Abstract
Introduction
COVID-19 continues to cause substantial health burden, particularly among vulnerable populations. Vaccines remain a vital tool in preventing severe disease outcomes. As the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve; therefore, updates may be needed to closely match COVID-19 vaccine composition to predominant circulating lineages to confer optimal protection.
Methods
In this cohort from a substudy of an ongoing phase 2/3 trial, 102 healthy adults (18‒55 and > 55 years of age, n = 51 each) were vaccinated with Omicron KP.2-adapted BNT162b2. Serum neutralizing titers against Omicron KP.2, JN.1, and KP.3 were assessed before and through 1 month after vaccination. Immunogenicity in KP.2-adapted BNT162b2 recipients was compared with participants who received JN.1-adapted BNT162b2 in an earlier cohort of this substudy. Local reactions and systemic events through 7 days and adverse events (AEs) through 1 month are reported.
Results
One month after vaccination, KP.2-adapted BNT162b2-elicited neutralizing titers against Omicron KP.2, JN.1, and KP.3 were numerically higher than those induced by JN.1-adapted BNT162b2. Geometric mean fold rises from before to 1 month after vaccination were numerically higher in those who received KP.2-adapted BNT162b2 compared with those who received JN.1-adapted BNT162b2 (9.4 vs. 6.8 for KP.2; 7.8 vs. 5.7 for JN.1; 9.2 vs. 7.0 for KP.3). Percentages of participants with seroresponses were numerically higher against KP.2 after KP.2-adapted BNT162b2 than JN.1-adapted BNT162b2 (75% vs. 65%) and similar against JN.1 and KP.3 for both vaccines (69% vs. 67% for JN.1; 74% vs. 73% for KP.3). Local reactions and systemic events were all mild to moderate in severity, AEs were infrequent, and no serious AEs or AEs leading to withdrawal were reported.
Conclusions
Collectively, these immunogenicity, safety, and tolerability data support administration of KP.2-adapted BNT162b2 to protect against contemporaneous circulating lineages.
ClinicalTrials.gov Identifier
Supplementary Information
The online version contains supplementary material available at 10.1007/s40121-025-01185-4.
Keywords: BNT162b2, Booster, COVID-19, Lineage, Omicron KP.2, SARS-CoV-2 vaccine, Sublineage, Variant adapted
Key Summary Points
| Why carry out this study? |
| Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve toward antigenically distinct lineages; therefore, regular updates to COVID-19 vaccines (such as BNT162b2) that most closely match dominant circulating lineages may be needed to optimize immune responses to SARS-CoV-2 and protection against COVID-19. |
| To further support the use of variant-adapted COVID-19 vaccines, we assessed the immunogenicity, safety, and tolerability through 1 month after vaccination of adults with Omicron KP.2-adapted BNT162b2 in a cohort of a substudy from a phase 2/3 trial. |
| What was learned from the study? |
| The KP.2-adapted BNT162b2 vaccine induced robust SARS-CoV-2–neutralizing responses against Omicron KP.2, JN.1, and KP.3 that were higher than those induced by JN.1-adapted BNT162b2; in addition, KP.2-adapted BNT162b2 demonstrated a favorable safety and tolerability profile. |
| These data are consistent with preclinical immunogenicity results that supported approval of the KP.2-adapted BNT162b2 vaccine. |
Introduction
COVID-19 is no longer a public health emergency of international concern; however, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause infections globally and accounts for a substantial health burden, particularly among older adults, pregnant individuals, and those with chronic illnesses or immunocompromising conditions [1, 2]. Vaccination against COVID-19 remains an important tool to prevent severe disease and death [1].
SARS-CoV-2 continues to evolve, with new variants emerging during endemic waves of infection [3, 4]. These variants have the potential to differ in terms of transmissibility, degree of immune evasion, and disease severity [3]. The Omicron variant, which became predominant globally from December 2021 and, along with its sublineages, exhibited a high level of immune escape compared with earlier variants, has necessitated periodic vaccine updates because of antigenic shifts [5–7]. In the United States in January 2025, descendants of the Omicron JN.1 lineage, including XEC, LP.8.1, and KP.3.1.1, comprised more than 90% of COVID-19 cases [8].
BNT162b2 is a modified messenger RNA vaccine that encodes variant-spike glycoprotein and is approved for the prevention of COVID-19 caused by SARS-CoV-2 [9, 10]. Booster doses with the original BNT162b2 provided a relatively short period of protection against Omicron sublineages [11, 12], and five variant-adapted vaccines have been approved subsequently, including bivalent BNT162b2 vaccines that encoded Wuhan-Hu-1 and Omicron BA.1 or BA.4/BA.5 spike glycoproteins and monovalent Omicron XBB.1.5, JN.1, and KP.2 variant-adapted BNT162b2 [13–15].
SARS-CoV-2 continues its evolution to new, antigenically distinct lineages, resulting in immune escape and diminished vaccine effectiveness [3]. Additionally, real-world evidence, including for KP.2-adapted BNT162b2, suggests that vaccine antigens more closely matched to circulating strains can improve protection against COVID-19 [16, 17]. Therefore, updates to BNT162b2 that are intended to closely match predominant circulating Omicron lineages or new distinct lineages will likely continue to be needed in preparation for annual autumn/winter respiratory virus seasons. The aim of this analysis from a clinical trial investigating variant-adapted COVID-19 vaccines is to provide 1-month immunogenicity and safety data of KP.2-adapted BNT162b2. This analysis also describes immune responses with KP.2-adapted BNT162b2, together with reported immune responses observed with an earlier population who received JN.1-adapted BNT162b2 from the same trial.
Methods
Study Design and Participants
This is an open-label substudy from an ongoing phase 2/3 trial (ClinicalTrials.gov Identifier: NCT05997290) evaluating the immunogenicity, safety, and tolerability of variant-adapted BNT162b2 vaccines. Methodologies and findings for the XBB.1.5-adapted and JN.1-adapted BNT162b2 vaccines at the 30-μg dose level from an earlier substudy and an earlier cohort of the current substudy, respectively, were reported previously [18–20]. In the current single-arm, nonrandomized cohort of this substudy, approximately 50 participants 18–55 years of age and 50 participants > 55 years of age were to receive a single KP.2-adapted BNT162b2 vaccine (lot number LL9838Y) at the 30-µg dose level by intramuscular injection. Neither participants nor study investigators or staff were blinded to study intervention.
Healthy participants who had either never received a COVID-19 vaccine or had previously received COVID-19 vaccination at least 150 days before study vaccination were eligible for enrollment. Participants who had a history of severe adverse reaction associated with vaccination, were immunocompromised or had known or suspected immunodeficiency or were receiving immunosuppressant medication, were pregnant or breastfeeding, had a condition associated with prolonged bleeding, or had a history of myocarditis or pericarditis were excluded.
Ethical Approval
The study protocol was approved by the WCG Central institutional review board (approval number: 20233321; Princeton, NJ, USA), which was utilized by each study site. This substudy was conducted according to the protocol and consensus ethical principles derived from international guidelines (i.e., Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines), applicable good clinical practice guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and other relevant laws and regulations. All participants were required to provide a signed statement of informed consent before study-specific procedures were performed.
Assessments
Serum samples for immunogenicity assessments were obtained before vaccination; 7 and 14 days after vaccination; and 1, 3, and 6 months after vaccination (reported here are immunogenicity assessments before and 14 days and 1 month after vaccination). Serum samples were tested in fluorescent focus reduction neutralization tests (FFRNTs) to assess immune responses against Omicron KP.2, JN.1, and KP.3 SARS-CoV-2 lineages. Neutralizing responses were analyzed and presented as neutralizing antibody geometric mean titers (GMTs) before and 14 days and 1 month after vaccination, as geometric mean fold rises (GMFRs) from before vaccination to 14 days or to 1 month after vaccination, and as percentages of participants with seroresponse at each time point after vaccination both overall and by age group (i.e., 18–55 and > 55 years of age). For immunogenicity assessments, adult participants who received JN.1-adapted BNT162b2 in another cohort of this substudy [20] were used as a comparator at matched time points.
Participants used an electronic diary to record local reactions and systemic events during a 7-day collection period after vaccination (severity gradings of local reactions and systemic events are described in Table S1). Per the protocol, adverse events (AEs) and serious AEs (SAEs) were collected through 1 month and 6 months after vaccination, respectively (reported here are AEs and SAEs through 1 month after vaccination). AEs of special interest (AESIs) included confirmed diagnoses of myocarditis or pericarditis occurring through 6 weeks after vaccination and potential menstrual cycle disturbances until 6 months after vaccination and, together with surveillance for cases of COVID-19, were assessed herein through the data cutoff date (October 16, 2024).
Statistics
No formal hypothesis testing or sample size determinations were undertaken for these descriptive analyses. Immunogenicity analyses were performed in the evaluable immunogenicity population, which was defined as all participants who received study vaccination (i.e., KP.2-adapted BNT162b2 for the current cohort or JN.1-adapted BNT162b2 for the comparator group), had valid and determinate immunogenicity results from samples collected between 28 and 42 days after vaccination, and had no major protocol deviations. Safety and tolerability analyses were performed in all participants who received KP.2-adapted BNT162b2 (i.e., the safety population).
The geometric means were calculated as the mean of the neutralization assay results after logarithmic transformation and then exponentiation of the mean to express results on the original scale. GMFRs were calculated as the mean of the difference of logarithmically transformed assay results (14 days or 1 month after vaccination time point minus before vaccination time point) and exponentiating the mean. The two-sided 95% CIs for GMTs and GMFRs were obtained by constructing CIs using the Student t distribution for the mean (for GMTs) or the mean difference (for GMFRs) on the logarithmic scale and exponentiating the CIs. Seroresponse was defined as achieving ≥ 4-fold rise from before vaccination or ≥ 4 × the lower limit of quantitation (LLOQ) for prevaccination measurements < LLOQ at time points after vaccination for each sublineage-specific neutralizing titer. The Clopper–Pearson method was used to calculate the two-sided 95% CIs for the percentages of participants with seroresponse.
Results
Participants
From September 5–11, 2024, 102 participants (18–55-year-olds, n = 51; > 55-year-olds, n = 51) at 8 sites in the United States received KP.2-adapted BNT162b2 (the corresponding date range for receipt of JN.1-adapted BNT162b2 in the comparator group was May 10–14, 2024). All but 1 participant who received KP-2-adapted BNT162b2 completed the 1-month postvaccination visit (an 18–55-year-old participant withdrew from the study; Figure S1).
In the safety population, 60.8% of participants were female, 74.5% were white, and the mean (SD) age at vaccination was 54.1 (15.1) years (Table 1). Overall, 91.2% of participants were SARS-CoV-2 positive at baseline, 90.2% had received previous COVID-19 vaccinations, and the median (range) duration since the previous COVID-19 vaccine was 13.3 (7.4–46.8) and 18.9 (5.5–47.3) months in 18–55-year-olds and > 55-year-olds, respectively.
Table 1.
Baseline demographic characteristics
| Characteristic | KP.2-adapted BNT162b2 30 µg | Total (N = 102) | |
|---|---|---|---|
| 18–55 years (N = 51) | > 55 years (N = 51) | ||
| Sex, n (%) | |||
| Male | 16 (31.4) | 24 (47.1) | 40 (39.2) |
| Female | 35 (68.6) | 27 (52.9) | 62 (60.8) |
| Race, n (%) | |||
| White | 39 (76.5) | 37 (72.5) | 76 (74.5) |
| Black | 6 (11.8) | 7 (13.7) | 13 (12.7) |
| Asian | 4 (7.8) | 6 (11.8) | 10 (9.8) |
| Multiracial | 2 (3.9) | 1 (2.0) | 3 (2.9) |
| Ethnicity, n (%) | |||
| Hispanic/Latino | 6 (11.8) | 9 (17.6) | 15 (14.7) |
| Non-Hispanic/non-Latino | 44 (86.3) | 42 (82.4) | 86 (84.3) |
| Not reported | 1 (2.0) | 0 | 1 (1.0) |
| Age at vaccination, years | |||
| Mean (SD) | 41.2 (8.55) | 67.1 (6.59) | 54.1 (15.05) |
| Median (range) | 41.0 (19–54) | 67.0 (56–83) | 55.0 (19–83) |
| Baseline SARS-CoV-2 status,a n (%) | |||
| Positive | 46 (90.2) | 47 (92.2) | 93 (91.2) |
| Medical history of COVID-19 | 24 (47.1) | 19 (37.3) | 43 (42.2) |
| Positive N-binding | 46 (90.2) | 46 (90.2) | 92 (90.2) |
| Positive NAAT | 3 (5.9) | 4 (7.8) | 7 (6.9) |
| Negative | 5 (9.8) | 4 (7.8) | 9 (8.8) |
| Received previous COVID-19 vaccine, n (%) | 46 (90.2) | 46 (90.2) | 92 (90.2) |
| Dose 1 | 46 (90.2) | 46 (90.2) | 92 (90.2) |
| Dose 2 | 41 (80.4) | 43 (84.3) | 84 (82.4) |
| Dose 3 | 34 (66.7) | 37 (72.5) | 71 (69.6) |
| Dose 4 | 32 (62.7) | 25 (49.0) | 57 (55.9) |
| Dose 5 | 23 (45.1) | 18 (35.3) | 41 (40.2) |
| Dose 6 | 3 (5.9) | 10 (19.6) | 13 (12.7) |
| Dose 7 | 1 (2.0) | 3 (5.9) | 4 (3.9) |
| Dose 8 | 0 | 2 (3.9) | 2 (2.0) |
| Time from last dose of COVID-19 vaccine to the study vaccination | |||
| n | 46 | 46 | 92 |
| Mean (SD), months | 18.0 (10.64) | 21.9 (12.79) | 20.0 (11.86) |
| Median (range), months | 13.3 (7.4–46.8) | 18.9 (5.5–47.3) | 13.8 (5.5–47.3) |
| 5–< 12 months, n (%) | 13 (25.5) | 13 (25.5) | 26 (25.5) |
| 12–24 months, n (%) | 21 (41.2) | 14 (27.5) | 35 (34.3) |
| > 24 months, n (%) | 12 (23.5) | 19 (37.3) | 31 (30.4) |
Data are for the safety population
N-binding SARS-CoV-2 nucleoprotein-binding, NAAT nucleic acid amplification test, SARS-CoV-2 severe acute respiratory coronavirus 2
aBaseline positivity determined by N-binding antibody result at baseline, positive NAAT result at baseline, or medical history of COVID-19
Demographic characteristics for the evaluable immunogenicity population of the current cohort who received KP.2-adapted BNT162b2 and the comparator group who received JN.1-adapted BNT162b2 are provided in Table 2. The median (range) time from the most recent COVID-19 vaccination to receipt of study vaccination in the comparator group was 19.3 (5.6‒41.0) months and 9.8 (7.0‒35.4) months in 18–55-year-olds and > 55-year-olds, respectively (compared with 13.3 [7.4–46.8] months and 21.0 [5.5–47.3] months in the group of 18–55-year-old and > 55-year-old participants who received KP.2-adapted BNT162b2 in the current cohort).
Table 2.
Demographic characteristics of participants who received KP.2-adapted BNT162b2 or JN.1-adapted BNT162b2 in the current substudy
| Characteristic | KP.2-adapted BNT162b2 30 μg | JN.1-adapted BNT162b2 30 μg | ||||
|---|---|---|---|---|---|---|
| 18–55 years (N = 50) | > 55 years (N = 50) | Total (N = 100) | 18–55 years (N = 27) | > 55 years (N = 24) | Total (N = 51) | |
| Sex, n (%) | ||||||
| Male | 16 (32.0) | 24 (48.0) | 40 (40.0) | 12 (44.4) | 8 (33.3) | 20 (39.2) |
| Female | 34 (68.0) | 26 (52.0) | 60 (60.0) | 15 (55.6) | 16 (66.7) | 31 (60.8) |
| Race, n (%) | ||||||
| White | 38 (76.0) | 37 (74.0) | 75 (75.0) | 15 (55.6) | 17 (70.8) | 32 (62.7) |
| Black or African American | 6 (12.0) | 7 (14.0) | 13 (13.0) | 9 (33.3) | 3 (12.5) | 12 (23.5) |
| Asian | 4 (8.0) | 5 (10.0) | 9 (9.0) | 2 (7.4) | 2 (8.3) | 4 (7.8) |
| Native Hawaiian or other Pacific Islander | 0 | 0 | 0 | 0 | 1 (4.2) | 1 (2.0) |
| Multiracial | 2 (4.0) | 1 (2.0) | 3 (3.0) | 0 | 1 (4.2) | 1 (2.0) |
| Not reported | 0 | 0 | 0 | 1 (3.7) | 0 | 1 (2.0) |
| Ethnicity, n (%) | ||||||
| Hispanic/Latino | 6 (12.0) | 9 (18.0) | 15 (15.0) | 8 (29.6) | 8 (33.3) | 16 (31.4) |
| Non-Hispanic/non-Latino | 43 (86.0) | 41 (82.0) | 84 (84.0) | 19 (70.4) | 16 (66.7) | 35 (68.6) |
| Not reported | 1 (2.0) | 0 | 1 (1.0) | 0 | 0 | 0 |
| Age at vaccination, years | ||||||
| Mean (SD) | 41.2 (8.63) | 66.9 (6.50) | 54.0 (14.97) | 38.0 (10.58) | 67.8 (7.51) | 52.0 (17.58) |
| Median (range) | 41.5 (19–54) | 67.0 (56–83) | 55.0 (19–83) | 41.0 (18–54) | 65.5 (56–83) | 51.0 (18–83) |
| Baseline SARS-CoV-2 status,a n (%) | ||||||
| Positive | 45 (90.0) | 46 (92.0) | 91 (91.0) | 26 (96.3) | 20 (83.3) | 46 (90.2) |
| Medical history of COVID-19 | 23 (46.0) | 18 (36.0) | 41 (41.0) | 10 (37.0) | 5 (20.8) | 15 (29.4) |
| Positive N-binding | 45 (90.0) | 45 (90.0) | 90 (90.0) | 26 (96.3) | 19 (79.2) | 45 (88.2) |
| Positive NAAT | 3 (6.0) | 3 (6.0) | 6 (6.0) | 1 (3.7) | 0 | 1 (2.0) |
| Negative | 5 (10.0) | 4 (8.0) | 9 (9.0) | 1 (3.7) | 4 (16.7) | 5 (9.8) |
| Received previous COVID-19 vaccine, n (%) | 45 (90.0) | 45 (90.0) | 90 (90.0) | 24 (88.9) | 23 (95.8) | 47 (92.2) |
| Time from last dose of mRNA COVID-19 vaccine to the study vaccination | ||||||
| n | 45 | 45 | 90 | 24 | 23 | 47 |
| Mean (SD), months | 18.2 (10.70) | 22.1 (12.84) | 20.2 (11.92) | 19.1 (11.01) | 15.6 (9.63) | 17.3 (10.40) |
| Median (range), months | 13.3 (7.4–46.8) | 21.0 (5.5–47.3) | 13.9 (5.5–47.3) | 19.3 (5.6–41.0) | 9.8 (7.0–35.4) | 16.0 (5.6–41.0) |
| 5 – < 12 months, n (%) | 12 (24.0) | 12 (24.0) | 24 (24.0) | 10 (37.0) | 12 (50.0) | 22 (43.1) |
| 12–24 months, n (%) | 21 (42.0) | 14 (28.0) | 35 (35.0) | 6 (22.2) | 6 (25.0) | 12 (23.5) |
| > 24 months, n (%) | 12 (24.0) | 19 (38.0) | 31 (31.0) | 8 (29.6) | 5 (20.8) | 13 (25.5) |
Data are for the evaluable immunogenicity population
mRNA modified messenger RNA, N-binding SARS-CoV-2 nucleoprotein-binding, NAAT nucleic acid amplification test, SARS-CoV-2 severe acute respiratory coronavirus 2
aBaseline positivity determined by N-binding antibody result at baseline, positive NAAT result at baseline, or medical history of COVID-19
Immunogenicity
Overall, 100 participants who received KP.2-adapted BNT162b2 were included in the evaluable immunogenicity population; two participants (one from each age group) were excluded because they did not have ≥ 1 valid and determinate immunogenicity result within the 28 to 42-day window after study vaccination, as specified in the protocol. Overall, 51 participants who received JN.1-adapted BNT162b2 in the comparator group were included in the evaluable immunogenicity population; three participants (18–55-year-olds, n = 1; > 55-year-olds, n = 2) were excluded from the evaluable immunogenicity population because they did not have ≥ 1 valid and determinate immunogenicity result within the protocol-specified window. In addition, the one 18 to 55-year-old participant did not receive study vaccination.
For KP.2-adapted BNT162b2, SARS-CoV-2 FFRNT 50% neutralizing titers against Omicron KP.2, JN.1, and KP.3 were substantially increased at 14 days and at 1 month after vaccination compared with baseline levels and were numerically higher at both postvaccination time points for the three lineages than those among the comparator group of participants who received JN.1-adapted BNT162b2 (Fig. 1; Table S2). Overall GMTs (95% CIs) at 1 month after receipt of KP.2-adapted BNT162b2 were 914.6 (684.7, 1221.7) for KP.2, 1021.8 (772.6, 1351.5) for JN.1, and 725.0 (543.0, 968.2) for KP.3. Corresponding values for JN.1-adapted BNT162b2 were 574.1 (407.8, 808.0) for KP.2, 728.2 (536.4, 988.6) for JN.1, and 437.4 (318.2, 601.3) for KP.3.
Fig. 1.
Serum-neutralizing GMTs (95% CIs) and GMFRs for all participants before and 14 days and 1 month after vaccination with KP.2-adapted or JN.1-adapted BNT162b2 30 μg to Omicron KP.2, JN.1, and KP.3. Data are for the evaluable immunogenicity population. Assay results < LLOQ were set to 0.5 × LLOQ. Values above bars are GMFRs from before to 14 days after vaccination (gray text) and from before to 1 month after vaccination (black italicized text). GMFRs with associated 95% CIs are in Table S2. 14d 14 days after vaccination, 1m 1 month after vaccination, FFRNT fluorescent focus reduction neutralization test, GMFR geometric mean fold rise, GMT geometric mean titer, LLOQ lower limit of quantitation
Overall GMFRs (95% CIs) from baseline to 1 month after receipt of KP.2-adapted BNT162b2 were 9.4 (7.0, 12.7) for KP.2, 7.8 (5.8, 10.4) for JN.1, and 9.2 (6.8, 12.3) for KP.3 (Fig. 1; Table S3). Corresponding GMFRs for JN.1-adapted BNT162b2 were 6.8 (5.0, 9.4) for KP.2, 5.7 (4.2, 7.7) for JN.1, and 7.0 (5.4, 9.0) for KP.3.
In both age groups, neutralizing titers generally peaked 14 days after vaccination and remained high 1 month after vaccination (Fig. 2; Table S2). One month after vaccination with KP.2-adapted BNT162b2, participants > 55 years of age had numerically higher GMTs against the 3 sublineages than those 18–55 years of age (KP.2, 1004 vs. 833; JN.1, 1114 vs. 937; KP.3, 777 vs. 677). For both age groups, GMTs at 14 days and at 1 month after vaccination with KP.2-adapted BNT162b2 were higher compared with JN.1-adapted BNT162b2 than with JN.1-adapted BNT162b2 against the 3 sublineages (KP.2: 14 days, 1084–1107 vs. 538–700; 1 month, 833–1004 vs. 486–655, JN.1: 1122–1186 vs. 708–871; 937–1114 vs. 698–756, and KP.3: 799–880 vs. 466–563; 677–777 vs. 403–470).
Fig. 2.
Serum-neutralizing GMTs (95% CIs) and GMFRs by age group before and 14 days and 1 month after vaccination with KP.2-adapted or JN.1-adapted BNT162b2 30 μg to Omicron KP.2 (a), JN.1 (b), and KP.3 (c). Data are for the evaluable immunogenicity population. Assay results < LLOQ were set to 0.5 × LLOQ. Numbers within the bars are GMTs. Values above bars are GMFRs from before to 14 days after vaccination (gray text) and from before to 1 month after vaccination (black italicized text). GMFRs with associated 95% CIs are in Table S2. 14d 14 days, 1m 1 month after vaccination, FFRNT fluorescent focus reduction neutralization test, GMFR geometric mean fold rise, GMT geometric mean titer, LLOQ lower limit of quantitation, Pre before vaccination
The percentages of overall participants with seroresponses were slightly higher against KP.2 (75% vs. 65%) and similar against JN.1 and KP.3 in participants receiving KP.2-adapted BNT162b2 compared with participants receiving JN.1-adapted BNT162b2 (Fig. 3).
Fig. 3.
Participants achieving seroresponse (95% CIs) 1 month after vaccination with KP.2-adapted BNT162b2 30 μg and JN.1-adapted BNT162b2 30 μg a overall and b by age group. Data are for the evaluable immunogenicity population. Seroresponse was defined as ≥ 4-fold rise from before vaccination in FFRNT 50% serum neutralizing titers. If participants had a baseline measurement < LLOQ, seroresponse was defined as a postvaccination assay result of ≥ 4 × LLOQ. FFRNT fluorescent focus reduction neutralization test, LLOQ lower limit of quantitation
Safety
Local reactions reported within 7 days of receipt of KP.2-adapted BNT162b2 were mild or moderate in severity (Fig. 4a). Pain at the injection site was the most common local reaction (58.8% of participants overall) and was more frequently reported among 18–55-year-olds (72.5%) than in > 55-year-olds (45.1%). The median onset and median duration of local reactions were both 1 to 3 days.
Fig. 4.
Local reactions (a) and systemic events (b) occurring within 7 days after receipt of KP.2-adapted BNT162b2 30 μg. Data are for the safety population. Numbers above the bars are the percentage of participants in each group reporting the specified local reaction or systemic event. The N values are 51, 51, and 102 for 18–55-year-olds, > 55-year-olds, and the total population, respectively
Systemic events reported within 7 days of receipt of KP.2-adapted BNT162b2 were also all mild to moderate in severity (Fig. 4b). The most frequently reported systemic events were fatigue, headache, and muscle pain (46.1%, 28.4%, and 21.6%, respectively, in the overall population), and all were reported more commonly among 18–55-year-olds than among > 55-year-olds (58.8% vs. 33.3%, 39.2% vs. 17.6%, and 33.3% vs. 9.8%). The median onset and median duration of systemic events were 2 to 4 days and 1 to 5 days, respectively.
Adverse events reported within 1 month of receipt of KP.2-adapted BNT162b2 were reported in 8.8% of participants overall and were more common among 18–55-year-olds (13.7%) than among > 55-year-olds (3.9%). One 18–55-year-old experienced an AE that was considered related to vaccination by the investigator (grade 1 bilateral breast tenderness that developed the day after vaccination and lasted 6 days in a female participant). No SAEs, AEs leading to withdrawal, or AESIs were reported. One case of COVID-19 was reported in an 18–55-year-old participant; this case occurred 22–28 days after vaccination and was of unknown lineage and not severe.
Discussion
This phase 2/3 study of the monovalent Omicron KP.2-adapted BNT162b2 vaccine in adults ≥ 18 years of age showed that KP.2-adapted BNT162b2 induced robust neutralizing responses against a panel of SARS-CoV-2 Omicron lineages (i.e., KP.2 and JN.1, as well as KP.3). The KP.3 lineage was tested as it and its daughter lineages were dominant at the time the current analyses were performed [8]. These robust neutralizing responses are consistent with preclinical investigations supporting approval of the KP.2-adapted vaccine, as well as previously published reports from earlier substudies from the same trial in which monovalent XBB.1.5-adapted BNT162b2 and JN.1-adapted BNT162b2 elicited robust neutralizing responses to antigenically similar Omicron sublineages [18–21].
In the current analysis, GMTs and GMFRs were numerically higher 1 month after vaccination against KP.2, JN.1, and KP.3 among participants who received KP.2-adapted BNT162b2 than for those who received JN.1-adapted BNT162b2. Notably, although there was a trend towards higher titers for the KP.2-adapted versus JN.1-adapted BNT162b2, available real-world evidence supports the effectiveness of both variant-adapted vaccines against COVID-19 [17, 22].
Although this analysis was not powered to detect differences in immune responses between cohorts, the results are nevertheless encouraging and highlight the importance of updating COVID-19 vaccines to antigenically matched strains for each season. Antigenic matching of vaccines is further supported by the observation that GMFRs from before to 1 month after vaccination with KP.2-adapted BNT162b2 for the closely related parental JN.1 lineage were slightly lower (7.8) compared with KP.2 and KP.3 lineages (9.4 and 9.2, respectively).
In the current cohort, the younger group of participants, 18–55 years of age, had higher baseline titers than the participants > 55 years of age. The reasons for this are not definitive but the shorter interval from last COVID-19 vaccination for the younger age group compared with the older age group (median of 13.3 vs. 18.9 months) might be contributory. A serologic survey also recently reported that increasing the number of exposures to SARS-CoV-2, through vaccination or natural infection, results in higher and more durable immune responses, highlighting the importance of booster doses to maintain immunity to help protect against severe disease and hospitalization [23].
The KP.2-adapted BNT162b2 vaccine had a favorable safety and tolerability profile that was consistent with data reported earlier from this trial for XBB.1.5-adapted and JN.1-adapted BNT162b2 [18, 20] and with phase 2/3 clinical trial data for the original and earlier bivalent versions of the vaccine in healthy adult populations [24–26]. All reactogenicity events occurring within 7 days of receipt of KP.2-adapted BNT162b2 were mild or moderate in severity; AEs were reported infrequently; and there were no SAEs, AESIs, or AEs leading to withdrawal occurring through 1 month after vaccination.
A study strength is the inclusion of participants regardless of SARS-CoV-2 seropositivity and COVID-19 vaccination status, reflecting real-world conditions. Limitations of this descriptive analysis include the relatively short 1-month follow-up and small study population size for assessment of the durability of neutralizing immune responses and safety following receipt of KP.2-adapted BNT162b2. Additional safety follow-up in this substudy and through ongoing safety surveillance, along with real-world evidence, should provide additional clarity on the durability of neutralizing immune responses and the safety profile of this vaccine. This was also not a direct randomized comparison but instead used a group of age-matched participants from an earlier cohort from this trial to assess potential differences in neutralizing immune responses between KP.2-adapted and JN.1-adapted BNT162b2. Therefore, there was potential for biases and confounding variables, including temporal differences since previous COVID-19 vaccination, between the two groups. Finally, this study population consisted of healthy US adults, which may limit generalizability of these findings to other populations and age groups.
Conclusions
These immunogenicity, safety, and tolerability findings support the administration of KP.2-adapted BNT162b2 in adults, which is in use in the United States and some countries within the European Union [14, 15, 27]. These data remain consistent with the preclinical and clinical data seen with previous variant-adapted vaccines [18–21, 28].
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the participants and the study site personnel for their contributions to this study; Tracy Aviles, Izabela Bialach-Lastowiecka, Pankaj Bhoir, Prajakta Chivate, Rucha Dadhe, Marie Hodrinsky, Richa Kala, Jeff Lu, Laura Melo, Prathamesh Rode, Carolyn Ryan, Helen Smith, Naren Surampali, Julia Usenko, Kathryn Elaine Vollmer, Caroline Westgarth, and Sara Wren from Pfizer; Nicola Charpentier, Mary Marovich, Ruben Rizzi, and Nadine Salisch from BioNTech; and the Pfizer and BioNTech colleagues not named here who contributed to the success of this trial.
Medical Writing, Editorial, and Other Assistance
Medical writing support was provided by Sheena Hunt, PhD, and Tricia Newell, PhD, of ICON (Blue Bell, PA), and was funded by Pfizer Inc.
Author Contributions
Conceptualization: Oyeniyi Diya, Juleen Gayed, Francine S. Lowry, Hua Ma, Vishva Bangad, Federico Mensa, Xia Xu, Kena A. Swanson, Kayvon Modjarrad, and Nicholas Kitchin. Methodology: Oyeniyi Diya, Juleen Gayed, Francine S. Lowry, Hua Ma, Vishva Bangad, Jing Zou, Xuping Xie, Yanping Hu, Mark Cutler, David Cooper, Xia Xu, Kena A. Swanson, Kayvon Modjarrad, and Nicholas Kitchin. Formal analysis and investigation: Oyeniyi Diya, Juleen Gayed, Francine S. Lowry, Hua Ma, Vishva Bangad, Federico Mensa, David Cooper, Xia Xu, and Nicholas Kitchin. Supervision: Juleen Gayed, David Cooper, Robin Mogg, Özlem Türeci, Uǧur Şahin, Kena A. Swanson, Kayvon Modjarrad, Annaliesa S. Anderson, Alejandra Gurtman, and Nicholas Kitchin. Writing review and editing: Oyeniyi Diya, Juleen Gayed, Francine S. Lowry, Hua Ma, Vishva Bangad, Federico Mensa, Jing Zou, Xuping Xie, Yanping Hu, Mark Cutler, Todd Belanger, David Cooper, Xia Xu, Robin Mogg, Özlem Türeci, Uǧur Şahin, Kena A. Swanson, Xia Xu, Kena A. Swanson, Kayvon Modjarrad, Annaliesa S. Anderson, Alejandra Gurtman, and Nicholas Kitchin. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This study was sponsored by BioNTech and funded by Pfizer Inc and BioNTech. The Rapid Service Fee was funded by Pfizer Inc.
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
Declarations
Conflicts of Interest
Federico Mensa, Özlem Türeci, and Uǧur Şahin are BioNTech employees and may hold stock or stock options. Özlem Türeci, Uǧur Şahin, Kena A. Swanson, and Kayvon Modjarrad report holding an interest in a patent relevant to this manuscript. Jing Zou, Xuping Xie, and Yanping Hu have received funding from Pfizer. Oyeniyi Diya is no longer an employee at Pfizer Ltd. All other authors (Juleen Gayed, Francine S. Lowry, Hua Ma, Vishva Bangad, Mark Cutler, Todd Belanger, David Cooper, Xia Xu, Robin Mogg, Annaliesa S. Anderson, Alejandra Gurtman and Nicholas Kitchin) are Pfizer employees and may hold stock or stock options.
Ethical Approval
The study protocol was approved by the WCG Central institutional review board (approval number: 20233321; Princeton, NJ, USA), which was utilized by each study site. This substudy was conducted according to the protocol and consensus ethical principles derived from international guidelines (i.e., Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines), applicable good clinical practice guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and other relevant laws and regulations. All participants were required to provide a signed statement of informed consent before study-specific procedures were performed.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.