Immunogenicity and safety of a fourth homologous dose of NVX-CoV2373

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5 µg SARS-CoV-2 recombinant spike [rS] protein + 50 µg Matrix-M™ adjuvant; Novavax, Gaithersburg, MD) was evaluated to determine induction of cross-reactive antibodies to variants of concern. A phase II randomized study (NCT04368988) recruited participants in Australia and the United States to assess a primary series of NVX-CoV2373 followed by two booster doses (third and fourth doses at 6-month intervals) in adults 18-84 years of age. The primary series was administered when the SARS-CoV-2 ancestral strain was prevalent and the third and fourth doses while the Alpha and Delta variants were prevalent in AUS and US. 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 serum immunoglobulin G (IgG) and neutralization assays against ancestral SARS-CoV-2 strain and Omicron sublineages. Among 1283 enrolled participants, 258 were randomized to receive the two-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 4. Unsolicited AEs were reported in 9 % of participants after dose 4 (none of which were severe or serious). Anti-rS IgG levels and neutralization antibody titers increased following booster doses to a level approximately four-fold higher than that observed after the primary series, with a progressively narrowed gap in response between the ancestral strain and Omicron BA.5. A fourth dose of NVX-CoV2373 enhanced immunogenicity for ancestral and variant SARS-CoV-2 strains without increasing reactogenicity, indicating that updates to the vaccine composition may not be currently warranted.

Keywords: Booster; COVID-19; NVX-CoV2373; SARS-CoV-2 vaccine; Vaccine immunogenicity; Vaccine safety.

Fig. 1

CONSORT Diagram. White boxes demonstrate the flow of participants included in this analysis, including those who received one, two, three, or four doses of 5 µg SARS-CoV-2 rS + 50 µg Matrix-M™ (Novavax, Gaithersburg, MD) adjuvant (5/50) on day 0, day 21, day 189, and day 357, respectively. Gray boxes include participant groups not covered in this analysis. 0/0: 0 µg SARS-CoV-2 rS + 0 µg Matrix-M adjuvant; 5/50: 5 µg SARS-CoV-2 rS + 50 µg Matrix-M adjuvant; 25/50: 25 µg SARS-CoV-2 rS + 50 µg Matrix-M adjuvant.

Fig. 2

Solicited (A) local and (B) systemic reactogenicity events for participants who received NVX-CoV2373, by dose number and severity.

Fig. 3

Immunogenicity of NVX-CoV2373 against ancestral and variant strains of SARS-CoV-2, by dose (n = 34). (Panel A) Anti-rS IgG levels by dose for the ancestral (n = 34) and BA.1 (n = 31) and BA.5 (n = 34) variants. Data were not available for the BA.1 variant for 3 of 34 participants. Dotted line represents approximate correlates of protection levels as derived for the ancestral strain . (Panel B) Neutralizing (ID₅₀) antibody titers by dose for the ancestral, BA.1, and BA.4/BA.5 variants (n = 34 for all strains). Dotted line represents approximate correlates of protection titers as derived for the ancestral strain . CoP, correlate of protection; CI, confidence interval; GMT, geometric mean titer; ID₅₀, 50 % inhibitory dose; IgG, immunoglobulin; rS, recombinant spike; VE, vaccine efficacy.

Fig. 4

hACE2 inhibition after 4 doses of NVX-CoV2373 (n = 34). Ancestral strain SARS-CoV-2 recombinant spike protein was used as the assay susbtrate. GMFR for various comparisons are depicted above the bars. CI, confidence interval; GMFR, geometric mean fold rise; LLOQ, lower limit of quantitation.