Comirnaty Mechanism of Action

Pharmacotherapeutic group: vaccines, viral vaccines. ATC code: J07BN01.
Pharmacology: Pharmacodynamics: Mechanism of action: The nucleoside-modified messenger RNA in COMIRNATY is formulated in lipid nanoparticles, which enable delivery of the non-replicating RNA into host cells to direct transient expression of the SARS-CoV-2 S antigen. The mRNA codes for membrane-anchored, full-length S with two point mutations within the central helix. Mutation of these two amino acids to proline locks S in an 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 and immunogenicity: Immunogenicity data supporting the use of a single dose of COMIRNATY in seropositive, vaccine-naïve individuals: In a subset of Study 7 (Study BNT162-17) in participants 18 through 85 years of age, immunogenicity of a single 30 micrograms dose of a Pfizer-BioNTech bivalent COVID-19 vaccine containing equal quantities of modRNA encoding the viral spike (S) glycoprotein for the Alpha and Delta SARS-CoV-2 variants (hereafter referred to as the bivalent Alpha and Delta vaccine which is not authorised or approved) was assessed in COVID-19 vaccine-naïve participants with prior SARS-CoV-2 infection (n=262) compared to participants without prior SARS-CoV-2 infection who received 2 doses of COMIRNATY (Original) in Study 2 (n=275). The immunogenicity of the bivalent Alpha and Delta vaccine is relevant to COMIRNATY (2023-2024 formula) because these vaccines are manufactured using the same process with differences only in the encoded spike proteins.
A primary immunogenicity objective of the study was to assess non-inferiority with respect to level of 50% neutralising titre (NT50) and to the seroresponse rate to the reference strain immune response induced by a single dose of the bivalent Alpha and Delta vaccine in COVID-19 vaccine-naïve participants with evidence of prior infection relative to the response in participants without evidence of SARS-CoV-2 infection who received 2 doses of COMIRNATY (Original).
Non-inferiority of the reference strain immune response with respect to level of NT50 was met, as the lower bound of the 2-sided 95% CI for GMR was >0.67. The GMT was higher after a single dose of bivalent Alpha and Delta vaccine in COVID-19 vaccine-naïve participants with evidence of prior SARS-CoV-2 infection (Table 3).
Non-inferiority of the seroresponse rate to the reference strain was not met, as the lower bound of the 2-sided 95% CIs for the difference in seroresponse rate of reference strain was -10.04%, below the non-inferiority margin of -10% (Table 4).
The immune responses to the Alpha, Delta and Omicron BA.5 variants in vaccine-naïve participants with evidence of prior SARS-CoV-2 infection after 1 dose of the bivalent Alpha and Delta vaccine, in vaccine-naïve participants without evidence of SARS-CoV-2 infection after 2 doses of the bivalent Alpha and Delta vaccine, and in participants who had previously received 2 doses of COMIRNATY (Original) without evidence of SARS-CoV-2 infection and received 1 dose of the bivalent Alpha and Delta vaccine are provided in Table 5. (See Tables 3, 4 and 5.)

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Study 2 is a multicentre, multinational, Phase 1/2/3 randomised, placebo-controlled, observer-blind dose-finding, vaccine candidate selection and efficacy study in participants 12 years of age and older. Randomisation was stratified by age: 12 through 15 years of age, 16 through 55 years of age, or 56 years of age and older, with a minimum of 40% of participants in the ≥56-year stratum. The study excluded participants who were immunocompromised and those who had previous clinical or microbiological diagnosis of COVID-19. Participants with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalisation for worsening disease during the 6 weeks before enrolment, were included as were participants with known stable infection with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV).
Efficacy in participants 16 years of age and older - after 2 doses: In the Phase 2/3 portion of Study 2, based on data accrued through 14 November 2020, approximately 44,000 participants were randomised equally and were to receive 2 doses of COMIRNATY (Original) or placebo. The efficacy analyses included participants that received their second vaccination within 19 to 42 days after their first vaccination. The majority (93.1%) of vaccine recipients received the second dose 19 days to 23 days after Dose 1. Participants are planned to be followed for up to 24 months after Dose 2, for assessments of safety and efficacy against COVID-19. In the clinical study, 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 COMIRNATY. In the clinical study, participants were required to observe a minimum interval of 60 days before or after receipt of blood/plasma products or immunoglobulins within through conclusion of the study in order to receive either placebo or COMIRNATY.
The population for the analysis of the primary efficacy endpoint included 36,621 participants 12 years of age and older [18,242 in the COMIRNATY (Original) group and 18,379 in the placebo group] who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose. In addition, 134 participants were between the ages of 16 through 17 years of age (66 in the COMIRNATY (Original) group and 68 in the placebo group) and 1,616 participants 75 years of age and older (804 in the COMIRNATY (Original) group and 812 in the placebo group). (See Table 6.)

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At the time of the primary efficacy analysis, participants had been followed for symptomatic COVID-19 for in total 2,214 person-years for the COMIRNATY (Original) and in total 2,222 person-years in the placebo group.
There were no meaningful clinical differences in overall vaccine efficacy in participants who were 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].
The vaccine efficacy information is presented in Table 7. (See Table 7.)

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Efficacy of COMIRNATY in preventing first COVID-19 occurrence from 7 days after Dose 2 compared to placebo was 94.6% (95% confidence interval of 89.6% to 97.6%) in participants 16 years of age and older with or without evidence of prior infection with SARS-CoV-2.
Additionally, subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across genders, ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19.
Updated efficacy analyses were performed with additional confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up through 13 March 2021, representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population.
The updated vaccine efficacy information is presented in Table 8. (See Table 8.)

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The updated subgroup analyses of vaccine efficacy by demographic characteristics are presented in Table 9 and Table 10. (See Tables 9 and 10.)

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The updated subgroup analyses of vaccine efficacy by risk status in participants are presented in Table 11 and Table 12. (See Tables 11 and 12.)

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Efficacy against severe COVID-19 - after 2 doses: Updated efficacy analyses of secondary efficacy endpoints supported benefit of COMIRNATY in preventing severe COVID-19. Vaccine efficacy against severe COVID-19 is presented only for participants with or without prior SARS-CoV-2 infection (Table 13) as the COVID-19 case counts 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 COMIRNATY (Original) and placebo groups. (See Table 13.)

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Efficacy and immunogenicity in adolescents 12 through 15 years of age - after 2 doses: In an analysis of Study 2 in adolescents 12 through 15 years of age without evidence of prior infection, there were no cases in 1005 participants who received the vaccine and 16 cases out of 978 who received placebo. The point estimate for efficacy is 100% (95% confidence interval 75.3, 100.0). In participants with or without evidence of prior infection there were 0 cases in the 1119 who received vaccine and 18 cases in 1110 participants who received placebo. This also indicates the point estimate for efficacy is 100% (95% confidence interval 78.1, 100.0).
In Study 2, an analysis of SARS-CoV-2 neutralising titres 1 month after Dose 2 was conducted in a randomly selected subset of participants who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2, comparing the response in adolescents 12 through 15 years of age (n = 190) to participants 16 through 25 years of age (n = 170).
The ratio of the geometric mean titres (GMT) in the 12 through 15 years of age group to the 16 through 25 years of age group was 1.76, with a 2-sided 95% CI of 1.47 to 2.10. Therefore, the 1.5-fold non-inferiority criterion was met as the lower bound of the 2-sided 95% CI for the geometric mean ratio [GMR] was >0.67.
An updated efficacy analysis of Study 2 has been performed in approximately 2,260 adolescents 12 through 15 years of age evaluating confirmed COVID-19 cases accrued up to a data cut-off date of September 2, 2021, representing up to 6 months of follow-up after Dose 2 for participants in the efficacy population.
The updated vaccine efficacy information in adolescents 12 through 15 years of age is presented in Table 14. (See Table 14.)

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Efficacy in children 5 through <12 years of age - after 2 doses: An initial descriptive efficacy analysis of Study 3 has been performed in 1,968 children 5 through <12 years of age without evidence of infection prior to 7 days after Dose 2. This analysis evaluated confirmed symptomatic COVID-19 cases accrued up to a data cut-off date of 8 October 2021.
Table 15 presents the specific demographic characteristics in participants who did not have evidence of prior infection with SARS-CoV-2 through 7 days after the second dose. (See Table 15.)

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The initial descriptive vaccine efficacy results in children 5 through <12 years of age without evidence of prior SARS-CoV-2 infection are presented in Table 16. None of the cases accrued met criteria for severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C). No cases of COVID-19 were observed in either the vaccine group or the placebo group in participants with evidence of prior SARS-CoV-2 infection. (See Table 16.)

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Prespecified hypothesis-driven efficacy analysis was performed with additional confirmed COVID-19 cases accrued during blinded placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacy population.
In the efficacy analysis of Study 3 in children 5 to 11 years of age without evidence of prior infection, there were 10 cases out of 2,703 participants who received the vaccine and 42 cases out of 1,348 participants who received placebo. The point estimate for efficacy is 88.2% (95% CI: 76.2, 94.7). In participants with or without evidence of prior infection there were 12 cases in the 3,018 who received vaccine and 42 cases in 1,511 participants who received placebo. The point estimate for efficacy is 85.7% (95% CI: 72.4, 93.2).
Immunogenicity in children 5 through <12 years of age - after 2 doses: Study 3 is a Phase 1/2/3 study comprised of an open-label vaccine dose finding portion (Phase 1) and a multicentre, multinational, randomised, saline placebo-controlled, observer-blind efficacy portion (Phase 2/3) that has enrolled participants 5 through <12 years of age.
In Study 3, an analysis of SARS-CoV-2 NT50 1 month after Dose 2 in a randomly selected subset of participants demonstrated effectiveness by immunobridging of immune responses comparing children 5 through <12 years of age in the Phase 2/3 part of Study 3 to participants 16 through 25 years of age in the Phase 2/3 part of Study 2 who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2, meeting the prespecified immunobridging criteria for both the GMR and the seroresponse difference with seroresponse defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from baseline (before Dose 1).
The ratio of the SARS-CoV-2 NT50 in children 5 through <12 years of age to that of young adults 16 through 25 years of age was 1.04 (2-sided 95% CI: 0.93, 1.18), as presented in Table 17. (See Table 17.)

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Among participants without prior evidence of SARS-CoV-2 infection up to 1 month after Dose 2, 99.2% of children 5 through <12 years of age and 99.2% of participants 16 through 25 years of age had a seroresponse from before vaccination to 1 month after Dose 2. The difference in proportions of participants who had seroresponse between the 2 age groups (children - young adult) was 0.0% (2-sided 95% CI: -2.0%, 2.2%), as presented in Table 18. ( See Table 18.)

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Efficacy and immunogenicity in individuals 6 months through <5 years of age - 3-dose primary course: Effectiveness in individuals 6 months through 4 years of age is based on a comparison of efficacy against symptomatic COVID-19 comparing to placebo and immune responses in this age group to individuals 16 through 25 years of age.
Efficacy in participants 6 months through 4 years of age - after 3 doses: The efficacy analysis of Study 3 was performed across the combined population of participants 6 months through 4 years of age based on cases confirmed among 873 participants in the COMIRNATY (Original) group and 381 participants in the placebo group (2:1 randomisation ratio) who received all 3 doses of study intervention during the blinded follow-up period when the Omicron variant of SARS-CoV-2 (BA.2) was the predominant variant in circulation (data cut-off date of 17 June 2022).
Table 19 presents the specific demographic characteristics in participants 6 months through 4 years of age who received 3 doses of COMIRNATY (Original) (3 micrograms modRNA) or placebo. (See Table 19.)

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The vaccine efficacy results after Dose 3 in participants 6 months through 4 years of age are presented in Table 20. (See Table 20.)

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Analysis of COVID-19 cases that excluded those involving coinfection with other respiratory pathogens did not meaningfully impact the estimated vaccine efficacy in this population.
Among participants 2 through 4 years of age, severe COVID-19 criteria (as described in the protocol, based on FDA definition and modified for children) were fulfilled for 9 cases [6 COMIRNATY (Original) and 3 placebo] of which 5 of the 6 cases in the COMIRNATY (Original) group fulfilled a single criterion of increased heart rate or respiratory rate and all 3 cases in the placebo group fulfilled a single criterion of increased heart rate or decreased peripheral oxygen saturation. None of the cases accrued met criteria for multisystem inflammatory syndrome in children (MIS-C).
Among participants 6 months through 23 months of age, severe COVID-19 criteria were fulfilled for 3 cases [2 COMIRNATY (Original) and 1 placebo] of which 1 of the 2 cases in the COMIRNATY (Original) group fulfilled a single criterion of increased heart rate (152 bpm) and 1 case in the placebo group fulfilled a single criterion of increased heart rate (172 bpm). None of the cases accrued met criteria for MIS-C.
Immunogenicity in participants 2 through 4 years of age - after 3 doses: Immunogenicity analyses have been performed in the immunobridging subset of 143 Study 3 participants 2 through 4 years of age without evidence of infection up to 1 month after Dose 3 based on a data cut-off date of 29 April 2022.
Table 21 presents the specific demographic characteristics in the studied evaluable immunogenicity population. (See Table 21.)

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SARS-CoV-2 NT50 were compared between an immunogenicity subset of Phase 2/3 participants 2 through 4 years of age from Study 3 at 1 month after the 3-dose primary course and a randomly selected subset from Study 2 (Phase 2/3) participants 16 through 25 years of age at 1 month after the 2-dose primary course, using a microneutralisation assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titres (using a GMR) and the seroresponse (defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from before Dose 1) rates in the evaluable immunogenicity population of participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 3 in participants 2 through 4 years of age and up to 1 month after Dose 2 in participants 16 through 25 years of age. The prespecified immunobridging criteria were met for both the GMR and the seroresponse difference (see Table 22 and Table 23, respectively).

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Using a non-validated fluorescence focus reduction neutralisation test assay against the Omicron variant of SARS-CoV-2 (BA.1), the NT50 GMT at 1 month after Dose 3 among a subset of 34 study participants without evidence of prior SARS-CoV-2 infection (82.5 [2-sided 95% CI: 55.4, 122.9]) was increased compared to the NT50 GMT before Dose 3 (14.0 [2-sided 95% CI: 10.6, 18.5]).
An additional descriptive immunogenicity analysis was performed for participants 2 through 4 years of age who received a 3-dose course of COMIRNATY (Original) in Study 3 (Phase 2/3), compared with a subset of participants 18 through 50 years of age in Study C4591017 (Phase 3) who had received a 2-dose primary course followed by a booster dose of COMIRNATY (Original) 30 micrograms. The comparator group (participants 18 through 50 years of age) in this analysis had a similar interval between COMIRNATY (Original) Dose 2 and Dose 3 (median 13.0 weeks) as the participants 2 to 4 years of age (median 10.6 weeks). Among 34 participants 2 through 4 years of age without evidence of prior SARS-CoV-2 infection who received 3 doses of COMIRNATY (Original) 3 micrograms, neutralising GMTs were 114.3 at 1-month post-Dose 3. Among 27 participants 18 through 50 years of age without evidence of prior SARS-CoV-2 infection who received 3 doses of COMIRNATY (Original) 30 micrograms, Omicron neutralising GMTs were 164.2 at 1-month post Dose 3.
Immunogenicity in participants 6 through 23 months of age - after 3 doses: Immunogenicity analyses have been performed in the immunobridging subset of 82 Study 3 participants 6 through 23 months of age without evidence of infection up to 1 month after Dose 3 based on a data cut-off date of 29 April 2022.
Table 24 presents the specific demographic characteristics in the studied evaluable immunogenicity population. (See Table 24.)

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SARS-CoV-2 NT50 1 month after the vaccination course were compared between an immunogenicity subset of Phase 2/3 participants 6 through 23 months of age from Study 3 and a randomly selected subset from Study 2 (Phase 2/3) participants 16 through 25 years of age, using a microneutralisation assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titres (using a GMR) and the seroresponse (defined as achieving at least 4-fold rise in SARS-CoV-2 NT50 from before Dose 1) rates in the evaluable immunogenicity population of participants without evidence of prior SARS-CoV-2 infection up to 1 month after Dose 3 in participants 6 through 23 months of age and up to 1 month after Dose 2 in participants 16 through 25 years of age. The prespecified immunobridging criteria were met for both the GMR and the seroresponse difference (see Table 25 and Table 26, respectively).

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Using a non-validated fluorescence focus reduction neutralisation test assay against the Omicron variant of SARS-CoV-2 (BA.1), the NT50 GMT at 1 month after Dose 3 among a subset of 32 study participants without evidence of prior SARS-CoV-2 infection (127.5 [2-sided 95% CI: 90.2, 180.1]) was increased compared to the NT50 GMT before Dose 3 (16.3 [2-sided 95% CI: 12.8, 20.8]).
An additional descriptive immunogenicity analysis was performed for participants 6 through 23 months of age who received a 3-dose course of COMIRNATY (Original) in Study 3 (Phase 2/3), compared with a subset of participants 18 through 50 years of age in Phase 3 Study C4591017 who had received a 2-dose primary course followed by a booster dose of COMIRNATY (Original) 30 micrograms. The comparator group (participants 18 through 50 years of age) in this analysis had a similar interval between COMIRNATY (Original) Dose 2 and Dose 3 (median 13.0 weeks) as the participants 6 through 23 months of age (median 12.9 weeks). Among 32 participants 6 through 23 months of age without evidence of prior SARS-CoV-2 infection who received 3 doses of COMIRNATY (Original) 3 micrograms, Omicron neutralising GMTs were 128.8 at 1-month post-Dose 3. Among 27 participants 18 through 50 years of age without evidence of prior SARS-CoV-2 infection who received 3 doses of COMIRNATY (Original) 30 micrograms, Omicron neutralising GMTs were 164.2 at 1-month post-Dose 3.
Immunogenicity in participants 18 years of age and older - after booster dose: Effectiveness of a booster dose of COMIRNATY (Original) was demonstrated by evaluating non-inferiority immune responses of SARS-CoV-2 NT50 1 month after a booster dose. In Study 2, an analysis of SARS-CoV-2 NT50 demonstrated non-inferior immune responses 1 month after a booster dose compared to 1 month after Dose 2 in participants at least 18 through 55 years of age who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after the booster dose, based on prespecified non-inferiority criteria for both GMR and difference in seroresponse rates. Seroresponse for a participant was defined as achieving a ≥4-fold rise from baseline (before Dose 1) in NT50 (Table 27 and Table 28).
The SARS-CoV-2 NT50 GMR of 1 month after the booster dose to 1 month after Dose 2 was 3.26 (2-sided 97.5% CI: 2.76, 3.86), which met the non-inferiority criteria for GMR (lower bound of the 2-sided 97.5% CI >0.67 and point estimate of the GMR ≥0.8).
A high proportion of participants (99.5%) had seroresponse 1 month after Dose 3 compared with 95.0% 1 month after Dose 2. The difference in proportions of participants with a seroresponse 1 month after the booster dose (Dose 3) and 1 month after Dose 2 (Dose 3 minus Dose 2) was 1.5% (2-sided 97.5% CI: 1.0%, 7.9%), which met the 10% non-inferiority criterion (i.e., lower bound of the 2-sided 97.5% CI >-10%). (See Tables 27 and 28.)

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Relative vaccine efficacy in participants 16 years of age and older - after booster dose: An interim efficacy analysis of Study 4, a placebo-controlled booster study, was performed in approximately 10,000 participants 16 years of age and older who were recruited from Study 2, evaluated confirmed COVID-19 cases accrued from at least 7 days after booster vaccination up to a data cut-off date of 08 February 2022 (a period when Delta and then Omicron was the predominant variant), which represents a median of 2.8 months (range 0.3 to 7.5 months) post-booster follow-up. Vaccine efficacy of the COMIRNATY (Original) booster dose after the primary series relative to the placebo booster group who only received the primary series dose was assessed. The relative vaccine efficacy information for participants 16 years of age and older is presented in Table 29. (See Table 29.)

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Immunogenicity in children 5 through <12 years of age - after booster dose: Effectiveness of a booster dose of COMIRNATY (Original) was based on an assessment of NT50 against the reference strain of SARS-CoV-2 (USA_WA1/2020). Analyses of NT50 1 month after the booster dose compared to before the booster dose (Dose 3) demonstrated a substantial increase in GMTs in individuals 5 through <12 years of age who had no serological or virological evidence of past SARS-CoV-2 infection up to 1 month after the booster dose. This analysis is summarised in Table 30. (See Table 30.)

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Immunogenicity in children 5 through <12 years of age on the Omicron variant - after booster dose: The neutralising GMTs against both the Omicron variant and reference strain were substantially increased after booster vaccination compared with after the 2-dose primary series. At 1-month post-Dose 2, the observed neutralising GMTs for the Omicron variant and reference strain were 27.6 and 323.8, respectively. At 1-month post-Dose 3, the observed neutralising GMTs for the Omicron variant and reference strain were 614.4 and 1702.8, respectively (see Table 31).
For the Omicron variant, neutralising titres after booster vaccination (1-month post-Dose 3) increased 22-fold over those after the 2-dose primary series (1-month post-Dose 2). For the reference strain, the increase after the booster relative to the primary series was 5.3-fold. (See Table 31.)

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Immunogenicity with concomitant vaccine administration - COMIRNATY 30 micrograms: Concomitant administration with seasonal influenza vaccine: In Study 8 (C4591030), a Phase 3 multicentre, randomised, observer-blind study, 1,134 participants 18 through 64 years of age who had received 3 doses of COMIRNATY (Original) at least 3 months prior were randomised in a 1:1 ratio to receive either COMIRNATY (Original) co-administered with a seasonal inactivated influenza vaccine (SIIV), quadrivalent (Afluria Quad) followed 1 month later by placebo (Group 1, n=568) or an inactivated influenza vaccine with placebo followed 1 month later with COMIRNATY (Original) (Group 2, n=566).
The immune responses to COMIRNATY (Original) and SIIV were similar after COMIRNATY (Original) administered concomitantly with SIIV compared with those elicited by either vaccine administered alone. The non-inferiority criterion was achieved for both full-length S-binding immunoglobulin G (IgG) and all 4 influenza strain-specific haemagglutination inhibition (HAI) titres.
The immunogenicity results are presented in Table 32 and Table 33. (See Tables 32 and 33.)

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Concomitant administration with pneumococcal conjugate vaccine: In Study 11 (B7471026), a double-blind, randomised descriptive study, participants 65 years of age and older who had received 2 doses of COMIRNATY (Original) at least 6 months earlier, were randomised in a 1:1:1 ratio to receive either 20vPnC concomitantly administered with a booster dose of COMIRNATY (Original) (n=190), or 20vPnC vaccine administered alone (n=191), or a booster dose of COMIRNATY (Original) administered alone (n=189).
Immune responses to both vaccines were observed after concomitant administration of 20vPnC vaccine and COMIRNATY (Original). Opsonophagocytic activity (OPA) GMTs for the 20 pneumococcal serotypes were similar to 20vPnC vaccine administered alone and IgG GMCs for the full-length S−binding protein were similar to COMIRNATY (Original) administered alone. A post-hoc analysis found the immune responses to all 20 serotypes elicited by 20vPnC vaccine when concomitantly administered with COMIRNATY (Original) would have met conventional 2-fold non-inferiority criteria compared to 20vPnC vaccine alone, and the full-length S-binding IgG GMC elicited by COMIRNATY (Original) would have met conventional 1.5-fold non-inferiority criteria compared to COMIRNATY (Original) alone.
Concomitant administration with an RSV vaccine or with an RSV vaccine and a high dose influenza vaccine: In Study 12 (C5481001) a Phase 1/2, randomised, multicentre, parallel group, observer-blinded study 1,083 participants 65 years of age and older who had previously received at least 3 prior doses of an mRNA COVID-19 vaccine, had not previously received any RSV vaccine, or an influenza vaccine in the ≤120 days prior to enrolment, were randomised in 1 of 2 enrolment strata.
The first stratum of approximately 750 participants were randomised 1:1 to evaluate the safety, tolerability, and immunogenicity of admixed COMIRNATY (Bivalent BA.4/BA.5) and RSV (bivalent, recombinant) vaccine concomitantly administered with high dose quadrivalent flu vaccine or placebo in the opposite arm, compared to the individual vaccines.
In the second stratum (total participants n=316) participants were randomised 1:1 to receive COMIRNATY (Bivalent BA.4/BA.5) with concomitantly administered RSV (bivalent, recombinant) vaccine (in one arm) with either placebo or high dose quadrivalent flu vaccine (opposite arm). The study objectives included assessing the impact on the immune response of COMIRNATY (Bivalent BA.4/BA.5) concomitantly administered with RSV (bivalent, recombinant) vaccine, the immune response of concomitant use of RSV (bivalent, recombinant) vaccine, COMIRNATY (Bivalent BA.4/BA.5), and high dose quadrivalent flu vaccine.
When COMIRNATY (Bivalent BA.4/BA.5) was concomitantly administered with RSV (bivalent, recombinant) vaccine immunologic non-inferiority was demonstrated for COMIRNATY (Bivalent BA.4/BA.5) and RSV (bivalent, recombinant) vaccine compared to individual administration. The lower limit of the 2 sided 97.5% CI for the GMR for RSV A, RSV B, both SARS-CoV-2 Omicron BA.4/BA.5 strain and SARS-COV-2 Wuhan-Hu 1 strain (wildtype) reference strain neutralising titres (NTs) all met the predefined 2-fold non-inferiority criterion.
When COMIRNATY (Bivalent BA.4/BA.5) and RSV (bivalent, recombinant) vaccine were concomitantly administered with high dose quadrivalent flu vaccine, immunologic non-inferiority was demonstrated for COMIRNATY (Bivalent BA.4/BA.5), RSV (bivalent, recombinant) vaccine and high dose quadrivalent flu vaccine group compared to each individual administration. The lower limit of the 2 sided 97.5% CI for the GMR for RSV A, RSV B, both SARS-CoV-2 Omicron BA.4/BA.5 strain and SARS-COV-2 Wuhan-Hu 1 strain (wildtype) reference strain NTs, and each of the 4 strain specific HAI titres all met the predefined 2-fold non-inferiority criterion.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data with COMIRNATY (Original) reveal no special hazard for humans based on conventional studies of repeat dose toxicity and reproductive and developmental toxicity.
General toxicity: Rats intramuscularly administered COMIRNATY (receiving 3 full human doses once weekly, generating relatively higher levels in rats due to body weight differences) demonstrated some injection site oedema and erythema and increases in white blood cells (including basophils and eosinophils) consistent with an inflammatory response as well as vacuolation of portal hepatocytes without evidence of liver injury. All effects were reversible.
Genotoxicity/Carcinogenicity: Neither genotoxicity nor carcinogenicity studies were performed. The components of the vaccine (lipids and mRNA) are not expected to have genotoxic potential.
Reproductive toxicity: Reproductive and developmental toxicity were investigated in rats in a combined fertility and developmental toxicity study where female rats were intramuscularly administered COMIRNATY prior to mating and during gestation (receiving 4 full human doses that generate relatively higher levels in rat due to body weight differences, spanning between pre-mating day 21 and gestational day 20). SARS-CoV-2 neutralising antibody responses were present in maternal animals from prior to mating to the end of the study on postnatal day 21 as well as in foetuses and offspring. There were no vaccine-related effects on female fertility, pregnancy, or embryo-foetal or offspring development. No COMIRNATY data are available on vaccine placental transfer or excretion in milk.