Summary of safety profileInfants 6 to 23 months of age - after 3 doses
In an analysis of Study 3 (Phase 2/3), 2 176 infants (1 458 Comirnaty 3 mcg and 718 placebo) were6 to 23 months of age. Based on data in the blinded placebo-controlled follow-up period up to thecut-off date of 28 February 2023, 720 infants 6 to 23 months of age who received a 3-dose primarycourse (483 Comirnaty 3 mcg and 237 placebo) have been followed for a median of 1.7 months afterthe third dose.
The most frequent adverse reactions in infants 6 to 23 months of age that received any primary coursedose included irritability (> 60%), drowsiness (> 40%), decreased appetite (> 30%), tenderness at theinjection site (> 20%), injection site redness and fever (> 10%).
Children 2 to 4 years of age - after 3 doses
In an analysis of Study 3 (Phase 2/3), 3 541 children (2 368 Comirnaty 3 mcg and 1 173 placebo) were2 to 4 years of age. Based on data in the blinded placebo-controlled follow-up period up to the cut-offdate of 28 February 2023, 1 268 children 2 to 4 years of age who received a 3-dose primary course(863 Comirnaty 3 mcg and 405 placebo) have been followed a median of 2.2 months after the thirddose.
The most frequent adverse reactions in children 2 to 4 years of age that received any primary coursedose included pain at injection site and fatigue (> 40%), injection site redness and fever (> 10%).
Children 5 to 11 years of age (i.e. 5 to less than 12 years of age) - after 2 doses
In Study 3, a total of 3 109 children 5 to 11 years of age received at least 1 dose of Comirnaty 10 mcgand a total of 1 538 children 5 to 11 years of age received placebo. At the time of the analysis of
Study 3 Phase 2/3 with data up to the cut-off date of 20 May 2022, 2 206 (1 481 Comirnaty 10 mcgand 725 placebo) children have been followed for ≥ 4 months after the second dose in theplacebo-controlled blinded follow-up period. The safety evaluation in Study 3 is ongoing.
The overall safety profile of Comirnaty in participants 5 to 11 years of age was similar to that seen inparticipants 16 years of age and older. The most frequent adverse reactions in children 5 to 11 years ofage that received 2 doses were injection site pain (> 80%), fatigue (> 50%), headache (> 30%),injection site redness and swelling (≥ 20%), myalgia, chills, and diarrhoea (> 10%).
Children 5 to 11 years of age (i.e. 5 to less than 12 years of age) - after booster dose
In a subset from Study 3, a total of 2 408 children 5 to 11 years of age received a booster dose of
Comirnaty 10 mcg at least 5 months (range of 5.3 to 19.4 months) after completing the primary series.
The analysis of the Study 3 Phase 2/3 subset is based on data up to the cut-off date of28 February 2023 (median follow-up time of 6.4 months).
The overall safety profile for the booster dose was similar to that seen after the primary course. Themost frequent adverse reactions in children 5 to 11 years of age after the booster dose were injectionsite pain (> 60%), fatigue (> 30%), headache (> 20%), myalgia, chills, injection site redness andswelling (> 10%).
Adolescents 12 to 15 years of age - after 2 dosesIn an analysis of long-term safety follow-up in Study 2, 2 260 adolescents (1 131 Comirnaty and1 129 placebo) were 12 to 15 years of age. Of these, 1 559 adolescents (786 Comirnaty and773 placebo) have been followed for ≥ 4 months after the second dose.
The overall safety profile of Comirnaty in adolescents 12 to 15 years of age was similar to that seen inparticipants 16 years of age and older. The most frequent adverse reactions in adolescents 12 to15 years of age that received 2 doses were injection site pain (> 90%), fatigue and headache (> 70%),myalgia and chills (> 40%), arthralgia and pyrexia (> 20%).
Participants 16 years of age and older - after 2 dosesIn Study 2, a total of 22 026 participants 16 years of age or older received at least 1 dose of Comirnaty30 mcg and a total of 22 021 participants 16 years of age or older received placebo (including 138 and145 adolescents 16 and 17 years of age in the vaccine and placebo groups, respectively). A total of20 519 participants 16 years of age or older received 2 doses of Comirnaty.
At the time of the analysis of Study 2 with a data cut-off of 13 March 2021 for the placebo-controlledblinded follow-up period up to the participants’ unblinding dates, a total of 25 651 (58.2%)participants (13 031 Comirnaty and 12 620 placebo) 16 years of age and older were followed up for≥ 4 months after the second dose. This included a total of 15 111 (7 704 Comirnaty and 7 407 placebo)participants 16 to 55 years of age and a total of 10 540 (5 327 Comirnaty and 5 213 placebo)participants 56 years of age and older.
The most frequent adverse reactions in participants 16 years of age and older that received 2 doseswere injection site pain (> 80%), fatigue (> 60%), headache (> 50%), myalgia (> 40%), chills(> 30%), arthralgia (> 20%), pyrexia and injection site swelling (> 10%) and were usually mild ormoderate in intensity and resolved within a few days after vaccination. A slightly lower frequency ofreactogenicity events was associated with greater age.
The safety profile in 545 participants 16 years of age and older receiving Comirnaty, that wereseropositive for SARS-CoV-2 at baseline, was similar to that seen in the general population.
Participants 12 years of age and older - after booster dose
A subset from Study 2 Phase 2/3 participants of 306 adults 18 to 55 years of age who completed theoriginal Comirnaty 2-dose course, received a booster dose of Comirnaty approximately 6 months(range of 4.8 to 8.0 months) after receiving Dose 2. Overall, participants who received a booster dose,had a median follow-up time of 8.3 months (range 1.1 to 8.5 months) and 301 participants had beenfollowed for ≥ 6 months after the booster dose to the cut-off date (22 November 2021).
The overall safety profile for the booster dose was similar to that seen after 2 doses. The most frequentadverse reactions in participants 18 to 55 years of age were injection site pain (> 80%),fatigue (> 60%), headache (> 40%), myalgia (> 30%), chills and arthralgia (> 20%).
In Study 4, a placebo-controlled booster study, participants 16 years of age and older recruited from
Study 2 received a booster dose of Comirnaty (5 081 participants), or placebo (5 044 participants) atleast 6 months after the second dose of Comirnaty. Overall, participants who received a booster dose,had a median follow-up time of 2.8 months (range 0.3 to 7.5 months) after the booster dose in theblinded placebo-controlled follow-up period to the cut-off date (8 February 2022). Of these,1 281 participants (895 Comirnaty and 386 placebo) have been followed for ≥ 4 months after thebooster dose of Comirnaty. No new adverse reactions of Comirnaty were identified.
A subset from Study 2 Phase 2/3 participants of 825 adolescents 12 to 15 years of age who completedthe original Comirnaty 2-dose course, received a booster dose of Comirnaty approximately11.2 months (range of 6.3 to 20.1 months) after receiving Dose 2. Overall, participants who received abooster dose, had a median follow-up time of 9.5 months (range 1.5 to 10.7 months) based on data upto the cut-off date (3 November 2022). No new adverse reactions of Comirnaty were identified.
Booster dose following primary vaccination with another authorised COVID-19 vaccine
In 5 independent studies on the use of a Comirnaty booster dose in individuals who had completedprimary vaccination with another authorised COVID-19 vaccine (heterologous booster dose), no newsafety issues were identified.
Tabulated list of adverse reactions from clinical studies and post-authorisation experience inindividuals 6 months of age and older
Adverse reactions observed during clinical studies are listed below according to the followingfrequency categories: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1 000 to< 1/100), Rare (≥ 1/10 000 to < 1/1 000), Very rare (< 1/10 000), Not known (cannot be estimatedfrom the available data).
Table 1. Adverse reactions from Comirnaty clinical trials and post-authorisation experiencein individuals 6 months of age and older
System Organ Class Frequency Adverse reactions
Blood and lymphatic system Common Lymphadenopathyadisorders
Immune system disorders Uncommon Hypersensitivity reactions (e.g. rashi,pruritus, urticaria, angioedemab)
Not known Anaphylaxis
Metabolism and nutrition disorders Uncommon Decreased appetitej
Psychiatric disorders Very common Irritabilityk
Uncommon Insomnia
Nervous system disorders Very common Headache; drowsinessk
Uncommon Dizzinessd; lethargy
Rare Acute peripheral facial paralysisc
Not known Paraesthesiad; hypoaesthesiad
Cardiac disorders Very rare Myocarditisd; pericarditisd
Gastrointestinal disorders Very common Diarrhoead
Common Nausea; vomitingd
Skin and subcutaneous tissue Uncommon Hyperhidrosis; night sweatsdisorder Not known Erythema multiformed
Musculoskeletal and connective Very common Arthralgia; myalgiatissue disorders Uncommon Pain in extremitye
Reproductive system and breast Not known Heavy menstrual bleedingldisorders
System Organ Class Frequency Adverse reactions
General disorders and Very common Injection site pain; injection siteadministration site conditions tendernessk; fatigue; chills; pyrexiaf;
Injection site swellingCommon Injection site rednessh
Uncommon Asthenia; malaise; injection site pruritus
Not known Extensive swelling of vaccinated limbd;facial swellingg
a. In participants 5 years of age and older, a higher frequency of lymphadenopathy was reported after a booster(≤ 2.8%) dose than after primary (≤ 0.9%) doses of the vaccine.
b. The frequency category for angioedema was rare.
c. Through the clinical trial safety follow-up period to 14 November 2020, acute peripheral facial paralysis (orpalsy) was reported by four participants in the COVID-19 mRNA Vaccine group. Onset was Day 37 after
Dose 1 (participant did not receive Dose 2) and Days 3, 9, and 48 after Dose 2. No cases of acute peripheralfacial paralysis (or palsy) were reported in the placebo group.
d. Adverse reaction determined post-authorisation.
e. Refers to vaccinated arm.
f. A higher frequency of pyrexia was observed after the second dose compared to the first dose.g. Facial swelling in vaccine recipients with a history of injection of dermatological fillers has been reported inthe post-marketing phase.h. Injection site redness occurred at a higher frequency (very common) in participants 6 months to 11 years ofage.i. The frequency category for rash was common in participants 6 to 23 months of age.j. The frequency category for decreased appetite was very common in participants 6 to 23 months of age.k. Irritability, injection site tenderness, and drowsiness pertain to participants 6 to 23 months of age.l. Most cases appeared to be non-serious and temporary in nature.
Description of selected adverse reactionsMyocarditis and pericarditisThe increased risk of myocarditis after vaccination with Comirnaty is highest in younger males (seesection 4.4).
Two large European pharmacoepidemiological studies have estimated the excess risk in youngermales following the second dose of Comirnaty. One study showed that in a period of 7 days after thesecond dose there were about 0.265 (95% CI 0.255 - 0.275) extra cases of myocarditis in 12-29 yearold males per 10 000 compared to unexposed persons. In another study, in a period of 28 days after thesecond dose there were 0.56 (95% CI 0.37 - 0.74) extra cases of myocarditis in 16-24 year old malesper 10 000 compared to unexposed persons.
Limited data indicate that the risk of myocarditis and pericarditis after vaccination with Comirnaty inchildren aged 5 to 11 years seems lower than in ages 12 to 17 years.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
Pharmacotherapeutic group: vaccines, viral vaccines, ATC code: J07BN01
Mechanism of actionThe nucleoside-modified messenger RNA in Comirnaty is formulated in lipid nanoparticles, whichenable 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 pointmutations within the central helix. Mutation of these two amino acids to proline locks S in anantigenically preferred prefusion conformation. The vaccine elicits both neutralizing antibody andcellular immune responses to the spike (S) antigen, which may contribute to protection against
COVID-19.
EfficacyStudy 2 is a multicentre, multinational, Phase 1/2/3 randomised, placebo-controlled, observer-blinddose-finding, vaccine candidate selection and efficacy study in participants 12 years of age and older.
Randomisation was stratified by age: 12 to 15 years of age, 16 to 55 years of age, or 56 years of ageand older, with a minimum of 40% of participants in the ≥ 56-year stratum. The study excludedparticipants who were immunocompromised and those who had previous clinical or microbiologicaldiagnosis of COVID-19. Participants with pre-existing stable disease, defined as disease not requiringsignificant change in therapy or hospitalization for worsening disease during the 6 weeks beforeenrolment, were included as were participants with known stable infection with humanimmunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV).
Efficacy in participants 16 years of age and older - after 2 dosesIn the Phase 2/3 portion of Study 2, based on data accrued through 14 November 2020, approximately44 000 participants were randomised equally and were to receive 2 doses of COVID-19 mRNA
Vaccine or placebo. The efficacy analyses included participants that received their second vaccinationwithin 19 to 42 days after their first vaccination. The majority (93.1%) of vaccine recipients receivedthe second dose 19 days to 23 days after Dose 1. Participants are planned to be followed for up to24 months after Dose 2, for assessments of safety and efficacy against COVID-19. In the clinicalstudy, participants were required to observe a minimum interval of 14 days before and afteradministration of an influenza vaccine in order to receive either placebo or COVID-19 mRNA
Vaccine. In the clinical study, participants were required to observe a minimum interval of 60 daysbefore or after receipt of blood/plasma products or immunoglobulins within through conclusion of thestudy in order to receive either placebo or COVID-19 mRNA Vaccine.
The population for the analysis of the primary efficacy endpoint included 36 621 participants 12 yearsof age and older (18 242 in the COVID-19 mRNA Vaccine 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 to 17 years of age (66 in the COVID-19mRNA Vaccine group and 68 in the placebo group) and 1 616 participants 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 had been followed for symptomatic
COVID-19 for in total 2 214 person-years for the COVID-19 mRNA Vaccine and in total2 222 person-years in the placebo group.
There were no meaningful clinical differences in overall vaccine efficacy in participants who were atrisk 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, diabetesmellitus, hypertension).
The vaccine efficacy information is presented in Table 2.
Table 2. Vaccine efficacy - First COVID-19 occurrence from 7 days after Dose 2, by agesubgroup - participants without evidence of infection prior to 7 days after
Dose 2 - evaluable efficacy (7 days) population
First COVID-19 occurrence from 7 days after Dose 2 in participants without evidence ofprior SARS-CoV-2 infection*
COVID-19 mRNA
Vaccine Placebo
Na = 18 198 Na = 18 325
Cases Casesn1b n1b Vaccine efficacy %
Subgroup Surveillance timec (n2d) Surveillance timec (n2d) (95% CI)e8 162 95.0
All participants 2.214 (17 411) 2.222 (17 511) (90.0, 97.9)7 143 95.116 to 64 years 1.706 (13 549) 1.710 (13 618) (89.6, 98.1)1 19 94.765 years and older 0.508 (3 848) 0.511 (3 880) (66.7, 99.9)1 14 92.965 to 74 years 0.406 (3 074) 0.406 (3 095) (53.1, 99.8)75 years and 0 5 100.0older 0.102 (774) 0.106 (785) (-13.1, 100.0)
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and atleast 1 symptom consistent with COVID-19 [*Case definition: (at least 1 of) fever, new or increased cough, newor 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 serological or virological evidence (prior to 7 days after receipt of the last dose) ofpast SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Visit 1 and SARS-CoV-2 notdetected by nucleic acid amplification tests (NAAT) [nasal swab] at Visits 1 and 2), and had negative NAAT(nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
a. N = Number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.
c. Total surveillance time in 1 000 person-years for the given endpoint across all participants within each groupat risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of thesurveillance period.
d. n2 = Number of participants at risk for the endpoint.
e. Two-sided confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson methodadjusted to the surveillance time. CI not adjusted for multiplicity.
Efficacy of COVID-19 mRNA Vaccine in preventing first COVID-19 occurrence from 7 days afterDose 2 compared to placebo was 94.6% (95% confidence interval of 89.6% to 97.6%) in participants16 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 pointestimates across genders, ethnic groups, and participants with medical comorbidities associated withhigh risk of severe COVID-19.
Updated efficacy analyses were performed with additional confirmed COVID-19 cases accrued duringblinded placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacypopulation.
The updated vaccine efficacy information is presented in Table 3.
Table 3. Vaccine efficacy - First COVID-19 occurrence from 7 days after Dose 2, by agesubgroup - participants without evidence of prior SARS-CoV-2 infection* prior to7 days after Dose 2 - evaluable efficacy (7 days) population during theplacebo-controlled follow-up period
COVID-19 mRNA
Vaccine Placebo
Na=20 998 Na=21 096
Cases Casesn1b n1b Vaccine efficacy
Surveillance timec Surveillance timec %
Subgroup (n2d) (n2d) (95% CIe)77 850 91.3
All participantsf 6.247 (20 712) 6.003 (20 713) (89.0, 93.2)70 710 90.616 to 64 years 4.859 (15 519) 4.654 (15 515) (87.9, 92.7)7 124 94.565 years and older 1.233 (4 192) 1.202 (4 226) (88.3, 97.8)6 98 94.165 to 74 years 0.994 (3 350) 0.966 (3 379) (86.6, 97.9)1 26 96.275 years and older 0.239 (842) 0.237 (847) (76.9, 99.9)
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and atleast 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new orincreased shortness of breath; chills; new or increased 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. 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 negative NAAT(nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
a. N = Number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.
c. Total surveillance time in 1 000 person-years for the given endpoint across all participants within each groupat risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of thesurveillance period.
d. n2 = Number of participants at risk for the endpoint.
e. Two-sided 95% confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearsonmethod adjusted to the surveillance time.
f. Included confirmed cases in participants 12 to 15 years of age: 0 in the COVID-19 mRNA Vaccine group; 16in the placebo group.
In the updated efficacy analysis, efficacy of COVID-19 mRNA Vaccine in preventing first COVID-19occurrence from 7 days after Dose 2 compared to placebo was 91.1% (95% CI of 88.8% to 93.0%)during the period when Wuhan/Wild type and Alpha variants were the predominant circulating strainsin participants in the evaluable efficacy population with or without evidence of prior infection with
SARS-CoV-2.
Additionally, the updated efficacy analyses by subgroup showed similar efficacy point estimatesacross sexes, ethnic groups, geography and participants with medical comorbidities and obesityassociated with high risk of severe COVID-19.
Efficacy against severe COVID-19Updated efficacy analyses of secondary efficacy endpoints supported 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 only for participantswith or without prior SARS-CoV-2 infection (Table 4) as the COVID-19 case counts in participantswithout 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 4. Vaccine efficacy - First severe COVID-19 occurrence in participants with or withoutprior SARS-CoV-2 infection based on the Food and Drug Administration (FDA)*after Dose 1 or from 7 days after Dose 2 in the placebo-controlled follow-up
COVID-19 mRNA
Vaccine Placebo
Cases Casesn1a n1a Vaccine efficacy %
Surveillance time (n2b) Surveillance time (n2b) (95% CIc)1 30 96.7
After Dose 1d 8.439e (22 505) 8.288e (22 435) (80.3, 99.9)1 21 95.37 days after Dose 2f 6.522g (21 649) 6.404g (21 730) (70.9, 99.9)
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and atleast 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new orincreased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat;diarrhoea; vomiting).
* Severe illness from COVID-19 as defined by FDA is confirmed COVID-19 and presence of at least 1 of thefollowing:
* Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 breaths per minute, heartrate ≥ 125 beats per minute, saturation of oxygen ≤ 93% on room air at sea level, or ratio of arterialoxygen partial pressure to fractional inspired oxygen < 300 mm Hg);
* Respiratory failure [defined as needing high-flow oxygen, noninvasive ventilation, mechanicalventilation or extracorporeal membrane oxygenation (ECMO)];
* Evidence of shock (systolic blood pressure < 90 mm Hg, diastolic blood pressure < 60 mm Hg, orrequiring vasopressors);
* Significant acute renal, hepatic, or neurologic dysfunction;
* Admission to an Intensive Care Unit;
* Death.
a. n1 = Number of participants meeting the endpoint definition.
b. n2 = Number of participants at risk for the endpoint.
c. Two-side confidence interval (CI) for vaccine efficacy is derived based on the Clopper and Pearson methodadjusted to the surveillance time.
d. Efficacy assessed based on the Dose 1 all available efficacy (modified intention-to-treat) population thatincluded all randomised participants who received at least 1 dose of study intervention.
e. Total surveillance time in 1 000 person-years for the given endpoint across all participants within each groupat risk for the endpoint. Time period for COVID-19 case accrual is from Dose 1 to the end of thesurveillance period.
f. Efficacy assessed based on the evaluable efficacy (7 Days) population that included all eligible randomisedparticipants who receive all dose(s) of study intervention as randomised within the predefined window, haveno other important protocol deviations as determined by the clinician.
g. Total surveillance time in 1 000 person-years for the given endpoint across all participants within each groupat risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of thesurveillance period.
Efficacy and immunogenicity in adolescents 12 to 15 years of age - after 2 dosesIn an initial analysis of Study 2 in adolescents 12 to 15 years of age (representing a median follow-upduration of > 2 months after Dose 2) without evidence of prior infection, there were no cases in1 005 participants who received the vaccine and 16 cases out of 978 who received placebo. The pointestimate for efficacy is 100% (95% confidence interval 75.3, 100.0). In participants with or withoutevidence of prior infection there were 0 cases in the 1 119 who received vaccine and 18 cases in1 110 participants who received placebo. This also indicates the point estimate for efficacy is 100%(95% confidence interval 78.1, 100.0).
Updated efficacy analyses were performed with additional confirmed COVID-19 cases accrued duringblinded placebo-controlled follow-up, representing up to 6 months after Dose 2 in the efficacypopulation.
In the updated efficacy analysis of Study 2 in adolescents 12 to 15 years of age without evidence ofprior infection, there were no cases in 1 057 participants who received the vaccine and 28 cases out of1 030 who received placebo. The point estimate for efficacy is 100% (95% confidence interval 86.8,100.0) during the period when Alpha variant was the predominant circulating strain. In participantswith or without evidence of prior infection there were 0 cases in the 1 119 who received vaccine and30 cases in 1 109 participants who received placebo. This also indicates the point estimate for efficacyis 100% (95% confidence interval 87.5, 100.0).
In Study 2, an analysis of SARS-CoV-2 neutralising titres 1 month after Dose 2 was conducted in arandomly 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 to15 years of age (n = 190) to participants 16 to 25 years of age (n = 170).
The ratio of the geometric mean titres (GMT) in the 12 to 15 years of age group to the 16 to 25 yearsof age group was 1.76, with a 2-sided 95% CI of 1.47 to 2.10. Therefore, the 1.5-fold noninferioritycriterion was 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) -after 2 doses
Study 3 is a Phase 1/2/3 study comprised of an open-label vaccine dose-finding portion (Phase 1) anda multicentre, multinational, randomised, saline placebo-controlled, observer-blind efficacy portion(Phase 2/3) that has enrolled participants 5 to 11 years of age. The majority (94.4%) of randomisedvaccine recipients received the second dose 19 days to 23 days after Dose 1.
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 5. No cases of COVID-19 were observed in either thevaccine group or the placebo group in participants with evidence of prior SARS-CoV-2 infection.
Table 5. Vaccine efficacy - First COVID-19 occurrence from 7 days after Dose 2: Withoutevidence of infection prior to 7 days after Dose 2 - Phase 2/3 - Children 5 to 11 yearsof age evaluable efficacy population
First COVID-19 occurrence from 7 days after Dose 2 in children 5 to 11 years of age withoutevidence of prior SARS-CoV-2 infection*
COVID-19 mRNA
Vaccine10 mcg/dose Placebo
Na=1 305 Na=663
Cases Casesn1b n1b Vaccine efficacy %
Surveillance timec (n2d) Surveillance timec (n2d) (95% CI)
Children 5 to 11 years of 3 16 90.7age 0.322 (1 273) 0.159 (637) (67.7, 98.3)
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and atleast 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increasedshortness of breath; chills; new or increased 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. 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 negative NAAT(nasal swab) at any unscheduled visit prior to 7 days after Dose 2 were included in the analysis.
a. N = Number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.
c. Total surveillance time in 1 000 person-years for the given endpoint across all participants within each groupat risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 2 to the end of thesurveillance period.
d. n2 = Number of participants at risk for the endpoint.
Pre-specified hypothesis-driven efficacy analysis was performed with additional confirmed
COVID-19 cases accrued during blinded placebo-controlled follow-up, representing up to 6 monthsafter 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 in 2 703 participants who received the vaccine and 42 cases out of 1 348 whoreceived placebo. The point estimate for efficacy is 88.2% (95% confidence interval 76.2, 94.7) duringthe period when Delta variant was the predominant circulating strain. In participants with or withoutevidence of prior infection there were 12 cases in the 3 018 who received vaccine and 42 cases in1 511 participants who received placebo. The point estimate for efficacy is 85.7% (95% confidenceinterval 72.4, 93.2).
In Study 3, an analysis of SARS-CoV-2 50% neutralising titres (NT50) 1 month after Dose 2 in arandomly selected subset of participants demonstrated effectiveness by immunobridging of immuneresponses comparing children 5 to 11 years of age (i.e. 5 to less than 12 years of age) in the Phase 2/3part of Study 3 to participants 16 to 25 years of age in the Phase 2/3 part of Study 2 who had noserological or virological evidence of past SARS-CoV-2 infection up to 1 month after Dose 2, meetingthe prespecified immunobridging criteria for both the geometric mean ratio (GMR) and theseroresponse difference with seroresponse defined as achieving at least 4-fold rise in SARS-CoV-2
NT50 from baseline (before Dose 1).
The GMR of the SARS-CoV-2 NT50 1 month after Dose 2 in children 5 to 11 years of age (i.e. 5 toless than 12 years of age) to that of 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 aseroresponse at 1 month after Dose 2. The difference in proportions of participants who hadseroresponse between the 2 age groups (children - young adult) was 0.0% (2-sided 95% CI: -2.0%,2.2%). This information is presented in Table 6.
Table 6. Summary of geometric mean ratio for 50% neutralising titre and difference inpercentages of participants with seroresponse - comparison of children 5 to 11 yearsof age (Study 3) to participants 16 to 25 years of age (Study 2) - participants withoutevidence of infection up to 1 month after Dose 2 - immunobridging subset -
Phase 2/3 - evaluable immunogenicity population
COVID-19 mRNA Vaccine10 mcg/dose 30 mcg/dose5 to 11 years 16 to 25 years 5 to 11 years/
Na=264 Na=253 16 to 25 years
Metimmunobridging
Time GMTc GMTc GMRd objectiveepointb (95% CIc) (95% CIc) (95% CId) (Y/N)
Geometricmean 50% 1 monthneutralizing after 1 197.6 1 146.5 1.04titref (GMTc) Dose 2 (1 106.1, 1 296.6) (1 045.5, 1 257.2) (0.93, 1.18) Y
Met
Difference immunobridging
Time ng (%) ng (%) %i objectivekpointb (95% CIh) (95% CIh) (95% CIj) (Y/N)
Seroresponserate (%) for50% 1 monthneutralizing after 262 (99.2) 251 (99.2) 0.0titref Dose 2 (97.3, 99.9) (97.2, 99.9) (-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 post-Dose 2 blood samplecollection) of past SARS-CoV-2 infection (i.e. N-binding antibody [serum] negative at Dose 1 visit and 1 monthafter Dose 2, SARS-CoV-2 not detected by NAAT [nasal swab] at Dose 1 and Dose 2 visits, and negative NAAT(nasal swab) at any unscheduled visit up to 1 month after Dose 2 blood collection) and had no medical 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 baselinemeasurement is below the LLOQ, a postvaccination assay result ≥ 4 × LLOQ is considered a seroresponse.
a. N = Number of participants with valid and determinate assay results before vaccination and at 1 month after
Dose 2. These values are also the denominators used in the percentage calculations for seroresponse rates.
b. Protocol-specified timing for blood sample collection.
c. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titres and thecorresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to0.5 × LLOQ.
d. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of thetitres (5 to 11 years of age minus 16 to 25 years of age) and the corresponding CI (based on the Student tdistribution).
e. Immunobridging based on GMT is declared if the lower bound of the 2-sided 95% CI for the GMR is greaterthan 0.67 and the point estimate of the GMR is ≥ 0.8.
f. SARS-CoV-2 NT50 were determined using the SARS-CoV-2 mNeonGreen Virus Microneutralization
Assay. The assay uses a fluorescent reporter virus derived from the USA_WA1/2020 strain and virusneutralisation is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilutionat which 50% of the virus is neutralised.
g. n = Number of participants with seroresponse based on NT50 1 month after Dose 2.h. Exact 2-sided CI based on the Clopper and Pearson method.i. Difference in proportions, expressed as a percentage (5 to 11 years of age minus 16 to 25 years of age).j. 2-Sided CI, based on the Miettinen and Nurminen method for the difference in proportions, expressed as apercentage.k. Immunobridging based on seroresponse rate is declared if the lower bound of the 2-sided 95% CI for theseroresponse difference is greater than -10.0%.
Immunogenicity in children 5 to 11 years of age (i.e. 5 to less than 12 years of age) - after boosterdose
A booster dose of Comirnaty was given to 401 randomly selected participants in Study 3.
Effectiveness of a booster dose in ages 5 to 11 is inferred by immunogenicity. The immunogenicity ofthis was assessed through 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 demonstrated asubstantial increase in GMTs in individuals 5 through 11 years of age who had no serological orvirological evidence of past SARS-CoV-2 infection up to 1 month after the dose 2 and the boosterdose. This analysis is summarized in Table 7.
Table 7. Summary of geometric mean titres - NT50 - participants without evidence ofinfection - phase 2/3 - immunogenicity set - 5 through 11 years of age - evaluableimmunogenicity population
Sampling time pointa1 month after booster1 month after booster 1 month after dose 2 dose/dose (nb=67) (nb=96) 1 month after dose 2
GMTc GMTc GMRd
Assay (95% CIc) (95% CIc) (95% CId)
SARS-CoV-2neutralization assay - 2 720.9 1 253.9 2.17
NT50 (titre) (2 280.1, 3 247.0) (1 116.0, 1 408.9) (1.76, 2.68)
Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre;
LLOQ = lower limit of quantitation; NT50 = 50% neutralizing titre; SARS-CoV-2 = severe acute respiratorysyndrome coronavirus 2.
a. Protocol-specified timing for blood sample collection.
b. n = Number of participants with valid and determinate assay results for the specified assay at the givendose/sampling time point.
c. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titres and thecorresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to0.5 × LLOQ.
d. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of thetitres (1-Month Post-Booster Dose minus 1-Month Post-Dose 2) and the corresponding CI (based on the
Student t distribution).
Efficacy and immunogenicity of a 3-dose primary course in infants and children 6 months to 4 years ofage
The efficacy analysis of Study 3 was performed across the combined population of participants6 months through 4 years of age based on cases confirmed among 873 participants in the COVID-19mRNA Vaccine group and 381 participants in the placebo group (2:1 randomization ratio) whoreceived all 3 doses of study intervention during the blinded follow-up period when the Omicronvariant of SARS-CoV-2 (BA.2) was the predominant variant in circulation (data cut-off date of17 June 2022).
The vaccine efficacy results after Dose 3 in participants 6 months through 4 years of age are presentedin Table 8.
Table 8. Vaccine Efficacy - First COVID-19 Occurrence From 7 Days After Dose 3 - Blinded
Follow-Up Period - Participants Without Evidence of Infection Prior to 7 Days After
Dose 3 - Phase 2/3 - 6 Months to 4 Years of Age - Evaluable Efficacy (3-Dose)
Population
First COVID-19 occurrence from 7 days after Dose 3 in participants without evidence of prior
SARS-CoV-2 infection*
COVID-19 mRNA
Vaccine 3 mcg/Dose Placebo
Na=873 Na=381
Cases Casesn1b n1b Vaccine Efficacy %
Subgroup Surveillance Timec (n2d) Surveillance Timec (n2d) (95% CIe)6 months through 13 21 73.24 yearse 0.124 (794) 0.054 (351) (43.8, 87.6)9 13 71.82 through 4 years 0.081 (498) 0.033 (204) (28.6, 89.4)6 months through 4 8 75.823 months 0.042 (296) 0.020 (147) (9.7, 94.7)
Abbreviations: NAAT = nucleic acid amplification test; N-binding = SARS-CoV-2 nucleoprotein-binding;
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; VE = vaccine efficacy.
* Participants who had no serological or virological evidence (prior to 7 days after receipt of Dose 3) of past
SARS-CoV-2 infection (i.e. negative N-binding antibody [serum] result at Dose 1, 1 month post-Dose 2 (ifavailable), Dose 3 (if available) visits, SARS-CoV-2 not detected by NAAT [nasal swab] at Dose 1, Dose 2,and Dose 3 study visits, and a negative NAAT [nasal swab] result at any unscheduled visit prior to 7 daysafter receipt of Dose 3) and had no medical history of COVID-19 were included in the analysis.
a. N = number of participants in the specified group.
b. n1 = Number of participants meeting the endpoint definition.
c. Total surveillance time in 1 000 person-years for the given endpoint across all participants within each groupat risk for the endpoint. Time period for COVID-19 case accrual is from 7 days after Dose 3 to the end of thesurveillance period.
d. n2 = Number of participants at risk for the endpoint.
e. Two-sided 95% confidence interval (CI) for VE is derived based on the Clopper and Pearson methodadjusted for surveillance time.
Vaccine efficacy in participants with or without prior SARS-CoV-2 infection was similar to thoseparticipants without prior SARS-CoV-2 infection.
Severe COVID-19 criteria (as described in the protocol, based on FDA definition and modified forchildren) were fulfilled for 12 cases (8 COVID-19 mRNA Vaccine and 4 placebo) among participants6 months to 4 years of age. Among participants 6 months through 23 months of age, severe
COVID-19 criteria were fulfilled for 3 cases (2 COVID-19 mRNA Vaccine and 1 placebo).
Immunogenicity analyses have been performed in the immunobridging subset of 82 Study 3participants 6 to 23 months of age and 143 Study 3 participants 2 to 4 years of age without evidence ofinfection up to 1 month after Dose 3 based on a data cut-off date of 29 April 2022.
SARS-CoV-2 50% neutralising antibody titres (NT50) were compared between an immunogenicitysubset of Phase 2/3 participants 6 to 23 months of age and 2 to 4 years of age from Study 3 at 1 monthafter the 3-dose primary course and a randomly selected subset from Study 2 Phase 2/3 participants 16to 25 years of age at 1 month after the 2-dose primary course, using a microneutralisation assayagainst the reference strain (USA_WA1/2020).
The primary immunobridging analyses compared the geometric mean titres (using a geometric meanratio [GMR]) and the seroresponse (defined as achieving at least 4-fold rise in SARS-CoV-2 NT50from before Dose 1) rates in the evaluable immunogenicity population of participants withoutevidence of prior SARS-CoV-2 infection up to 1 month after Dose 3 in participants 6 to 23 months ofage and 2 to 4 years of age and up to 1 month after Dose 2 in participants 16 to 25 years of age. Theprespecified immunobridging criteria were met for both the GMR and the seroresponse difference forboth age groups (Table 9).
Table 9. SARS-CoV-2 GMTs (NT50) and difference in percentages of participants withseroresponse at 1 month after vaccination course - immunobridging subset -participants 6 months to 4 years of age (Study 3) 1 month after Dose 3 andparticipants 16 to 25 years of age (Study 2) 1 month after Dose 2 - without evidenceof SARS-CoV-2 infection - evaluable immunogenicity population
SARS-CoV-2 GMTs (NT50) at 1 month after vaccination course
SARS-CoV-2 neutralization assay - NT50 (titre)e
GMTb GMTb(95% CIb) (95% CIb)(1 month after (1 month after GMRc,d
Age Na Dose 3) Age Na Dose 2) Age (95% CI)2 to16 to 1 180.0 4 years/16 to1 535.2 25 years (1 066.6, 25 years of 1.302 to 4 years 143 (1 388.2, 1 697.8) of age 170 1 305.4) age (1.13, 1.50)6 to23 months16 to 1 180.0 years/16 to6 to 1 406.5 25 years (1 066.6, 25 years of 1.1923 months 82 (1 211.3, 1 633.1) of age 170 1 305.4) age (1.00, 1.42)
Difference in percentages of participants with seroresponse at 1 month after vaccination course
SARS-CoV-2 neutralization assay - NT50 (titre)enf (%) nf (%) Difference in(95% CIg) (95% CIg) seroresponse(1 month after (1 month after rates %h
Age Na Dose 3) Age Na Dose 2) Age (95% CIi)j2 to16 to 4 years/16 to141(100.0) 25 years 168 (98.8) 25 years of 1.22 to 4 years 141 (97.4, 100.0) of age 170 (95.8, 99.9) age (1.5, 4.2)6 to23 months16 to years/16 to6 to 80 (100.0) 25 years 168 (98.8) 25 years of 1.223 months 80 (95.5, 100.0) of age 170 (95.8, 99.9) age (3.4, 4.2)
Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titre;
LLOQ = lower limit of quantitation; NAAT = nucleic acid amplification test; N-binding = SARS-CoV-2nucleoprotein-binding; NT50 = 50% neutralising titre; SARS-CoV-2 = severe acute respiratory syndromecoronavirus 2.
Note: Participants who had no serological or virological evidence [(up to 1 month after Dose 2 (Study 2) or1 month after Dose 3 (Study 3) blood sample collection)] of past SARS-CoV-2 infection [(i.e. N-bindingantibody [serum] negative at Dose 1, Dose 3 (Study 3) and 1 month after Dose 2 (Study 2) or 1 month after
Dose 3 (Study 3), SARS-CoV-2 not detected by NAAT [nasal swab] at Dose 1, Dose 2, and Dose 3 (Study 3)study visits, and negative NAAT (nasal swab) at any unscheduled visit up to 1 month after Dose 2 (Study 2) or1 month after Dose 3 (Study 3) blood collection)] and had no medical history of COVID-19 were included in theanalysis.
Note: Seroresponse is defined as achieving a ≥ 4-fold rise from baseline (before Dose 1). If the baselinemeasurement is below the LLOQ, a postvaccination assay result ≥ 4 × LLOQ is considered a seroresponse.
a. N = Number of participants with valid and determinate assay results for the specified assay at the givendose/sampling time point for GMTs and number of participants with valid and determinate assay results forthe specified assay at both baseline and the given dose/sampling time point for seroresponse rates.
b. GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titres and thecorresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to0.5 × LLOQ.
c. GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of thetitres (younger age group minus 16 to 25 years of age) and the corresponding CI (based on the
Student t distribution).
d. For each younger age group (2 to 4 years, 6 to 23 months), immunobridging based on GMR is declared if thelower bound of the 2-sided 95% CI for the GMR ratio is greater than 0.67 and the point estimate of the GMRis ≥ 0.8.
e. SARS-CoV-2 NT50 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 virusneutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilutionat which 50% of the virus is neutralised.
f. n = Number of participants with seroresponse for the given assay at the given dose/sampling time point.g. Exact 2-sided CI based on the Clopper and Pearson method.h. Difference in proportions, expressed as a percentage (younger age group minus 16 to 25 years of age).i. 2-sided CI, based on the Miettinen and Nurminen method for the difference in proportions, expressed as apercentage.j. For each younger age group (2 to 4 years, 6 to 23 months), immunobridging based on seroresponse rate isdeclared if the lower bound of the 2-sided 95% CI for the difference in proportions is greater than -10.0%provided that the immunobridging criteria based on GMR were met.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with
Comirnaty in the paediatric population in prevention of COVID-19 (see section 4.2 for information onpaediatric use).