Immunogenicity and safety of a 4th homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): a phase 2, randomized, placebo-controlled trial (preprint)

Background The emergence of SARS-CoV-2 variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5g SARS-CoV-2 rS + 50g Matrix-M adjuvant) was evaluated to determine induction of cross-reactive antibodies to variants of concern. Methods A phase 2 randomized study assessed a fourth dose of NVX-CoV2373 in adults 18-84 years of age (2-dose primary series followed by third and fourth doses at 6-month intervals). Local/systemic reactogenicity was assessed the day of vaccination and for 6 days thereafter. Unsolicited adverse events (AEs) were reported. Immunogenicity was measured before, and 14 days after, fourth dose administration using anti-spike neutralization assays against the ancestral SARS-CoV-2 strain and Omicron sublineages. Antigenic cartography assessed antigenic distances between ancestral and variant strains. Results Among 1283 enrolled participants, 258 were randomized to receive the 2-dose primary series, of whom 104 received a third dose, and 45 received a fourth dose of NVX-CoV2373. The incidence of local/systemic reactogenicity events increased after the first three doses of NVX-CoV2373, and leveled off after dose four. Unsolicited AEs were reported in 9% of participants after dose 4 (none severe or serious). Neutralization antibody titers increased following booster doses. Antigenic cartography demonstrated reductions in antigenic distance between ancestral and variant SARS-CoV-2 strains with increased number of NVX-CoV2373 doses. Conclusions A fourth dose of NVX-CoV2373 enhanced immunogenicity without increasing reactogenicity. Antigenic cartography demonstrated a more universal-like response against SARS-CoV-2 variants after a fourth dose of NVX-CoV2373, indicating that updates to the vaccine composition may not be warranted. Trial registration number: NCT04368988

Immunogenicity and Safety Following a Homologous Booster Dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): A Phase 2 Randomized Placebo-Controlled Trial (preprint)

Background Emerging SARS-CoV-2 variants and evidence of waning vaccine efficacy present significant obstacles toward controlling the COVID-19 pandemic. Booster doses of SARS-CoV-2 vaccines may address these concerns by both amplifying and broadening the immune responses seen with initial vaccination regimens. Methods In a phase 2 study, a single booster dose of a SARS-CoV-2 recombinant spike protein vaccine with Matrix-M adjuvant (NVX-CoV2373) was administered to healthy adult participants 18 to 84 years of age approximately 6 months following their primary two-dose vaccination series. Safety and immunogenicity parameters were assessed, including assays for IgG, MN50, and hACE2 receptor binding inhibition against the ancestral SARS-CoV-2 strain and select variants (B.1.351 [Beta], B.1.1.7 [Alpha], B.1.617.2 [Delta], and B.1.1.529 [Omicron]). This trial is registered with ClinicalTrials.gov, NCT04368988. Findings An incremental increase in the incidence of solicited local and systemic reactogenicity events was observed with subsequent vaccinations. Following the booster, incidence rates of local and systemic reactions were 82.5% (13.4% [≥] Grade 3) and 76.5% (15.3% [≥] Grade 3), respectively, compared to 70.0% (5.2% [≥] Grade 3) and 52.8% (5.6% [≥] Grade 3), respectively, following the primary vaccination series. Events were primarily mild or moderate in severity and transient in nature, with a median duration of 1.0 to 2.5 days. Immune responses seen 14 days following the primary vaccination series were compared with those observed 28 days following the booster (Day 35 and Day 217, respectively). For the ancestral SARS-CoV-2 strain, serum IgG geometric mean titers (GMTs) increased ~4.7-fold from 43,905 ELISA units (EU) at day 35 to 204,367 EU at Day 217. Neutralization (MN50) assay GMTs showed a similar increase of ~4.1-fold from 1,470 at day 35 to 6,023 at Day 217. A functional hACE2 receptor binding inhibition assay analyzing activity against ancestral and variant strains of SARS-CoV-2 at Day 189 vs Day 217 found 54.4-fold (Ancestral), 21.9 fold (Alpha), 24.5-fold (Beta), 24.4-fold (Delta), and 20.1-fold (Omicron) increases in titers. An anti-rS IgG activity assay comparing the same time points across the same SARS-CoV-2 strains found titers improved 61.2-fold, 85.9-fold, 65.0-fold, 92.5 fold, and 73.5 fold, respectively. Interpretation Administration of a booster dose of NVX-CoV2373 approximately 6 months following the primary vaccination series resulted in an incremental increase in reactogenicity along with enhanced immune responses. For both the prototype strain and all variants evaluated, immune responses following the booster were notably higher than those associated with high levels of efficacy in phase 3 studies of the vaccine.