Title : Safety and immunogenicity of different antigen and adjuvant booster dose levels of protein-based Novavax COVID-19 vaccines in adults ≥50 years previously vaccinated with mRNA COVID-19 vaccines
Abstract:
Novavax’s Matrix-M®–adjuvanted protein nanoparticle SARS-CoV-2 vaccine has demonstrated robust immunogenicity and acceptable safety in adult and pediatric populations worldwide and among immunocompromised individuals. The original vaccine targeting the ancestral strain (NVX-CoV2373) and subsequent updated formulations against emerging SARS-CoV-2 variants contained 5μg of the recombinant spike (rS) protein and 50μg of Matrix-M. This randomized, double-blind Phase 2/3 trial (NCT05925127) evaluated the immunogenicity and safety of different dose levels of SARS-CoV-2 rS against the Omicron subvariant XBB.1.5 (NVX-COV2601) formulated with different Matrix-M adjuvant levels in previously COVID-19–vaccinated participants.
900 participants aged ≥50 years in the USA who had received ≥3 doses of a COVID-19 prototype or bivalent licensed mRNA vaccine ≥90-days before Day-0 were randomized to receive NVX-CoV2373 (Group A) or NVX-CoV2601 (Groups: B(5μg rS+50μg Matrix-M); C(5μg+75μg); D(35μg+50μg); E(35μg+75μg); F(50μg+100μg)) in a 1:2:2:2:2:1 ratio in a double-blind fashion. Ninety participants received a bivalent mRNA COVID-19 vaccine (Group G) in an open-label fashion. Neutralizing antibody (NAb) titers against XBB.1.5 and seroresponse rates (SRRs) were measured at Day-28 post-vaccination to assess superiority (95%CI LB for GMTR>1.0) and non-inferiority (SRRs; 95%CI LB for the differences in SRR>-5), respectively, of the five NVX-CoV2601 formulations versus NVX-CoV2373. The tolerability and safety of the study vaccines were evaluated by assessing reactogenicity for 7-days post-dose, unsolicited adverse events (AEs) through Day-28, and related MAAEs and all AESIs and SAEs through Day-180.
Demographic and baseline characteristics were balanced across groups (median age=66 years, 59.2% female, 79.5% White, median interval of 427 days since last COVID-19 vaccine). The primary immunogenicity endpoints were met as NAb responses were superior for each NVX-CoV2601 formulation versus NVX-CoV2373, with between-group GMTRs ranging from 3.6 (95%CI: 2.58–4.92) in Group B to 8.6 (5.85–12.51) in Group F. SRR non-inferiority was also met for each NVX-CoV2601 formulation versus NVX-CoV2373 (Group A), with the differences between SRRs ranging from 44.5 (32.8–54.5) in Group B to 58.1 (46.8–67.3) in Group D.
Any-grade solicited AEs were reported less frequently in Groups A (58.4%) and B–F (53.7–67.8%) versus Group G (83.3%). Solicited Grade 3 AEs were rare across all groups (0–2.2%) and Grade 4 AEs were reported in 1 (0.6%) Group D and 3 (1.7%) Group E participants. Any-grade solicited local injection site AEs were reported slightly less frequently in Group A (37.1%) than in Groups B–F (41.2–57.8%) or Group G (78.9%), with pain/tenderness being the most frequent (78.9% in Group G). Any-grade solicited systemic AEs were similarly reported between Groups A (43.8%) and B–F (38.9–44.4%) versus Group G (60.0%).
All combinations of rS and Matrix-M levels in NVX-CoV2601 induced stronger anti–XBB.1.5 NAb responses versus NVX-CoV2373. All NVX-CoV2601 formulations, including those with an antigen dose 10-fold higher and a Matrix-M dose 2-fold higher than in the FDA-approved vaccine, were well tolerated with an acceptable safety profile when used as a heterologous booster. These data provided support for updating the SARS-CoV-2 rS vaccine to include the XBB.1.5 strain and indicate that higher doses of both antigen and Matrix-M are well tolerated.
