is a multicentre, multinational, randomised, placebo-controlled, observer-blind, Phase 1/2/3 study evaluating dose, vaccine selection, and efficacy in participants 12 years of age and older. Randomisation was stratified by age: 12 to 15 years, 16 to 55 years, and 56 years and older; at least 40% of participants were in the ≥ 56-year age stratum. The study excluded immunocompromised participants and individuals with a prior clinical or microbiological diagnosis of COVID-19. Participants with pre-existing stable disease, defined as disease that had not required significant change in therapy or hospitalisation for worsening within 6 weeks before enrolment, were eligible for inclusion, as were participants with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). Efficacy in participants 16 years of age and older — following 2 doses During Phase 2/3 of Study 2, based on data accrued through 14 November 2020, approximately 44,000 participants were equally randomised and received 2 doses of either the originally authorised mRNA COVID-19 vaccine or placebo. Efficacy analyses included participants who received their second dose 19 to 42 days after the first dose. Most (93.1%) vaccine recipients received the second dose 19 to 23 days after the first dose. Per the prespecified plan, participants will continue to be followed for vaccine safety and efficacy for up to 24 months after the second dose. The clinical study required participants to observe a minimum interval of 14 days before and after administration of an influenza vaccine to receive either placebo or the mRNA COVID-19 vaccine. The study also required a minimum interval of 60 days before or after receipt of blood/plasma products or immunoglobulins during the study to receive either placebo or the mRNA COVID-19 vaccine. The primary efficacy analysis population included 36,621 participants 12 years of age and older (18,242 in the mRNA COVID-19 vaccine group and 18,379 in the placebo group) without evidence of prior SARS-CoV-2 infection through 7 days after the second dose. In addition, 134 participants were 16 to 17 years of age (66 in the mRNA COVID-19 vaccine group and 68 in the placebo group) and 1,616 were 75 years of age and older (804 in the mRNA COVID-19 vaccine group and 812 in the placebo group). At the time of the primary efficacy analysis, participants in the mRNA COVID-19 vaccine group were followed for symptomatic COVID-19 for a total of 2,214 person-years, and participants in the placebo group were followed for at least 2,222 person-years. In participants at risk for severe COVID-19, including those with 1 or more comorbidities that increase the risk of severe COVID-19 (e.g., asthma, body mass index [BMI] ≥ 30 kg/m2, chronic pulmonary disease, diabetes mellitus, hypertension), no clinically meaningful differences in overall vaccine efficacy were identified. Vaccine efficacy information is presented in Table 6. Table 6. Vaccine efficacy — first occurrence of COVID-19 from 7 days after Dose 2, by age subgroup — participants without evidence of infection prior to 7 days after Dose 2 — evaluable efficacy (7-day) population First occurrence of COVID-19 from 7 days after Dose 2 in participants without evidence of prior SARS-CoV-2 infection* Subgroup mRNA COVID-19 vaccine n a = 18,198 Cases n1 b Surveillance time c (n2 d) Placebo n a = 18,325 Cases n1 b Surveillance time c (n2 d) Vaccine efficacy % (95% CI) e All participants: 8; 162; 95.0; 2.214 (17,411); 2.222 (17,511); (90.0; 97.9) 16 to 64 years: 7; 143; 95.1; 1.706 (13,549); 1.710 (13,618); (89.6; 98.1) 65 years and older: 1; 19; 94.7; 0.508 (3,848); 0.511 (3,880); (66.7; 99.9) 65 to 75 years: 1; 14; 92.9; 0.406 (3,074); 0.406 (3,095); (53.1; 99.8) 75 years and older: 0; 5; 100.0; 0.102 (774); 0.106 (785); (-13.1; 100.0) Note: Confirmed cases were determined by reverse transcription polymerase chain reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 [*Case definition: (at least 1 of) fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhoea, or vomiting.] * Participants who had no serologic or virologic evidence (within 7 or more days before receipt of the last dose) of prior SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by nucleic acid amplification tests (NAAT) [nasal swab] at Visits 1 and 2) and had a negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis. n = number of participants in the specified group. n1 = number of participants meeting the endpoint definition. Total surveillance time in 1,000 person-years for the given endpoint across all participants in each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 through the end of the surveillance period. n2 = number of participants at risk for the endpoint. The 2-sided confidence interval for vaccine efficacy is derived using the Clopper–Pearson method adjusted for surveillance time. The CI is not adjusted for multiplicity. Vaccine efficacy of the mRNA COVID-19 vaccine in preventing first occurrence of COVID-19 from 7 days after Dose 2 versus placebo was 94.6% (95% confidence interval 89.6% to 97.6%) in participants 16 years of age and older with or without evidence of prior SARS-CoV-2 infection. Subgroup analyses of the primary efficacy endpoint additionally showed similar point estimates of efficacy across sexes, ethnic groups, and participants with comorbidities associated with high risk of severe COVID-19. Updated efficacy analyses were performed with additional confirmed COVID-19 cases that occurred during blinded, placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacy population. Updated vaccine efficacy information is presented in Table 7. Table 7. Vaccine efficacy — first occurrence of COVID-19 from 7 days after Dose 2, by age subgroup — participants without evidence of prior SARS-CoV-2 infection* prior to 7 days after Dose 2 — evaluable efficacy (7-day) population during the placebo-controlled follow-up period Subgroup mRNA COVID-19 vaccine N a = 20,998 Cases n1 b Surveillance time c (n2 d) Placebo N a = 21,096 Cases n1 b Surveillance time c (n2 d) Vaccine efficacy % (95% CI e) All participants f: 77; 850; 91.3; 6.247 (20,712); 6.003 (20,713); (89.0; 93.2) 16 to 64 years: 70; 710; 90.6; 4.859 (15,519); 4.654 (15,515); (87.9; 92.7) 65 years and older: 7; 124; 94.5; 1.233 (4,192); 1.202 (4,226); (88.3; 97.8) 65 to 74 years: 6; 98; 94.1; 0.994 (3,350); 0.966 (3,379); (86.6; 97.9) 75 years and older: 1; 26; 96.2; 0.239 (842); 0.237 (847); (76.9; 99.9) Note: Confirmed cases were determined by reverse transcription polymerase chain reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhoea, or vomiting). * Participants without evidence of prior SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2) and with a negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis. N = number of participants in the specified group. n1 = number of participants meeting the endpoint definition. Total surveillance time in 1,000 person-years for the given endpoint across all participants in each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 through the end of the surveillance period. n2 = number of participants at risk for the endpoint. The 2-sided 95% confidence interval for vaccine efficacy is derived using the Clopper–Pearson method adjusted for surveillance time. The CI is not adjusted for multiplicity. Confirmed cases included in participants 12 to 15 years of age: 0 in the mRNA COVID-19 vaccine group; 16 in the placebo group. In the updated efficacy analysis, during the period when the Wuhan/wild-type and Alpha variants were the predominant circulating strains in the population, vaccine efficacy of the mRNA COVID-19 vaccine in preventing first occurrence of COVID-19 from 7 days after Dose 2 versus placebo was 91.1% (95% CI 88.8% to 93.0%) in participants in the evaluable efficacy population with or without evidence of prior SARS-CoV-2 infection. Updated subgroup analyses additionally showed similar efficacy point estimates across sexes, ethnic groups, geographic regions, and participants with medical comorbidities and obesity associated with high risk of severe COVID-19. Efficacy against severe COVID-19 Updated efficacy analyses of secondary efficacy endpoints supported the benefit of the mRNA COVID-19 vaccine in preventing severe COVID-19. As of 13 March 2021, vaccine efficacy against severe COVID-19 is presented only for participants with or without prior SARS-CoV-2 infection (Table 8), as the case counts among participants without prior SARS-CoV-2 infection were the same as among participants with or without prior SARS-CoV-2 infection in both the mRNA COVID-19 vaccine and placebo groups. Table 8. Vaccine efficacy — first severe occurrence of COVID-19 in participants with or without prior SARS-CoV-2 infection based on FDA criteria* after Dose 1 or from 7 days after Dose 2 in the placebo-controlled follow-up period mRNA COVID-19 vaccine Cases n1 a Surveillance time c (n2 b) Placebo Cases n1 a Surveillance time c (n2 b) Vaccine efficacy % (95% CI c) After Dose 1 d: 1; 30; 96.7; 8.439 e (22,505); 8.288 e (22,435); (80.3; 99.9) 7 days after Dose 2 f: 1; 21; 95.3; 6.522 g (21,649); 6.404 g (21,730); (70.9; 99.9) Note: Confirmed cases were determined by reverse transcription polymerase chain reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhoea, or vomiting). * Severe COVID-19 as defined by the FDA is confirmed COVID-19 and the presence of at least 1 of the following: Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 breaths/minute, heart rate ≥ 125 beats/minute, oxygen saturation ≤ 93% on room air at sea level, or ratio of arterial partial pressure of oxygen to fraction of inspired oxygen < 300 mmHg). Respiratory failure [defined as the need for high-flow oxygen, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)]. Evidence of shock (systolic blood pressure < 90 mmHg, diastolic blood pressure < 60 mmHg, or the need for vasopressors). Significant acute renal, hepatic, or neurologic dysfunction. Admission to an intensive care unit. Death. n1 = number of participants meeting the endpoint definition. n2 = number of participants at risk for the given endpoint. The 2-sided confidence interval (CI) for vaccine efficacy is derived using the Clopper–Pearson method adjusted for surveillance time. Efficacy assessed based on the all-available efficacy (modified intent-to-treat) population for Dose 1, which included all randomised participants who received at least 1 dose of study intervention. Total surveillance time in 1,000 person-years for the given endpoint across all participants in each group at risk for the endpoint. Time period for COVID-19 case accrual is from after Dose 1 through the end of the surveillance period. Efficacy assessed based on the evaluable efficacy (7-day) population, which included all eligible randomised participants who received all doses of study intervention as randomised within a prespecified time window and had no other important protocol deviations as determined by the clinician. Total surveillance time in 1,000 person-years for the given endpoint across all participants in each group at risk for the given endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 through the end of the surveillance period. Efficacy and immunogenicity in adolescents 12 to 15 years of age — following 2 doses In the initial Study 2 analysis in adolescents 12 to 15 years of age (representing a median follow-up duration of > 2 months after Dose 2) without evidence of prior infection, there were no cases among 1,005 vaccine recipients and 16 cases among 978 placebo recipients. The point estimate of efficacy is 100% (95% confidence interval 75.3; 100.0). In participants with or without evidence of prior infection, there were 0 cases among 1,119 vaccine recipients and 18 cases among 1,110 placebo recipients. This also indicates a point estimate of efficacy of 100% (95% confidence interval 78.1; 100.0). Updated efficacy analyses were performed with additional confirmed COVID-19 cases that occurred during blinded, placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacy evaluation population. In the updated Study 2 efficacy analysis in adolescents 12 to 15 years of age without evidence of prior infection, no cases occurred among 1,057 vaccine recipients and 28 cases occurred among 1,030 placebo recipients. The point estimate of efficacy during the period when the Alpha variant was the predominant circulating strain is 100% (95% confidence interval 86.8; 100.0). In participants with or without evidence of prior infection, no cases occurred among 1,119 vaccine recipients and 30 cases occurred among 1,109 placebo recipients. This also indicates a point estimate of efficacy of 100% (95% confidence interval 87.5; 100.0). In Study 2, an analysis of SARS-CoV-2 neutralising titres one month after Dose 2 was performed in a randomly selected subset of participants without serologic or virologic evidence of prior SARS-CoV-2 infection through 1 month after Dose 2, comparing the response in adolescents 12 to 15 years of age (n = 190) with participants 16 to 25 years of age (n = 170). The geometric mean titre (GMT) ratio of the 12- to 15-year-old group to the 16- to 25-year-old group was 1.76, with a 2-sided 95% CI of 1.47 to 2.10. The 1.5-fold non-inferiority criterion was therefore met, as the lower bound of the 2-sided 95% CI for the geometric mean ratio [GMR] was > 0.67. Efficacy and immunogenicity in children 5 to 11 years of age (i.e. 5 to less than 12 years of age) — following 2 doses Study 3 is a Phase 1/2/3 study consisting of an open-label, dose-finding portion (Phase 1) and a multicentre, multinational, randomised, saline placebo-controlled, observer-blind efficacy portion (Phase 2/3) that enrolled participants 5 to 11 years of age. Most (94.4%) randomised vaccine recipients received the second dose 19 to 23 days after the first dose. Initial descriptive vaccine efficacy results in children 5 to 11 years of age without evidence of prior SARS-CoV-2 infection are presented in Table 9. In participants with documented prior SARS-CoV-2 infection, no cases of COVID-19 were observed in either the vaccine or placebo group. Table 9. Vaccine efficacy — first occurrence of COVID-19 from 7 days after Dose 2: without evidence of infection prior to 7 days after Dose 2 — Phase 2/3 — children 5 to 11 years of age, evaluable efficacy population First occurrence of COVID-19 from 7 days after Dose 2 in children 5 to 11 years of age without evidence of prior SARS-CoV-2 infection* mRNA COVID-19 vaccine Dose 10 micrograms/dose N a = 1,305 Cases n1 b Surveillance time c (n2 d) Placebo N a = 663 Cases n1 b Surveillance time c (n2 d) Vaccine efficacy % (95% CI) 3; 16; 90.7 Children 5 to 11 years of age: 0.322 (1,273); 0.159 (637); (67.7; 98.3) Note: Confirmed cases were determined based on reverse transcription polymerase chain reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat; diarrhoea; vomiting). * Participants without evidence of prior SARS-CoV-2 infection (i.e. negative N-binding antibody [serum] at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visits 1 and 2) and with a negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis. N = number of participants in the specified group. n1 = number of participants meeting the endpoint definition. Total surveillance time in 1,000 person-years for the given endpoint across all participants in each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 through the end of the surveillance period. n2 = number of participants at risk for the given endpoint. Prespecified hypothesis-driven efficacy analyses were performed with additional confirmed COVID-19 cases that occurred during blinded, placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacy evaluation population. In the Study 3 efficacy analysis in children 5 to 11 years of age without evidence of prior infection, 10 cases occurred among 2,703 vaccine recipients and 42 cases occurred among 1,348 placebo recipients. The point estimate of efficacy during the period when the Delta variant was the predominant circulating strain is 88.2% (95% confidence interval 76.2; 94.7). In participants with or without evidence of prior infection, 12 cases occurred among 3,018 vaccine recipients and 42 cases occurred among 1,511 placebo recipients. The point estimate of efficacy is 85.7% (95% confidence interval 72.4; 93.2). In Study 3, an analysis of SARS-CoV-2 50% neutralising titres (NT50) 1 month after Dose 2 in a randomly selected subset of participants demonstrated efficacy by immunological bridging of immune responses, comparing children 5 to 11 years of age (i.e. 5 to less than 12 years of age) in the Phase 2/3 portion of Study 3 with participants 16 to 25 years of age in the Phase 2/3 portion of Study 2 who had no serologic or virologic evidence of prior SARS-CoV-2 infection through 1 month after Dose 2. Prespecified immunological bridging criteria were met for both the geometric mean ratio (GMR) and the difference in seroresponse rate, where seroresponse was defined as achieving at least a 4-fold rise in SARS-CoV-2 NT50 from baseline (before Dose 1). The SARS-CoV-2 NT50 GMR 1 month after Dose 2 in children 5 to 11 years of age (i.e. 5 to less than 12 years of age) versus young adults 16 to 25 years of age was 1.04 (2-sided 95% CI: 0.93; 1.18). Among participants without prior evidence of SARS-CoV-2 infection through 1 month after Dose 2, 99.2% of children 5 to 11 years of age and 99.2% of participants 16 to 25 years of age had a seroresponse 1 month after Dose 2. For both children 5 to 11 years of age and young adults 16 to 25 years of age, seroresponse was demonstrated only at 1 month after Dose 2. The difference in proportions of participants with a seroresponse between the two age groups (children minus young adults) was 0.0% (2-sided 95% CI: -2.0%; 2.2%). These findings are presented in Table 10. Table 10. Summary of geometric mean ratio for 50% neutralising titre and difference in percentages of participants with seroresponse — comparison of children 5 to 11 years of age (Study 3) with participants 16 to 25 years of age (Study 2) — participants without evidence of infection through 1 month after Dose 2 — immunological bridging subset — Phase 2/3 — evaluable immunogenicity population mRNA COVID-19 vaccine 5 to 11 years/16 to 25 years Dose 10 micrograms/dose 5 to 11 years N a = 264 Dose 30 micrograms/dose 16 to 25 years N a = 253 Time point b; GMT c (95% CI c); GMT c (95% CI c); GMR d (95% CI d); Met immunological bridging objective e (Y/N) Geometric mean 50% neutralising titre f (GMT c) 1 month after Dose 2: 1,197.6 (1,106.1; 1,296.6); 1,146.5 (1,045.5; 1,257.2); 1.04 (0.93; 1.18); Y Time point b; n g (%) (95% CI h); n g (%) (95% CI h); Difference % i (95% CI j); Met immunological bridging objective k (Y/N) Seroresponse rate (%) for 50% neutralising titre f 1 month after Dose 2: 262 (99.2) (97.3; 99.9); 251 (99.2) (97.2; 99.9); 0.0 (-2.0; 2.2); Y Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre; LLOQ = lower limit of quantitation; NAAT = nucleic acid amplification test; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Note: Participants without serologic or virologic evidence (through 1 month after the post–Dose 2 blood sample) of prior SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at the Dose 1 visit and 1 month after Dose 2, SARS-CoV-2 not detected by NAAT [nasal swab] at the Dose 1 and Dose 2 visits, and a negative NAAT [nasal swab] at any unscheduled visit through 1 month after the post–Dose 2 blood draw) and without a history of COVID-19 were included in the analysis. Note: Seroresponse is defined as achieving a ≥ 4-fold rise from baseline (before Dose 1). If baseline measurement is below the LLOQ, a post-vaccination assay result of ≥ 4 × LLOQ is regarded as a seroresponse. N = number of participants with valid and determinate assay results before vaccination and 1 month after Dose 2. These values are also used as the denominators for calculating seroresponse percentages. Protocol-specified blood sampling time points. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titre and corresponding CIs (based on the Student t-distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference in log titres (5 to 11 years minus 16 to 25 years) and corresponding CIs (based on the Student t-distribution). Immunological bridging based on GMT is declared if the lower bound of the 2-sided 95% CI for the GMR is greater than 0.67 and the GMR point estimate is ≥ 0.8. SARS-CoV-2 NT50 was determined using the SARS-CoV-2 mNeonGreen Virus Microneutralisation Assay. The assay uses a fluorescent reporter virus derived from the USA_WA1/2020 strain, and viral neutralisation is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralised. n = number of participants with seroresponse based on NT50 1 month after Dose 2. Exact 2-sided CI based on the Clopper–Pearson method. Difference in proportions, expressed as a percentage (5 to 11 years minus 16 to 25 years). Exact 2-sided CI based on the Miettinen and Nurminen method for the difference in proportions, expressed as a percentage. Immunological bridging based on seroresponse rate is declared if the lower bound of the 2-sided 95% CI for the difference in seroresponse is greater than -10.0%. Immunogenicity in participants 18 years of age and older — following a booster dose The efficacy of the Comirnaty booster dose in Study 2 was based on the assessment of 50% neutralising antibody titres (NT50) against SARS-CoV-2 (USA_WA1/2020). In this study, the booster dose was administered 5 to 8 months (median 7 months) after the second dose. In Study 2, NT50 analyses 1 month after the booster dose, compared with 1 month after the primary series, in individuals 18 to 55 years of age without serologic or virologic evidence of prior SARS-CoV-2 infection through 1 month after booster vaccination demonstrated non-inferiority for both the geometric mean ratio (GMR) and the difference in seroresponse rates. Participant seroresponse was defined as achieving a ≥ 4-fold rise in NT50 from baseline (before the primary series). These analyses are summarised in Table 11. Table 11. SARS-CoV-2 neutralisation assay — NT50 (titre) † (SARS-CoV-2 USA_WA1/2020) — comparison of GMT and seroresponse rate 1 month after the booster dose and 1 month after the primary series — participants 18 to 55 years of age without evidence of infection through 1 month after the booster dose* — evaluable post-booster immunogenicity population ± n 1 month after the booster dose (95% CI) 1 month after the primary series (95% CI) 1 month after booster dose / 1 month after primary series (97.5% CI) Met non-inferiority objective (Y/N) Geometric mean 50% neutralising titre: 212 a; 2,466.0 b (2,202.6; 2,760.8); 755.7 b (663.1; 861.2); 3.26 c (2.76; 3.86); Y d Seroresponse rate (%) for 50% neutralising titre †: 199 f; 190 f; 200 e; 99.5% (97.2%; 100.0%); 95.0% (91.0%; 97.6%); 4.5% g (1.0%; 7.9% h); Y i Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre; LLOQ = lower limit of quantitation; N-binding = SARS-CoV-2 nucleoprotein binding; NAAT = nucleic acid amplification test; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; Y/N = yes/no. † SARS-CoV-2 NT50 was determined using the SARS-CoV-2 mNeonGreen Virus Microneutralisation Assay. The assay uses a fluorescent reporter virus derived from the USA_WA1/2020 strain, and viral neutralisation is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralised. * Participants without serologic or virologic evidence (through 1 month after the Comirnaty booster dose) of prior SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative and SARS-CoV-2 not detected by NAAT [nasal swab]) and with a negative NAAT (nasal swab) at any unscheduled visit through 1 month after the booster dose were included in the analysis. ± All eligible participants who received 2 doses of Comirnaty as initially randomised, with the second dose administered within the prespecified window (19 to 42 days after Dose 1), received a booster dose of Comirnaty, had at least 1 valid and determinate post-booster immunogenicity result from a blood draw within the applicable window (28 to 42 days after the booster dose), and had no other important protocol deviations as determined by the clinician. n = number of participants with valid and determinate assay results at both sampling time points within the prespecified windows. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titre and corresponding CIs (based on the Student t-distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. GMRs and 2-sided 97.5% CIs were calculated by exponentiating the mean differences in log assay results and corresponding CIs (based on the Student t-distribution). Non-inferiority is declared if the lower bound of the 2-sided 97.5% CI for the GMR is > 0.67 and the GMR point estimate is ≥ 0.80. n = number of participants with valid and determinate assay results for the specified assay at baseline, 1 month after Dose 2, and 1 month after the booster dose, within the prespecified windows. These values serve as denominators for the percentage calculations. Number of participants with seroresponse to the specified assay at the given dose/sampling time point. Exact 2-sided CI based on the Clopper–Pearson method. Difference in proportions, expressed as a percentage (1 month after the booster dose – 1 month after Dose 2). Adjusted 2-sided Wald CI for the difference in proportions, expressed as a percentage. Non-inferiority is declared if the lower bound of the 2-sided 97.5% CI for the difference in percentages is > 10%. Relative vaccine efficacy in participants 16 years of age and older — following a booster dose The interim efficacy analysis from Study 4, a placebo-controlled booster study conducted in approximately 10,000 participants 16 years of age and older enrolled from Study 2, evaluated confirmed cases of COVID-19 occurring at least 7 days after booster vaccination through the data cut-off of 5 October 2021, representing a median of 2.5 months of post-booster follow-up. The booster dose was administered 5 to 13 months (median 11 months) after the second dose. The efficacy of Comirnaty booster vaccination after a primary series was evaluated relative to a group that received placebo as a booster and had received only the primary series. Information on relative vaccine efficacy in participants 16 years of age and older without evidence of prior SARS-CoV-2 infection is presented in Table 12. Relative vaccine efficacy in participants with or without evidence of prior SARS-CoV-2 infection was 94.6% (95% confidence interval 88.5% to 97.9%), similar to that observed in participants without evidence of prior infection. Primary cases of COVID-19 observed from 7 days after the booster dose included 7 primary cases in the Comirnaty group and 124 primary cases in the placebo group. Table 12. Vaccine efficacy — first occurrence of COVID-19 from 7 days after the booster dose — participants 16 years of age and older without evidence of infection — evaluable efficacy population First occurrence of COVID-19 from 7 days after the booster dose in participants without evidence of prior SARS-CoV-2 infection* Comirnaty n a = 4,695 Cases n1 b Surveillance time c (n2 d) Placebo n a = 4,671 Cases n1 b Surveillance time c (n2 d) Relative vaccine efficacy e % (95% CI f) First occurrence of COVID-19 from 7 days after the booster vaccine dose: 6; 0.823 (4,659); 123; 0.792 (4,614); 95.3 (89.5; 98.3) Note: Confirmed cases were determined by reverse transcription polymerase chain reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhoea, or vomiting). * Participants who had no serologic or virologic evidence (within 7 or more days before receipt of the booster dose) of prior SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at Visit 1) and had a negative NAAT (nasal swab) at any unscheduled visit prior to 7 days after the booster dose were included in the analysis. n = number of participants in the specified group. n1 = number of participants meeting the endpoint definition. Total surveillance time in 1,000 person-years for the given endpoint across all participants in each group at risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after the booster vaccine dose through the end of the surveillance period. n2 = number of participants at risk for the endpoint. Relative vaccine efficacy in the Comirnaty booster group versus the placebo group (no booster). The 2-sided confidence interval for relative vaccine efficacy is derived using the Clopper–Pearson method adjusted for surveillance time. Immunogenicity in children 5 to 11 years of age (i.e. 5 to less than 12 years of age) — following a booster dose A booster dose of Comirnaty was administered in Study 3 to 401 randomly selected participants. The efficacy of the booster dose in 5- to 11-year-olds is inferred from immunogenicity data. Immunogenicity was assessed using NT50 against the SARS-CoV-2 reference strain (USA_WA1/2020). NT50 analyses 1 month after the booster dose, compared with pre-booster, demonstrated a substantial increase in GMT in individuals 5 to 11 years of age, inclusive, who had no serologic or virologic evidence of prior SARS-CoV-2 infection through 1 month after Dose 2 and after the booster dose. This analysis is summarised in Table 13. Table 13. Summary of geometric mean titres — NT50 — participants without evidence of infection — Phase 2/3 — immunogenicity set — ages 5 to 11 years inclusive — evaluable immunogenicity population Sampling time point a Assay 1 month after the booster dose (n b = 67) GMT c (95% CI c) 1 month after Dose 2 (n b = 96) GMT c (95% CI c) 1 month after the booster dose / 1 month after Dose 2 GMR d (95% CI d) SARS-CoV-2 neutralisation assay — NT50 (titre): 2,720.9 (2,280.1; 3,247.0); 1,253.9 (1,116.0; 1,408.9); 2.17 (1.76; 2.68) Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre; LLOQ = lower limit of quantitation; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Protocol-specified blood sampling time points. n = number of participants with valid and determinate assay results for the specified assay at the dose/sampling time point. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titre and corresponding CIs (based on the Student t-distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference in log titres (1 month after the booster dose minus 1 month after Dose 2) and the corresponding CIs (based on the Student t-distribution). Booster dose immunogenicity following primary vaccination with another approved COVID-19 vaccine The efficacy of a Comirnaty booster dose (30 micrograms) in individuals who completed primary vaccination with another approved COVID-19 vaccine (heterologous booster) is inferred from immunogenicity data from an independent open-label, Phase 1/2 National Institutes of Health (NIH) clinical study (NCT04889209) conducted in the United States. In this study, adults (age range 19 to 80 years) who had completed primary vaccination with Moderna 100 micrograms in a 2-dose series (n = 51, mean age 54 ± 17 years), a single dose of Janssen vaccine (n = 53, mean age 48 ± 14 years), or Comirnaty 30 micrograms in a 2-dose series (n = 50, mean age 50 ± 18 years) at least 12 weeks before enrolment, and who reported no history of SARS-CoV-2 infection, received a booster dose of Comirnaty (30 micrograms). The Comirnaty booster dose elicited 36-, 12-, and 20-fold increases in the GMR of neutralising titres after primary doses of Janssen, Moderna, and Comirnaty vaccines, respectively. A heterologous Comirnaty booster dose was also evaluated in the CoV-BOOST study (EudraCT 2021-002175-19), a multicentre, randomised, controlled Phase 2 study of a third booster dose of COVID-19 vaccine, in which 107 adult participants (median age 71 years, interquartile range 54 to 77 years) were randomised at least 70 days after receipt of 2 doses of AstraZeneca COVID-19 vaccine. Following the AstraZeneca COVID-19 primary series, the fold-change in GMR of pseudovirus (wild-type) neutralising antibody NT50 increased 21.6-fold with a heterologous Comirnaty booster dose (n = 95). Immunogenicity in participants over 55 years of age — following a booster dose (fourth dose) of Comirnaty (30 micrograms) In a sub-analysis from Study 4 (Substudy E), 305 participants over 55 years of age who completed a 3-dose series of Comirnaty received a booster (fourth) dose of Comirnaty (30 micrograms) 5 to 12 months after Dose 3. Subgroup immunogenicity data are shown in Table 8. Immunogenicity in participants 18 to ≤ 55 years of age — following a booster dose (fourth dose) of Comirnaty (30 micrograms) In Substudy D (a subset from Study 2 [Phase 3] and Study 4 [Phase 3]), 325 participants 18 to ≤ 55 years of age who completed a 3-dose series of Comirnaty received a booster (fourth) dose of Comirnaty (30 micrograms) 90 to 180 days after Dose 3. Subgroup immunogenicity data are shown in Table 14. Table 14. Summary of immunogenicity data from participants in Study C4591031, Substudy D (full expanded Cohort 2 set) and Substudy E (expanded cohort — immunogenicity subset), who received a booster (fourth) dose of Comirnaty 30 micrograms — participants without evidence of infection through 1 month after the booster dose — evaluable immunogenicity population Dose/blood sampling time point a Substudy D (18 to ≤ 55 years) Comirnaty 30 micrograms Substudy E (> 55 years) Comirnaty 30 micrograms GMT N b; GMT (95% CI d); N b; GMT (95% CI d) SARS-CoV-2 neutralisation assay — Omicron BA.1 — NT50 (titre) 1/Pre-vaccination: 226; 315.0 (269.0; 368.9); 167; 67.5 (52.9; 86.3) 1/1 month: 228; 1,063.2 (935.8; 1,207.9); 163; 455.8 (365.9; 567.6) SARS-CoV-2 neutralisation assay — reference strain — NT50 (titre) 1/Pre-vaccination: 226; 3,999.0 (3,529.5; 4,531.0); 179; 1,389.1 (1,142.1; 1,689.5) 1/1 month: 227; 12,009.9 (10,744.3; 13,424.6); 182; 5,998.1 (5,223.6; 6,887.4) Seroresponse rate 1 month after Dose 4 N c; n e (%) (95% CI f); N c; n e (%) (95% CI f) SARS-CoV-2 neutralisation assay — Omicron BA.1 — NT50 (titre) 1/1 month: 226; 91 (40.3%) (33.8; 47.0); 149; 85 (57.0%) (48.7; 65.1) SARS-CoV-2 neutralisation assay — reference strain — NT50 (titre) 1/1 month: 225; 76 (33.8%) (27.6; 40.4); 179; 88 (49.2%) (41.6; 56.7) Abbreviations: CI = confidence interval; GMT = geometric mean titre; LLOQ = lower limit of quantitation; N-binding = SARS-CoV-2 nucleoprotein binding; NAAT = nucleic acid amplification test; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Note: Median time from Dose 3 to Dose 4 of Comirnaty 30 micrograms is 4.0 months for Substudy D, Cohort 2 and 6.3 months for Substudy E, expanded cohort. Note: Substudy D full expanded set = Cohort 2 without verification group; Substudy E immunogenicity subset = a random sample of 230 participants in each vaccine group selected from the expanded cohort. Note: Participants without serologic or virologic evidence (blood sampling earlier than 1 month after study vaccination) of prior SARS-CoV-2 infection (i.e. negative N-binding antibody [serum] result at the study vaccination visit and 1 month post-vaccination, negative NAAT [nasal swab] result at the study vaccination visit and at any unscheduled visit before the 1-month post-vaccination blood sample) and without a history of COVID-19 were included in the analysis. Note: Seroresponse is defined as achieving a ≥ 4-fold rise in NT50 from baseline (before study vaccination). If the baseline measurement is below the LLOQ, a post-vaccination value of ≥ 4 × LLOQ is regarded as a seroresponse. Protocol-specified blood sampling time points. N = number of participants with valid and determinate assay results for the specified assay at the given sampling time point. N = number of participants with valid and determinate assay results for the specified assay both at the pre-vaccination time point and at the given sampling time point. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titre and corresponding CIs (based on the Student t-distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. Number of participants with seroresponse to the specified assay at the given sampling time point. Exact 2-sided CI based on the Clopper–Pearson method. Immunogenicity in pregnant participants and infants born to pregnant participants — following 2 doses of Comirnaty Study 9 was an international, placebo-controlled, observer-blind, Phase 2/3 study that enrolled pregnant participants 18 years of age and older who received 2 doses of Comirnaty (n = 173) or placebo (n = 173). Pregnant participants received their first dose of Comirnaty during weeks 24 to 34 of pregnancy, and most (90.2%) received their second dose 19 to 23 days after the first dose. A descriptive immunogenicity analysis was performed in pregnant participants who received Comirnaty in Study 9, compared with a comparator subgroup of non-pregnant participants from Study 2. The neutralising GMT ratio (GMR) at 1 month after Dose 2 was assessed. The immunogenicity evaluable population that received Comirnaty in either the pregnant participant group of Study 9 (n = 111) or the non-pregnant participant group of Study 2 (n = 114) had a median age of 30 years (range 18 to 44 years) and included 37.8% and 3.5% of participants, respectively, who were SARS-CoV-2 positive at baseline. Among participants without evidence of prior SARS-CoV-2 infection through 1 month after Dose 2, the observed SARS-CoV-2 50% neutralising GMT 1 month after Dose 2 was lower in pregnant participants (Study 9) than in non-pregnant participants (Study 2) (GMT ratio [GMR] 0.67 [95% CI: 0.50; 0.90]). Among participants with or without evidence of prior SARS-CoV-2 infection through 1 month after Dose 2, the model-adjusted GMT 1 month after Dose 2 was similar in pregnant and non-pregnant participants (model-adjusted GMT ratio [GMR] 0.95 [95% CI: 0.69; 1.30]). Model-adjusted GMTs and GMR were calculated based on a regression model adjusting for age and baseline neutralising titre. Immunogenicity in immunocompromised participants (adults and children) Study 10 is an open-label Phase 2b study (n = 124) that enrolled immunocompromised participants 2 to < 18 years of age treated with immunomodulators, participants who had undergone solid organ transplantation (within the previous 3 months) and were receiving immunosuppressants, or participants who had undergone bone marrow or stem cell transplantation at least 6 months before enrolment. The study also enrolled immunocompromised participants 18 years of age and older treated for non-small cell lung cancer (NSCLC) or chronic lymphocytic leukaemia (CLL), receiving haemodialysis for secondary or end-stage renal disease, or receiving immunomodulator therapy for an autoimmune inflammatory disorder. Participants received 4 age-appropriate doses of Comirnaty (3 µg, 10 µg, or 30 µg); the first 2 doses were administered 21 days apart, the third dose 28 days after the second dose, and the fourth dose 3 to 6 months after Dose 3. Analysis of immunogenicity data 1 month after Dose 3 (26 participants 2 to < 5 years of age, participants 5 to < 12 years of age, 11 participants 12 to < 18 years of age, and 4 participants ≥ 18 years of age) and 1 month after Dose 4 (16 participants 2 to < 5 years of age, 31 participants 5 to < 12 years of age, 6 participants 12 to < 18 years of age, and 4 participants ≥ 18 years of age) in the immunogenicity evaluation population without evidence of prior infection demonstrated a vaccine-induced immune response. One month after Dose 3, markedly higher GMTs were observed; these increased further 1 month after Dose 4 and remained elevated 6 months after Dose 4 compared with pre-vaccination values across all age groups and disease subgroups. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Comirnaty in the paediatric population for the prevention of COVID-19 (see section 4.2 for information on paediatric use).