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 for direct, transient expression of the SARS-CoV-2 S antigen. The mRNA encodes the membrane-anchored, full-length S protein with two point mutations in the central helix. Mutation of these two amino acids to 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 vaccine Immunogenicity in children 5 to 11 years of age (i.e., 5 to less than 12 years) — after a booster dose (fourth dose) A subgroup analysis from Study 6 included 103 participants 5 to 11 years of age who had previously completed a 2-dose primary series and a booster dose of Comirnaty and then received a booster dose (fourth dose) of Comirnaty Original/Omicron BA.4-5. The findings include immunogenicity data from a comparator subgroup of participants 5 to 11 years of age in Study 3 who 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 a booster dose (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 that received 3 doses of Comirnaty. Comirnaty Original/Omicron BA.4-5 also produced reference-strain–specific titres comparable to those in the comparator group. Vaccine immunogenicity results after a booster dose 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 titres and the corresponding CIs (based on the Student's 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 in LS means and the corresponding CIs derived from analysis of log-transformed assay results using a linear regression model with log-transformed baseline neutralising titre, post-baseline infection status, and vaccine group as covariates. SARS-CoV-2 NT50 values were determined using a validated 384-well titration assay (original strain [USA-WA1/2020, isolated in January 2020] and Omicron variant B.1.1.529, sub-variant BA.4/BA.5). Immunogenicity in participants 12 years of age and older — after a booster dose (fourth dose) A subgroup analysis from Study 5 included 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 a booster dose of Comirnaty and then received a booster dose (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 the Omicron BA.4-5 variant and against the reference strain in participants 56 years of age and older who received a booster dose (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 dose (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 dose (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 dose (fourth dose), the study also evaluated NT50 against the SARS-CoV-2 Omicron BA.4-5 variant and reference strains pre-vaccination and 1 month post-vaccination (Table 5). Table 4. SARS-CoV-2 GMTs (NT50) and difference in percentage of participants with seroresponse 1 month after vaccination — Comirnaty Original/Omicron BA.4-5 from Study 5 and Comirnaty subgroup from Study 4 — participants with or without evidence of SARS-CoV-2 infection — evaluable immunogenicity population SARS-CoV-2 GMTs (NT50) 1 month after 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 18–55 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 percentage of participants with seroresponse 1 month after vaccination Comirnaty Original/Omicron BA.4-5 Study 4 subgroup Comirnaty Comparison by age group Comparison by vaccine group ≥56 years 18 to 55 years 56 years and older 56 years and older Comirnaty Original/Omicron BA.4-5 18–55 years/≥56 years 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 achieving a ≥4-fold rise from baseline. If the baseline value is below the LLOQ, a post-vaccination assay result of ≥4 × LLOQ is considered 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 titres and the corresponding CIs (based on the Student's 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 in LS means and the corresponding CIs derived from analysis of log-transformed neutralising titres using a linear regression model with baseline neutralising titre (log scale) and age group or vaccine group as covariates. SARS-CoV-2 NT50 values were determined using a validated 384-well titration assay (original strain [USA-WA1/2020, isolated in January 2020] and Omicron variant B.1.1.529, sub-variant BA.4/BA.5). Non-inferiority is declared if the lower bound of the 2-sided 95% CI for the GMR exceeds 0.67. Superiority is declared if the lower bound of the 2-sided 95% CI for the GMR exceeds 1. Non-inferiority is declared if the lower bound of the 2-sided 95% CI for the GMR exceeds 0.67 and the GMR point estimate is ≥0.8. N = number of participants with valid and determinate assay results for the specified assay at both pre-vaccination and the given sampling time point. This value is the denominator for the percentage calculation. n = number of participants with seroresponse for 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 of baseline neutralising titres 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 percentage of participants with seroresponse is > −10%. Non-inferiority is declared if the lower bound of the 2-sided 95% CI for the difference in percentage of participants with seroresponse is > −5%. Table 5. Geometric mean titres — Study 5 subgroups receiving Comirnaty Original/Omicron BA.4-5 — pre–booster dose (fourth dose) and 1 month post-booster — 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 titres and the corresponding CIs (based on the Student's 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 assay (original strain [USA-WA1/2020, isolated in January 2020] and Omicron variant B.1.1.529, sub-variant BA.4-5). Originally authorised Comirnaty Study 2 is a multicentre, multinational, randomised, placebo-controlled, observer-blinded 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, with at least 40% of participants in the ≥56-year age group. Immunocompromised participants and individuals with a previously established clinical or microbiological diagnosis of COVID-19 were excluded. Participants with pre-existing stable conditions, defined as conditions not requiring significant treatment change or hospitalisation for worsening disease in the 6 weeks before enrolment, were eligible, as were participants with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). Efficacy in individuals 16 years of age and older — after 2 doses During Phase 2/3 of Study 2, on the basis of data accrued through 14 November 2020, approximately 44,000 participants were equally randomised and received 2 doses of the originally authorised COVID-19 mRNA vaccine or placebo. Efficacy analyses included participants who received the second dose of vaccine 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 planned protocol, participants will continue to be followed for assessment of vaccine safety and efficacy against COVID-19 for up to 24 months after Dose 2. In the clinical trial, participants were required to observe a minimum interval of 14 days before and after administration of an influenza vaccine in order to receive either placebo or the COVID-19 mRNA vaccine. In the clinical trial, participants were required to observe 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 COVID-19 mRNA vaccine. The primary efficacy endpoint analysis population included 36,621 participants 12 years of age and older (18,242 in the COVID-19 mRNA 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 COVID-19 mRNA vaccine group and 68 in the placebo group) and 1,616 participants were 75 years of age and older (804 in the COVID-19 mRNA vaccine group and 812 in the placebo group). At the time of the primary efficacy analysis, participants in the COVID-19 mRNA vaccine group had been followed for symptomatic COVID-19 for a total of 2,214 person-years, and participants in the placebo group for a minimum of 2,222 person-years. No clinically meaningful differences in overall vaccine efficacy were observed in participants at risk of 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). 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 population (7 days) First occurrence of COVID-19 from 7 days after Dose 2 in participants without evidence of prior SARS-CoV-2 infection* Subgroup COVID-19 mRNA 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 worsening cough, new or worsening shortness of breath, chills, new or worsening muscle pain, new loss of taste or smell, sore throat, diarrhoea, or vomiting.] * Participants who had no serological or virological evidence (7 or more days before receipt of the last dose) of past 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, expressed in 1,000 person-years, for the specified 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 to 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. The efficacy of the COVID-19 mRNA vaccine in preventing first occurrence of COVID-19 from 7 days after Dose 2 compared with 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 efficacy point estimates across sex, 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 the 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 population (7 days) during the placebo-controlled follow-up period Subgroup COVID-19 mRNA 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 worsening cough, new or worsening shortness of breath, chills, new or worsening muscle pain, new loss of taste or smell, sore throat, diarrhoea, or vomiting). * Participants who had no evidence of past 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 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, expressed in 1,000 person-years, for the specified 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 to 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 COVID-19 mRNA vaccine group; 16 in the placebo group. In the updated efficacy analysis, during a period when the predominant strains in the population were the Wuhan strain/wild-type and the Alpha variant, the efficacy of the COVID-19 mRNA vaccine in preventing first occurrence of COVID-19 from 7 days after Dose 2 compared with 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 of efficacy additionally showed similar efficacy point estimates across sex, 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 secondary efficacy endpoint analyses supported the benefit of the COVID-19 mRNA vaccine in preventing severe COVID-19. As of 13 March 2021, vaccine efficacy against severe COVID-19 is presented for participants with or without prior SARS-CoV-2 infection only (Table 8), as the case counts of COVID-19 in participants without prior SARS-CoV-2 infection were the same as those in participants with or without prior SARS-CoV-2 infection in both the COVID-19 mRNA 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 during the placebo-controlled follow-up period COVID-19 mRNA 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 worsening cough, new or worsening shortness of breath, chills, new or worsening 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 with the presence of at least 1 of the following: Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths per minute, heart rate ≥125 beats per 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 need for vasopressor agents). Significant acute renal, hepatic, or neurological dysfunction. Admission to an intensive care unit. Death. n1 = number of participants meeting the endpoint definition. n2 = number of participants at risk for the specified 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 dose 1 all-available efficacy population (modified intent-to-treat), which included all randomised participants who received at least 1 dose of study treatment. Total surveillance time, expressed in 1,000 person-years, for the specified endpoint across all participants in each group at risk for the endpoint. Time period for COVID-19 case accrual is from after Dose 1 to the end of the surveillance period. Efficacy assessed based on the evaluable efficacy population (7 days), which included all eligible randomised participants who received all doses of study treatment as randomised within the predefined window and had no other important protocol deviations as determined by the clinician. Total surveillance time, expressed in 1,000 person-years, for the specified endpoint across all participants in each group at risk for the specified endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of the surveillance period. Efficacy and immunogenicity in adolescents 12 to 15 years of age — after 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 in 1,005 participants who received the vaccine and 16 cases in 978 participants who received placebo. 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 in 1,119 vaccine recipients and 18 cases in 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 the blinded, placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacy population. In the updated efficacy analysis in Study 2, conducted in adolescents 12 to 15 years of age without evidence of prior infection, no cases occurred in 1,057 participants who received the vaccine, and 28 cases occurred in 1,030 participants who received placebo. The point estimate of efficacy during a period when the Alpha variant was the predominant strain in the population is 100% (95% confidence interval 86.8; 100.0). In participants with or without evidence of prior infection, no cases occurred in 1,119 vaccine recipients and 30 cases occurred in 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 was performed 1 month after Dose 2 in a randomly selected subgroup of participants who had no serological or virological evidence of prior SARS-CoV-2 infection up to 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 ratio of geometric mean titres (GMTs) in the 12-to-15-year group to the 16-to-25-year 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, since 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) — after 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-blinded efficacy portion (Phase 2/3) in which participants 5 to 11 years of age were enrolled. 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 group or the 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* COVID-19 mRNA 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 on the basis of reverse transcription–polymerase chain reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or worsening cough; new or worsening shortness of breath; chills; new or worsening muscle pain; new loss of taste or smell; sore throat; diarrhoea; vomiting). * Participants who had no evidence of past SARS-CoV-2 infection (i.e., negative N-binding antibodies [serum] at Visit 1 and SARS-CoV-2 not detected by 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, expressed in 1,000 person-years, for the specified endpoint across all participants in each group at risk for the endpoint. Time period for accrual of COVID-19 cases is from 7 days after Dose 2 to the end of the surveillance period. n2 = number of participants at risk for the specified endpoint. Pre-specified hypothesis-driven efficacy analyses were performed with additional confirmed COVID-19 cases that occurred during the blinded, placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacy population. In the Study 3 efficacy analysis in children 5 to 11 years of age without evidence of prior infection, 10 cases occurred in 2,703 participants who received the vaccine and 42 cases occurred in 1,348 participants who received placebo. The point estimate of efficacy during a period when the Delta variant was the predominant strain in the population is 88.2% (95% confidence interval 76.2; 94.7). In participants with or without evidence of prior infection, 12 cases occurred in 3,018 vaccine recipients and 42 cases occurred in 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 subgroup 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) 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 serological or virological evidence of prior SARS-CoV-2 infection up to 1 month after Dose 2, meeting the pre-specified immunological bridging criteria for both the geometric mean ratio (GMR) and the difference in seroresponse, with seroresponse defined as achieving at least a four-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) compared with 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 up to 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, the seroresponse was assessed at 1 month after Dose 2 only. 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%). This information is presented in Table 10. Table 10. Summary of geometric mean ratio for 50% neutralising titre and difference in percentage 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 up to 1 month after Dose 2 — immunological bridging subgroup — Phase 2/3 — evaluable immunogenicity population COVID-19 mRNA 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 the 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 Met the immunological bridging objective k (Y/N) Time point b n g (%) (95% CI h) n g (%) (95% CI h) Difference % i (95% CI j) Seroresponse rate (%) for the 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 who had no serological or virological evidence (up to 1 month after the post–Dose 2 blood draw) of past 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 negative NAAT [nasal swab] at any unscheduled visit up to 1 month after the post–Dose 2 blood draw) and had no 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 the baseline measurement is below the LLOQ, a post-vaccination assay result of ≥4 × LLOQ is considered a seroresponse. N = number of participants with valid and determinate assay results pre-vaccination and 1 month after Dose 2. These values are also the denominators used in the seroresponse rate calculations. Protocol-specified blood sampling time point. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titres and the corresponding CIs (based on the Student's 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 the corresponding CI (based on the Student's t distribution). Immunological bridging by 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 values were 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 virus neutralisation is read on Vero cell monolayers. The NT50 of a sample 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 seroresponse difference is greater than −10.0%. Immunogenicity in participants 18 years of age and older — after a booster dose The efficacy of a 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 who had no serological or virological evidence of prior SARS-CoV-2 infection up to 1 month after booster vaccination demonstrated non-inferiority for both the geometric mean ratio (GMR) and the difference in seroresponse rates. Seroresponse in a participant 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 GMTs and seroresponse rates 1 month after the booster dose and 1 month after the primary series — participants 18 to 55 years of age without evidence of infection up to 1 month after the booster dose* — post-booster evaluable immunogenicity population ± n 1 month after the booster dose (95% CI) 1 month after the primary series (95% CI) 1 month after booster / 1 month after primary series (97.5% CI) Met the 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 the 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 values were 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 virus neutralisation is read on Vero cell monolayers. The NT50 of a sample is defined as the reciprocal serum dilution at which 50% of the virus is neutralised. * Participants who had no serological or virological evidence (up to 1 month after receipt of the booster dose of Comirnaty) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative and SARS-CoV-2 not detected by NAAT [nasal swab]) and had a negative NAAT (nasal swab) at any unscheduled visit up to 1 month after the booster dose were included in the analysis. ± All eligible participants who received 2 doses of Comirnaty per their original randomisation, with the second dose received within the predefined window (19 to 42 days after Dose 1), received the booster dose of Comirnaty, had at least 1 valid and determinate post-booster immunogenicity result from a blood draw within the appropriate 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 specified window. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titres and the corresponding CIs (based on the Student's 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 values and the corresponding CIs (based on the Student's 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 specified window. These values are the denominators for the percentage calculations. Number of participants with seroresponse for 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 percentage difference is >−10%. Relative vaccine efficacy in participants 16 years of age and older — after a booster dose An interim efficacy analysis in Study 4, a placebo-controlled booster dose study conducted in approximately 10,000 participants 16 years of age and older enrolled from Study 2, evaluated confirmed COVID-19 cases identified at least 7 days after booster vaccination through the data cut-off date of 5 October 2021, representing a median 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 booster vaccination with Comirnaty after the primary series was assessed compared with a group that received placebo for the booster dose 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. The primary COVID-19 cases 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 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 worsening cough, new or worsening shortness of breath, chills, new or worsening muscle pain, new loss of taste or smell, sore throat, diarrhoea, or vomiting). * Participants who had no serological or virological evidence (7 or more days before receipt of the booster dose) of past 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, expressed in 1,000 person-years, for the specified 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 dose to the end of the surveillance period. n2 = number of participants at risk for the endpoint. Relative vaccine efficacy in the Comirnaty booster group compared with the placebo (no booster) group. 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) — after a booster dose A booster dose of Comirnaty was administered to 401 randomly selected participants in Study 3. The efficacy of the booster dose in those 5 to 11 years of age 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 GMTs in individuals 5 to 11 years of age, inclusive, who had no serological or virological evidence of prior SARS-CoV-2 infection up to 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 — 5 to 11 years of age, 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 point. 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 titres and the corresponding CIs (based on the Student's 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 CI (based on the Student's t distribution). Booster dose immunogenicity following primary vaccination with another authorised COVID-19 vaccine The efficacy of a Comirnaty booster dose (30 micrograms) in individuals who completed primary vaccination with another authorised COVID-19 vaccine (heterologous booster) is inferred from immunogenicity data from an independent open-label Phase 1/2 clinical study by the National Institutes of Health (NIH) (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 as a 2-dose series (n = 51, mean age 54 ± 17 years), a single dose of the Janssen vaccine (n = 53, mean age 48 ± 14 years), or Comirnaty 30 micrograms as 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 elicited 36-, 12-, and 20-fold increases in the GMR of neutralising titres after primary vaccination with the Janssen, Moderna, and Comirnaty vaccines, respectively. A heterologous booster dose of Comirnaty was also evaluated in the CoV-BOOST study (EudraCT 2021-002175-19), a multicentre, randomised, controlled Phase 2 study of a third COVID-19 booster dose, in which 107 adult participants (median age 71 years, interquartile range 54 to 77 years) were randomised at least 70 days after receiving 2 doses of the AstraZeneca COVID-19 vaccine. After the primary AstraZeneca COVID-19 vaccine series, the fold-rise in the GMR of pseudovirus-neutralising antibody NT50 (wild-type) increased 21.6-fold with a heterologous booster dose of Comirnaty (n = 95). Immunogenicity in participants over 55 years of age — after a booster dose (fourth dose) of Comirnaty (30 micrograms) In a sub-analysis of a subset from Study 4 (sub-study E), 305 participants over 55 years of age who had completed a 3-dose Comirnaty series received a booster dose (fourth dose) of Comirnaty (30 micrograms) 5 to 12 months after Dose 3. For subgroup immunogenicity data, see Table 8. Immunogenicity in participants 18 to ≤55 years of age — after a booster dose (fourth dose) of Comirnaty (30 micrograms) In sub-study D (a subset from Study 2 [Phase 3] and Study 4 [Phase 3]), 325 participants 18 to ≤55 years of age who had completed a 3-dose Comirnaty series received a booster dose (fourth dose) of Comirnaty (30 micrograms) 90 to 180 days after Dose 3. For subgroup immunogenicity data, see Table 14. Table 14. Summary of immunogenicity data from participants in Study C4591031, sub-study D (full expanded cohort 2 set) and sub-study E (expanded cohort — immunogenicity subset), who received a booster dose (fourth dose) of Comirnaty 30 micrograms — participants without evidence of infection up to 1 month after the booster dose — evaluable immunogenicity population Dose/blood sampling time point a Sub-study D (18 to ≤55 years of age) Comirnaty 30 micrograms Sub-study E (>55 years of age) 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: The median time from Dose 3 to Dose 4 of Comirnaty 30 micrograms is 4.0 months for sub-study D, cohort 2 and 6.3 months for sub-study E, expanded cohort. Note: Sub-study D full expanded set = cohort 2 without the verification group; sub-study E immunogenicity subset = a random sample of 230 participants in each vaccine group selected from the expanded cohort. Note: Participants who had no serological or virological evidence (blood sampling earlier than 1 month after study vaccination) of past 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 prior to the 1-month post-vaccination blood sample), and who had no medical 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 value is below the LLOQ, a post-vaccination assay result of ≥4 × LLOQ is considered a seroresponse. 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. N = number of participants with valid and determinate assay results for the specified assay at both pre-vaccination and the given sampling time point. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean log titres and the corresponding CIs (based on the Student's t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. Number of participants with seroresponse for 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 — after 2 doses of Comirnaty Study 9 was a multinational, placebo-controlled, observer-blinded 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 the first dose of Comirnaty at 24 to 34 weeks of gestation, and most (90.2%) received the second dose 19 to 23 days after the first. A descriptive immunogenicity analysis was conducted in pregnant participants who received Comirnaty in Study 9 compared with a comparator subgroup of non-pregnant participants from Study 2. It evaluated the neutralising GMT ratio (GMR) 1 month after Dose 2. The immunogenicity evaluation population, which received Comirnaty in either the pregnant participant group in Study 9 (n = 111) or the non-pregnant participant group in 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 positive for SARS-CoV-2 at baseline. Among participants without documented prior SARS-CoV-2 infection up to 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] was 0.67 [95% CI: 0.50; 0.90]). Among participants with or without documented prior SARS-CoV-2 infection up to 1 month after Dose 2, the model-adjusted GMT 1 month after Dose 2 was similar between pregnant and non-pregnant participants (model-adjusted GMT ratio [GMR] was 0.95 [95% CI: 0.69; 1.30]). Model-adjusted GMTs and GMRs were derived from a regression model adjusted for age and baseline neutralising titres. 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, and that also enrolled immunocompromised participants 18 years of age and older treated for non–small cell lung cancer (NSCLC) or chronic lymphocytic leukaemia (CLL), undergoing haemodialysis for secondary or end-stage renal disease, or receiving immunomodulator therapy for autoimmune inflammatory disease. 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 Dose 2, 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, which 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 results of studies with Comirnaty in the paediatric population for the prevention of COVID-19 (see section 4.2 for information on paediatric use).