Pfizer-BioNTech Covid-19 Vaccine Pharmacological Properties

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The full Summary of Product Characteristics for COMIRNATY is available here.

 

 

 

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: vaccines, other viral vaccines, ATC code: J07BX03

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 neutralizing antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID-19.

Efficacy

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 to 15 years of age, 16 to 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 hospitalization for worsening disease during the 6 weeks before enrolment, were included as were participants with known stable infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV).

Efficacy in participants 16 years of age and older
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 COVID-19 mRNA Vaccine 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 COVID-19 mRNA Vaccine. 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 COVID‑19 mRNA Vaccine.

The population for the analysis of the primary efficacy endpoint 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) 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-19 mRNA 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 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 2.

 

Table 2: Vaccine efficacy – First COVID-19 occurrence from 7 days after Dose 2, by age subgroup – participants without evidence of infection prior to 7 days after Dose 2 – evaluable efficacy (7 days) population
 
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT‑PCR) and at least 1 symptom consistent with COVID-19 [*Case definition: (at least 1 of) fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhoea or vomiting.]
*
Participants who had no serological or virological evidence (prior to 7 days after 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 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 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.
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 method adjusted to the surveillance time. CI not adjusted for multiplicity.

First COVID-19 occurrence from 7 days after Dose 2 in participants without evidence of prior SARS‑CoV-2 infection*

Subgroup

COVID‑19 mRNA Vaccine
Na = 18,198
Cases

n1b
Surveillance timec (n2d)

Placebo
 

Na = 18,325
Cases

n1b
Surveillance timec (n2d)

Vaccine efficacy %
(95% CI)e

All participants

8
2.214 (17,411)

162
2.222 (17,511)

95.0
(90.0, 97.9)

16 to 64 years

7
1.706 (13,549)

143
1.710 (13,618)

95.1
(89.6, 98.1)

65 years and older

1
0.508 (3848)

19
0.511 (3880)

94.7
(66.7, 99.9)

65 to 74 years

1
0.406 (3074)

14
0.406 (3095)

92.9
(53.1, 99.8)

75 years and older

0
0.102 (774)

5
0.106 (785)

100.0
(-13.1, 100.0)

Efficacy of COVID-19 mRNA Vaccine 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, representing up to 6 months after Dose 2 in the efficacy population. 

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 age subgroup – participants without evidence of prior SARS-CoV-2 infection* prior to 7 days after Dose 2 – evaluable efficacy (7 days) population during the placebo‑controlled follow-up period
 
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT‑PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat; diarrhoea; 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 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.
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 Pearson method 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; 16 in the placebo group.

Subgroup

COVID‑19 mRNA Vaccine
Na=20,998
Cases
n1b
Surveillance timec (n2d)

Placebo
Na=21,096
Cases
n1b
Surveillance timec (n2d)

Vaccine efficacy %
(95% CIe)

All participantsf

77
6.247 (20,712)

850
6.003 (20,713)

91.3
(89.0, 93.2)

16 to 64 years

70
4.859 (15,519)

710
4.654 (15,515)

90.6
(87.9, 92.7)

65 years and older

7
1.233 (4192)

124
1.202 (4226)

94.5
(88.3, 97.8)

65 to 74 years

6
0.994 (3350)

98
0.966 (3379)

94.1
(86.6, 97.9)

75 years and older

1
0.239 (842)

26
0.237 (847)

96.2
(76.9, 99.9)

In the updated efficacy analysis, efficacy of COVID-19 mRNA Vaccine in preventing first COVID-19 occurrence from 7 days after Dose 2 compared to placebo was 91.1% (95% CI of 88.8% to 93.0%) in 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 estimates across sexes, ethnic groups, geography and participants with medical comorbidities and obesity associated with high risk of severe COVID-19. 

Efficacy against severe COVID‑19
Updated efficacy analyses of secondary efficacy endpoints supported 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 participants with or without prior SARS-CoV-2 infection (Table 4) 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 COVID‑19 mRNA Vaccine and placebo groups. 
 

Table 4: Vaccine efficacy – First severe COVID-19 occurrence in participants with or without prior 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
 
Note: Confirmed cases were determined by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and at least 1 symptom consistent with COVID-19 (symptoms included: fever; new or increased cough; new or increased shortness of breath; chills; new or increased muscle pain; new loss of taste or smell; sore throat; diarrhoea; vomiting).
*
Severe illness from COVID‑19 as defined by FDA is confirmed COVID‑19 and 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, saturation of oxygen ≤ 93% on room air at sea level, or ratio of arterial oxygen partial pressure to fractional inspired oxygen < 300 mm Hg);
  • Respiratory failure [defined as needing high‑flow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation (ECMO)];
  • Evidence of shock (systolic blood pressure < 90 mm Hg, diastolic blood pressure < 60 mm Hg, or requiring 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 method adjusted to the surveillance time.
d
Efficacy assessed based on the Dose 1 all available efficacy (modified intention-to-treat) population that included 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 group at risk for the endpoint. Time period for COVID-19 case accrual is from Dose 1 to the end of the surveillance period.
f
Efficacy assessed based on the evaluable efficacy (7 Days) population that included all eligible randomised participants who receive all dose(s) of study intervention as randomised within the predefined window, have no 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 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.

 

COVID‑19 mRNA Vaccine
Cases
n1a
Surveillance time (n2b)

Placebo
Cases
n1a
Surveillance time (n2b)

Vaccine efficacy %
(95% CIc)

After Dose 1d

1
8.439e (22,505)

30
8.288e (22,435)

96.7
(80.3, 99.9)

7 days after Dose 2f

1
6.522g (21,649)

21
6.404g (21,730)

95.3
(70.9, 99.9)

Efficacy and immunogenicity in adolescents 12 to 15 years of age   
 
In an analysis of Study 2 in adolescents 12 to 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 SARSCoV-2 infection up to 1 month after Dose 2, comparing the response in adolescents 12 to 15 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 years of age group was 1.76, with a 2sided 95% CI of 1.47 to 2.10. Therefore, the 1.5fold noninferiority criterion was met as the lower bound of the 2sided 95% CI for the geometric mean ratio [GMR] was > 0.67.

Paediatric population

The 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 on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data 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 neutralizing 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.