Vaccine Information: Pfizer-BioNTech Covid-19 Vaccine, Bivalent (Page 9 of 14)

14.5 Efficacy of 3-Dose Primary Series of Pfizer-BioNTech COVID-19 Vaccine in Participants 6 Months Through 4 Years of Age

Study 3 is an ongoing Phase 1/2/3 multicenter, randomized, dose finding, open label (Phase 1) and multinational, saline placebo-controlled, observer-blind, immunogenicity and efficacy (Phase 2/3) study to evaluate the safety and effectiveness of Pfizer-BioNTech COVID-19 Vaccine in individuals 6 months through 11 years of age. Randomization was stratified by age: 6 through 23 months of age, 2 through 4 years of age, or 5 through 11 years of age. The study excluded participants who were immunocompromised and those who had previous clinical or microbiological diagnosis of COVID-19. Results from participants 6 months through 4 years of age are presented in this subsection. In Phase 2/3, a total of 1,776 participants 6 through 23 months of age and 2,750 participants 2 through 4 years of age were randomized 2:1 and received 3 doses of the Pfizer-BioNTech COVID-19 Vaccine or saline placebo.

Effectiveness in individuals 6 months through 4 years of age is based on a comparison of immune responses in this age group to individuals 16 through 25 years of age.

Immunogenicity in Participants 2 Through 4 Years of Age After a 3-Dose Primary Series

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 cutoff date of April 29, 2022.

The evaluable immunogenicity population without prior evidence of SARS-CoV-2 infection up to 1 month after Dose 3 of Pfizer-BioNTech COVID-19 Vaccine was comprised of 143 participants 2 through 4 years of age. Most participants in this analysis population were White (69.2%), with 5.6% Black or African American participants, 11.2% Asian participants, and 11.9% multiracial participants. There were 11.2% Hispanic/Latino participants. The median age was 3.0 years and 44.1% of participants were male. There were 6.3% of participants reported as obese. In the evaluable immunogenicity population (regardless of evidence of prior infection), 11/204 participants (5.4%) were baseline positive for prior SARS-CoV-2 infection.

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 series 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 series, using a microneutralization assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titers (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 (Table 30 and Table 31, respectively).

Table 30: SARS-CoV-2 GMTs (NT50) at 1 Month After Completion of Primary Vaccination – Immunobridging Subset — Participants 2 Through 4 Years of Age (Study 3) 1 Month After Dose 3 and Participants 16 Through 25 Years of Age (Study 2) 1 Month After Dose 2 – Without Evidence of SARS-CoV-2 Infection – Evaluable Immunogenicity Population

Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titer; LLOQ = lower limit of quantitation; NAAT = nucleic-acid amplification test; NT50 = 50% neutralizing titer; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Note: Participants who had no serological or virological evidence [(up to 1 month after Dose 2 (Study 2) or 1 month after Dose 3 (Study 3) blood sample collection)] of past SARS-CoV-2 infection [(i.e., N-binding antibody [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) or 1 month after Dose 3 (Study 3) blood collection)] and had no medical history of COVID-19 were included in the analysis.
* GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers ([2 through 4 years of age] — [16 through 25 years of age]) and the corresponding CI (based on the Student t distribution). † Immunobridging is declared if the lower bound of the 2-sided 95% CI for the GMR ratio is greater than 0.67 and the point estimate of the GMR is ≥0.8. ‡ n = Number of participants with valid and determinate assay results for the specified assay at the given dose/sampling time point. § GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. ¶ 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 virus neutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.
Assay	Pfizer-BioNTech COVID-19 Vaccine		GMR (95%CI) (2 Through 4 Years of Age/16 Through 25 Years of Age) * , †
	3 mcg modRNA/Dose 2 Through 4 Years of Age (1 Month After Dose 3) n ‡ =143	30 mcg modRNA /Dose 16 Through 25 Years of Age (1 Month After Dose 2) n ‡ =170
	GMT § (95% CI § )	GMT § (95% CI § )
SARS-CoV-2 neutralization assay — NT50 (titer)¶	1535.2 (1388.2, 1697.8)	1180.0(1066.6, 1305.4)	1.30(1.13, 1.50)

Table 31: Difference in Percentages of Participants with Seroresponse at 1 Month After Completion of Primary Vaccination – Immunobridging Subset – Participants 2 Through 4 Years of Age (Study 3) 1 Month after Dose 3 and Participants 16 Through 25 Years of Age (Study 2) 1 Month after Dose 2 Without Evidence of Infection – Evaluable Immunogenicity Population

Abbreviations: LLOQ = lower limit of quantitation; NAAT = nucleic acid amplification test; N-binding = SARS-CoV-2 nucleoprotein–binding; NT50 = 50% neutralizing titer 50; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.Note: Seroresponse is defined as achieving a ≥4-fold rise from baseline (before Dose 1). If the baseline measurement is below the LLOQ, a postvaccination assay result ≥4 × LLOQ is considered a seroresponse. Note: Participants who had no serological or virological evidence (up to 1 month after Dose 2 [(Study 2) or 1 month after Dose 3 (Study 3) blood sample collection)[ of past SARS-CoV-2 infection [(i.e., N-binding antibody [serum] negative at pre-Dose 1, pre-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 pre-Dose 1, pre-Dose 2, and pre-Dose 3 (Study 3) study visits, and negative NAAT (nasal swab) at any unscheduled visit up to 1 month after Dose 2 (Study 2) or 1 month after Dose 3 (Study 3) blood collection)] and had no medical history of COVID-19 were included in the analysis.
* Difference in proportions, expressed as a percentage ([2 through 4 years of age] – [16 through 25 years of age]). † 2-sided CI, based on the Miettinen and Nurminen method for the difference in proportions, expressed as a percentage. ‡ Immunobridging is declared 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. § N = number of participants with valid and determinate assay results both before vaccination and at 1 month after Dose 2. These values are the denominators for the percentage calculations. ¶ n = Number of participants with seroresponse for the given assay at the given dose/sampling time point. # Exact 2-sided CI based on the Clopper and Pearson method. Þ 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 virus neutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.
	Pfizer-BioNTech COVID-19 Vaccine		Difference in Seroresponse Rates % * (95% CI † ) (2 Through 4 Years of Age minus 16 Through 25 Years of Age) ‡
	3 mcg modRNA/Dose 2 Through 4 Years of Age (1 Month After Dose 3) N § =141	30 mcg modRNA/Dose 16 Through 25 Years of Age (1 Month After Dose 2) N § =170
Assay	n ¶ (%) (95% CI # )	n ¶ (%) (95% CI # )
SARS-CoV-2 neutralization assay — NT50 (titer)Þ	141 (100.0)(97.4, 100.0)	168 (98.8)(95.8, 99.9)	1.2(-1.5, 4.2)

Using a non-validated fluorescence focus reduction neutralization 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 [95% CI: 55.4, 122.9]) was increased compared to the NT50 GMT before Dose 3 (14.0 [95% CI: 10.6, 18.5]).

Immunogenicity in Participants 6 Through 23 Months of Age After a 3-Dose Primary Series

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 cutoff date of April 29, 2022.

The evaluable immunogenicity population without prior evidence of SARS-CoV-2 infection up to 1 month after Dose 3 of Pfizer-BioNTech COVID-19 Vaccine was comprised of 82 participants 6 through 23 months of age. Most participants in this analysis population were White (72.0%), with 1.2% Black or African American participants, 13.4% Asian participants, and 12.2% multi-racial participants. There were 15.9% Hispanic/Latino participants. The median age was 16.0 months and 62.2% of participants were male. In the evaluable immunogenicity population (regardless of evidence of prior infection), 6/132 participants (4.5%) were baseline positive for prior SARS-CoV-2 infection.

SARS-CoV-2 NT50 1 month after the vaccination series 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 microneutralization assay against the reference strain (USA_WA1/2020). The primary immunobridging analyses compared the geometric mean titers (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 (Table 32 and Table 33, respectively).

Table 32: SARS-CoV-2 GMTs (NT50) at 1 Month After Completion of Primary Vaccination – Immunobridging Subset — Participants 6 Through 23 Months of Age (Study 3) 1 Month After Dose 3 and Participants 16 Through 25 Years of Age (Study 2) 1 Month After Dose 2 – Without Evidence of SARS-CoV-2– Evaluable Immunogenicity Population

Abbreviations: CI = confidence interval; GMR = geometric mean ratio; GMT = geometric mean titer; LLOQ = lower limit of quantitation; NAAT = nucleic-acid amplification test; NT50 = 50% neutralizing titer; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.Note: Participants who had no serological or virological evidence [(up to 1 month after Dose 2 (Study 2) or 1 month after Dose 3 (Study 3) blood sample collection)] of past SARS-CoV-2 infection (i.e., N-binding antibody [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) or 1 month after Dose 3 (Study 3) blood collection)] and had no medical history of COVID-19 were included in the analysis.
* GMRs and 2-sided 95% CIs were calculated by exponentiating the mean difference of the logarithms of the titers ([6 through 23 months of age] — [16 through 25 years of age]) and the corresponding CI (based on the Student t distribution). † Immunobridging is declared if the lower bound of the 2-sided 95% CI for the GMR ratio is greater than 0.67 and the point estimate of the GMR is ≥0.8. ‡ n = Number of participants with valid and determinate assay results for the specified assay at the given dose/sampling time point. § GMTs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. ¶ 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 virus neutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.
	Pfizer-BioNTech COVID-19 Vaccine		GMR (95%CI) (6 Through 23 months of Age/16 Through 25 Years of Age) * †
	3 mcg modRNA/Dose 6 Through 23 months of Age (1 Month After Dose 3) n ‡ =82	30 mcg modRNA/Dose 16 Through 25 Years of Age (1 Month After Dose 2) n ‡ =170
Assay	GMT § (95% CI § )	GMT § (95% CI § )
SARS-CoV-2 neutralization assay — NT50 (titer)¶	1406.5 (1211.3, 1633.1)	1180.0 (1066.6, 1305.4)	1.19 (1.00, 1.42)

Table 33: Difference in Percentages of Participants with Seroresponse at 1 Month After Completion of Primary Vaccination – Immunobridging Subset – Participants 6 Through 23 months of Age (Study 3) 1 Month After Dose 3 and Participants 16 Through 25 Years of Age (Study 2) to 1 Month After Dose 2 Without Evidence of Infection – Evaluable Immunogenicity Population

Abbreviations: LLOQ = lower limit of quantitation; NAAT = nucleic acid amplification test; N-binding = SARS-CoV-2 nucleoprotein–binding; NT50 = 50% neutralizing titer 50; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.Note: Seroresponse is defined as achieving a ≥4-fold rise from baseline (before Dose 1). If the baseline measurement is below the LLOQ, a postvaccination assay result ≥4 × LLOQ is considered a seroresponse. Note: Participants who had no serological or virological evidence [(up to 1 month after Dose 2 (Study 2) or 1 month after Dose 3 (Study 3) blood sample collection) of past SARS-CoV-2 infection (i.e., N-binding antibody [serum] negative at pre-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 pre-Dose 1, pre-Dose 2, and pre-Dose 3 (Study 3) study visits, and negative NAAT (nasal swab) at any unscheduled visit up to 1 month after Dose 2 (Study 2) or 1 month after Dose 3 (Study 3) blood collection)] and had no medical history of COVID-19 were included in the analysis.
* Difference in proportions, expressed as a percentage ([6 through 23 months of age] – [16 through 25 years of age]). † 2-sided CI, based on the Miettinen and Nurminen method for the difference in proportions, expressed as a percentage. ‡ Immunobridging is declared 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. § N = number of participants with valid and determinate assay results both before vaccination and at 1 month after Dose 2. These values are the denominators for the percentage calculations. ¶ n = Number of participants with seroresponse for the given assay at the given dose/sampling time point. # Exact 2-sided CI based on the Clopper and Pearson method. Þ 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 virus neutralization is read on Vero cell monolayers. The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized.
	Pfizer-BioNTech COVID-19 Vaccine		Difference in Seroresponse Rates % * (95% CI † ) (6 Through 23 months of Age minus 16 Through 25 Years of Age) ‡
	3 mcg modRNA/Dose 6 Through 23 months of Age (1 Month After Dose 3) N § =80	30 mcg modRNA/Dose 16 Through 25 Years of Age (1 Month After Dose 2) N § =170
Assay	n ¶ (%) (95% CI # )	n ¶ (%) (95% CI # )
SARS-CoV-2 neutralization assay — NT50 (titer)Þ	80 (100.0)(95.5, 100.0)	168 (98.8)(95.8, 99.9)	1.2 (-3.4, 4.2)

Using a non-validated fluorescence focus reduction neutralization 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 [95% CI: 90.2, 180.1]) was increased compared to the NT50 GMT before Dose 3 (16.3 [95% CI: 12.8, 20.8]).

Efficacy in Participants 6 Months Through 4 Years of Age After a 3-Dose Primary Series

A descriptive efficacy analysis of Study 3 was performed across the combined population of participants 6 months through 4 years of age based on PCR-confirmed COVID-19 cases among 873 participants in the Pfizer-BioNTech COVID-19 Vaccine group and 381 participants in the placebo group (2:1 randomization) who received 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 cutoff date of June 17, 2022).

The evaluable efficacy population without prior evidence of SARS-CoV-2 infection up to 7 days after Dose 3 of Pfizer-BioNTech COVID-19 Vaccine was comprised of 873 vaccine recipients and 381 placebo recipients 6 months through 4 years of age. Most vaccine recipients in this analysis population were White (76.3%), with 3.4% Black or African American participants, 10.0% Asian participants, and 10.1% who identified as multi-racial, other or not reported. There were 11.2% Hispanic/Latino vaccine recipients. Among the vaccine recipients, 51.1% were female. The median age was 16.0 months in vaccine recipients 6 through 23 months of age and the median age was 3.0 years in vaccine recipients 2 through 4 years of age. In the evaluable efficacy population, 8.7% of vaccine recipients had one or more comorbidities that increase the risk of severe COVID-19 as described in the Morbidity and Mortality Weekly Report (MMWR) 69(32);1081-8 and/or obesity (BMI ≥95^th percentile) for participants 2 through 4 years of age. Between participants who received Pfizer-BioNTech COVID-19 Vaccine and those who received placebo, there were no notable differences in demographics.

The median dose interval between Dose 2 and Dose 3 was 13.4 weeks (range 8 to 33 weeks) among participants 6 through 23 months of age and 10 weeks (range 8 to 34 weeks) among participants 2 through 4 years of age who received Pfizer-BioNTech COVID-19 Vaccine. The median length of blinded follow-up for efficacy after Dose 3 was 1.7 months for participants 6 through 23 months of age and 2.1 months for participants 2 through 4 years of age in the Dose 3 Evaluable Efficacy Population who received Pfizer-BioNTech COVID-19 Vaccine or placebo.

The vaccine efficacy results after Dose 3 in participants 6 months through 4 years of age are presented in Table 34.

Table 34: Vaccine Efficacy – First COVID-19 Occurrence From 7 Days After Dose 3 – Blinded Follow-Up Period – Participants Without Evidence of Infection and Participants With or Without Evidence of Infection Prior to 7 Days After Dose 3 – Phase 2/3 – 6 Months Through 4 Years of Age – Evaluable Efficacy (3-Dose) Population

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.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; diarrhea; vomiting; inability to eat/poor feeding).
* 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 (if available), 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 days after receipt of Dose 3) and had no medical history of COVID-19 were included in the analysis. † N = number of participants in the specified group. ‡ n1 = Number of participants meeting the endpoint definition. § Total surveillance time in 1000 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 3 to the end of the surveillance period. ¶ n2 = Number of participants at risk for the endpoint. # Two-sided 95% confidence interval (CI) for VE is derived based on the Clopper and Pearson method adjusted for surveillance time.
First COVID-19 occurrence from 7 days after Dose 3 in participants without evidence of prior SARS-CoV-2 infection *
Subgroup	Pfizer-BioNTech COVID-19 Vaccine 3 mcg modRNA/Dose N † =873 Cases n1 ‡ Surveillance Time § (n2 ¶ )	Placebo N † =381 Cases n1 ‡ Surveillance Time § (n2 ¶ )	Vaccine Efficacy % (95% CI # )
6 months through 4 years #	130.124 (794)	210.054 (351)	73.2(43.8, 87.6)
2 through 4 years	90.081 (498)	130.033 (204)	71.8(28.6, 89.4)
6 through 23 months	40.042 (296)	80.020 (147)	75.8(9.7, 94.7)
First COVID-19 occurrence from 7 days after Dose 3 in participants with or without evidence of prior SARS-CoV-2 infection
Subgroup	Pfizer-BioNTech COVID-19 Vaccine 3 mcg modRNA/Dose N † =1294 Cases n1 ‡ Surveillance Time § (n2 ¶ )	Placebo N † =612 Cases n1 ‡ Surveillance Time § (n2 ¶ )	Vaccine Efficacy % (95% CI # )
6 months through 4 years #	140.149 (981)	230.067 (459)	72.5 (44.3, 86.9)
2 through 4 years	100.100 (639)	150.044 (286)	70.7(30.3, 88.2)
6 through 23 months	40.048 (342)	80.023 (173)	76.2(11.1, 94.8)

Among participants 6 months through 4 years of age, severe COVID-19 case criteria were fulfilled after Dose 3 in 1 placebo recipient in the 6 through 23-month age group. This case occurred 44 days after Dose 3, based on a single criterion (increased heart rate) and did not require hospitalization. There were no cases of multisystem inflammatory syndrome in children reported through the June 17, 2022 data cutoff date.