Preliminary Safety and Effectiveness Estimate of 2023-2024 COVID-19 Vaccines (XBB.1.5) in Preventing Symptomatic Infections in U.S. Adults

This study evaluated the real-world effectiveness (VE) of the 2023-2024 updated Novavax and Pfizer-BioNTech COVID-19 vaccines (monovalent XBB.1.5) against symptomatic SARS-CoV-2 infections in U.S. adults, comparing boosted individuals with non-boosted ones. Limited data exists from randomized controlled trials (RCTs) directly comparing Novavax and Pfizer-BioNTech vaccines. We also assessed the relative vaccine efficacy (rVE) between these two vaccines and examined the time to onset of COVID-19 infection confirmed by rapid antigen testing (RAT). This double-blinded, partially randomized, controlled, multi-arm trial included 1,176 participants (444 Novavax, 454 mRNA, 278 non-boosted). All participants received the assigned vaccine (0.3 mL Pfizer-BioNTech or 0.5 mL Novavax) and completed post-vaccination surveys. They self-tested for SARS-CoV-2 weekly for 24 weeks. The Cox proportional hazards model was used to analyze time-to-event data for VE and rVE. The boosted group (NVX or mRNA) showed a lower infection rate than the non-boosted group. Adjusted VE was 43.5% (95% CI, 18.3% to 61.0%) for the boosted vs. non-boosted comparison. The adjusted rVE between NVX and mRNA was -26.7% (90% CI, -78.6% to 10.1%). In the per-protocol (PP) group, adjusted VE was 46.2% (95% CI, 21.9% to 62.9%) for boosted vs. non-boosted, with rVE of -29.2% (90% CI, -82.5% to 8.5%). Additional vaccination protected against symptomatic infection during co-circulation of the XBB.1.5 and JN.1 variants. However, the study's limited enrollment and attack rate hindered precise assessment of non-inferiority between Novavax and Pfizer vaccines.

Preliminary Safety and Effectiveness Estimate of 2023–2024 COVID-19 vaccines (XBB.1.5) in Preventing Symptomatic Infections in U.S. adults Sarang K. Yoon,1 Matthew S. Thiese,1 Andrew L. Phillips,1 German L. Ellsworth,1 Sarah Ball,2 Elizabeth Rowley,2 Steph Battan-Wraith, 2 Rebecca Fink,2 Adam Yates,2 Seth Toback,3 Lisa M. Dunkle,3 Matthew D. Rousculp,3 and Hongwei Zhao1 P0404 1 University of Utah School of Medicine, 2 Westat, 3 Novavax, Inc. Contact: Sarang Yoon Kim [e-mail] METHODS BACKGROUND • Real-world effectiveness of the 2023-2024 updated Novavax Participants: and Pfizer-BioNTech COVID-19 vaccines (monovalent • Adults aged ≥18 from the Salt Lake City metropolitan area who had received at least 2 doses of an mRNA COVID-19 vaccine before study enrollment • Out of 1188 enrolled participants, 898 underwent 1:1 randomization between November 22, 2023, and March 15, 2024 (boosted group), and 278 who declined the updated vaccine were placed in the non-randomized comparator arm (non-boosted group) Figure 1. Study design XBB.1.5) against symptomatic SARS-CoV-2 infections in U.S. adults is currently supported by observational data, with randomized clinical trial results not yet available • There is little efficacy data from randomized controlled trials (RCTs) directly comparing the Novavax vaccine (NVX) with the Pfizer-BioNTech mRNA vaccine (mRNA) OBJECTIVES Study design (Figure 1): • Double-blinded, partially randomized, controlled, multi-arm trial • All randomized participants received: o A single dose of the study vaccine: This study aimed to compare the vaccine effectiveness (VE) of boosted (2023–2024 Novavax or Pfizer-BioNTech COVID-19 vaccines) against symptomatic SARS-CoV-2 infection with a COVID-like illness, confirmed by rapid antigen testing (RAT) 0.5 mL Novavax • All participants received the OHC COVID19 Antigen Self-Test kit and swabbed weekly regardless of symptoms to detect a SARS-CoV-2 infection for 24 weeks • The Cox proportional hazards model was used to analyze time-to-event data to evaluate the study VE and rVE in preventing symptomatic SARS-CoV-2 infection between vaccines The time to onset of a COVID-19 infection associated with - and 7 to assess solicited adverse events In addition, we examined the relative vaccine efficacy (rVE) PRIMARY ENDPOINT 0.3 mL Pfizer-BioNTech OR o Post-vaccination surveys on days 1, 2, cohort of individuals who were recommended to, but did not receive an updated 2023–2024 vaccine (non-boosted) - *The boosted group was younger, had a higher prevalence of obesity, lower income levels, a greater proportion of vape smokers, higher rates of lung disease/asthma and mental health conditions, and a more recent history of COVID-19 infection or vaccination (89% and 82% non-smokers in the Novavax and Pfizer groups, respectively) **The modified intent-to-treat (mITT) group, all participants who completed at least one surveillance check; ***The per-protocol (PP) group, participants who fully adhered to the protocol RESULTS Figure 2. Cumulative incidence of symptomatic COVID-19 infection in the mITT group, comparing the Novavax, Pfizer (mRNA), and non-boosted groups The mITT group (n=1176: 444 NVX recipients, 454 mRNA recipients, 278 non- boosted): • The boosted group vaccinated with either NVX or mRNA vaccine demonstrated a lower SARS-CoV-2 infection event rate vs the non-boosted group (Fig 2) • Adjusted VE of 43.5% (95% CI, 18.3 to 61.0%) over 24 weeks (boosted vs nonboosted) (Fig 3) • Adjusted VE's by age group: - 44.7% (95% CI, 13.4% to 64.7%) in the 18–49 age group Figure 3. Adjusted vaccine effectiveness against symptomatic infection: comparison of the non-boosted participants vs those boosted with the 2023–2024 booster CONCLUSIONS An additional dose of a 2023-2024 COVID-19 vaccine conferred protection during cocirculation of the XBB.1.5 and JN.1 variants against symptomatic infection. Due to a lower-than-expected enrollment number and attack rate, as well as a higher assumed relative vaccine efficacy, the study was unable to assess with precision noninferiority between Novavax and Pfizer. - 49.7% (95% CI, 5.4% to 73.2%) in the 50+ age group • Adjusted rVE of -26.7% (90% CI, -78.6% to 10.1%) (NVX vs mRNA vaccine) The PP group (n=1162: 441 NVX recipients, 448 mRNA recipients, 273 non- LIMITATIONS boosted): • Ethically not feasible to randomly assign to a placebo comparison group • A slightly higher adjusted VE of 46.2% (95% CI, 21.9% to 62.9%) (boosted vs non- • Homogenous demographic representation limits generalizability boosted) (Fig 3) • An adjusted rVE of -29.2% (90% CI, -82.5% to 8.5%) (NVX vs mRNA vaccine) Safety and severity • Mild SARS-CoV-2 infection cases in the boosted and non-boosted groups • Use of rapid antigen tests to reflect real-world settings is mitigated by repeat confirmatory testing • Direct comparison of the two vaccine types: all the lower confidence limits were below the predefined non-inferiority margin of –50% so we were unable to determine if 2023-24 Novavax vaccine is non-inferior to the Pfizer-BioNTech vaccine • No study subjects with symptomatic infection resulted in hospitalization or death • No SAE, myocarditis, pericarditis, or death related to either NVX or mRNA vaccines Disclosures/Conflicts of Interest: SB, ER, SB-W, RF, and AY are funded through contract agreement with University of Utah. SKY, MST, ALP, GLE, and HZ are funded through contract agreement with University of Utah with prime funding and study drug provided by Novavax, Inc. SKY serves as an advisory board member for Pfizer-BioNTech without compensation. ST, LMD, and MDR are employees or consultants at Novavax, Inc and may hold stock in the company.