Immunogenicity and safety of a monovalent omicron XBB.1.5 SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose in US adults: interim analysis of a single-arm phase 2/3 study.

Background: Authorities globally recommended a monovalent omicron XBB.1.5-based COVID-19 vaccine for the 2023-24 season. The Novavax COVID-19 vaccine, NVX-CoV2601, contains XBB.1.5 recombinant spike protein, based on an authorised prototype vaccine (NVX-CoV2373) technology. We aimed to determine whether a single dose of NVX-CoV2601 versus NVX-CoV2373 (from a previous study [2019nCoV-311 part 2]) produced superior neutralising antibody (nAb) responses, and non-inferior seroresponse rates to XBB.1.5, after three or more previous mRNA-based COVID-19 vaccinations.

Methods: In part 1 of this single-arm, phase 2/3 study (2019nCoV-313), participants aged 18 years or older who had been previously vaccinated with three or more doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) were enrolled across 30 US centres (research groups and universities) located across 20 states. Participants received one intramuscular injection of NVX-CoV2601 (5 μg XBB.1.5 spike plus 50 μg Matrix-M adjuvant). Coprimary endpoints were superiority of baseline-adjusted nAb geometric mean XBB.1.5 titres (adjusted GMTs), with superiority declared when the lower bound of the 95% CI for the GMT ratio (GMTR) was greater than 1, and non-inferiority of seroresponse rates, with non-inferiority declared when the lower bound of the 95% CI for the seroresponse rate difference was greater than -10%, on day 28; comparisons were made for NVX-CoV2601 administered in this study versus NVX-CoV2373 administered in part 2 (group G) of the 2019nCoV-311 study. Coprimary endpoints were assessed in the per-protocol immunogenicity set (ie, all participants who received study vaccine, underwent 28 days of follow-up, had day 0 and day 28 samples available, and had no major protocol deviations). Safety was a secondary endpoint and included assessments of solicited treatment-emergent adverse events up to 7 days and unsolicited treatment-emergent adverse events up to 28 days after vaccination in the safety analysis set (ie, all participants who received study vaccine). Here we report the prespecified interim analysis of immunogenicity and safety up to day 28. This study is registered with ClinicalTrials.gov, NCT05975060, and is now complete.

Findings: Between Sept 7 and Sept 8, 2023, 380 individuals were screened, of whom 332 were enrolled and received study vaccine. At the 28-day interim analysis database lock (Jan 17, 2023), the per-protocol analysis sets included 309 (93%) of 332 NVX-CoV2601 recipients and 227 (90%) of 252 NVX-CoV2373 recipients. Mean age of NVX-CoV2601 recipients was 52·1 years (SD 16·1); 192 (62%) of 309 were female and 117 (38%) were male. Mean age of NVX-CoV2373 recipients was 42·2 years (13·4); 128 (56%) of 227 were female and 99 (44%) were male. At day 28, the baseline-adjusted nAb GMT for NVX-CoV2601 was 905·9 (95% CI 807·1-1016·8) and for NVX-CoV2373 was 156·6 (137·0-179·0); the between-group adjusted GMTR was 5·8 (95% CI 4·9-6·9). In the per-protocol immunogenicity set, seroresponse rates were 64% (196 of 305) among recipients of NVX-CoV2601 and 7% (16 of 227) among recipients of NVX-CoV2373, with a seroresponse rate difference of 57% (95% CI 51-63). In the NVX-CoV2601 group, within 7 days, solicited local treatment-emergent adverse events were reported in 189 (57%) of 332 participants (including one [<1%] grade 3 or worse event; tenderness) and solicited systemic treatment-emergent adverse events were reported in 158 (48%) participants (including four [1%] participants with one or more grade 3 events; malaise [n=3], headache [n=2], fatigue [n=1], and muscle pain [n=1]). The most common solicited treatment-emergent adverse events were tenderness (171 [52%]) and pain (98 [30%]) at the injection site, fatigue (97 [29%]), and muscle pain (97 [29%]). Up to day 28, unsolicited adverse events considered related to study vaccination in the NVX-CoV2601 group occurred in five (2%) participants (one for each of asthma, axillary pain, diarrhoea, hypertension [which was medically attended], and presyncope). No serious adverse events due to study product, adverse events of special interest, or deaths due to study product occurred, and no study discontinuations due to treatment-emergent adverse events occurred.

Interpretation: The coprimary endpoints were met, and NVX-CoV2601 was well tolerated. These interim data support NVX-CoV2601 use per guidance for XBB.1.5-directed COVID-19 vaccines and demonstrate the adaptability of this vaccine platform for updated SARS-CoV-2 spike proteins.

Funding: Novavax.