Different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373) in younger and older adults: A phase 2 randomized placebo-controlled trial

Abstract

Background: NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant.

Methods and findings: The phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose. Reactogenicity occurred less frequently and was of lower intensity in older participants. Both 2-dose regimens of 5-μg and 25-μg NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 μg, geometric mean titers (GMTs) for IgG anti-spike protein were 65,019 (95% confidence interval (CI) 55,485 to 76,192) and 28,137 (95% CI 21,617 to 36,623) EU/mL and for wild-type virus neutralizing antibody (with an inhibitory concentration of 50%-MN50%) were 2,201 (95% CI 1,343 to 3,608) and 981 (95% CI 560 to 1,717) titers for younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in a panel of convalescent sera for both age groups. Study limitations include the relatively short duration of safety follow-up to date and current lack of immune persistence data beyond the primary vaccination regimen time point assessments, but these data will accumulate over time.

Conclusions: The study confirmed the phase 1 findings that the 2-dose regimen of 5-μg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 μg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies.

Trial registration: ClinicalTrials.gov NCT04368988.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: Authors RM, GA, JSP, IC, AR, FD, MR and GG all state to be employees and/or stock owners at Novavax. Dr. NF reports through my personal consulting company vehicle I consult for a variety of pre and post-licensure clinical development and medical affairs activities for other vaccine pharmaceutical and biotech companies. In the area of coronavirus vaccines I have a current consulting contract for post-licensure COVID vaccine support for approval and implementation of rollout of the AstraZeneca/Oxford COVID vaccine in Australia and New Zealand. Dr. GG reports grants from CEPI during the conduct of the study; personal fees and other from Novavax, grants from Bill and Melinda Gates Foundation, grants from Department of Defense, grants from Operation Warp Speed, other from RA Capital outside the submitted work.

Figures

Fig 1. CONSORT flow diagram.

Notes: Study treatments Dose 1 / Dose 2: Group A: placebo / placebo; Group B: 5-μg SARS-CoV-2 rS + M1 / 5-μg SARS-CoV-2 rS + M1; Group C: 5-μg SARS-CoV-2 rS + M1 / placebo; Group D: 25-μg SARS-CoV-2 rS + M1 / 25-μg SARS-CoV-2 rS + M1; Group E: 25-μg SARS-CoV-2 rS + M1 / placebo (M1 = 50-μg Matrix M1 adjuvant). Details of the analysis sets are included in the Supporting methods section.

Fig 2. Solicited local and systemic AEs.

The percentage of participants in each vaccine group (Groups A, B, C, D, and E) with solicited local and systemic AEs according to the maximum toxicity grade (mild, moderate, severe, or potentially life-threatening) during the 7 days after each vaccination is plotted for solicited local (Panel A) and systemic (Panel B) AEs and for both local and systemic events by age group (Panel C). Grade 4 (potentially life-threatening) events met these criteria by emergency department attendances in Australia, where nonemergency conditions are frequently managed as an alternative to regular primary care. (See Tables E, F, and G in S1 Text for complete solicited local and systemic AE data by dose, by all participants, and by younger and older age groups.) (A) Solicited local AEs. (B) Solicited systemic AEs. (C) Reactogenicity by age. AE, adverse event; Plc, placebo.

Fig 3. SARS-CoV-2 anti-spike IgG and neutralizing antibody responses at Day 35.

Shown are geometric mean anti-spike IgG ELISA unit responses to the NVX-CoV2373 protein antigen (Panel A) for younger adult and older adult age groups in the phase 2 study for the 2-dose primary vaccination treatment regimens (Groups B and D), along with aligned group results by the same assay in the phase 1 study, and wild-type SARS-CoV-2 MN assay at an inhibitory concentration >50% (MN50) titer responses (Panel B) for younger adult and older adult age groups in the phase 2 study. These panels also include immune responses from a panel of participants by age group from a clinical case series of participants (see Methods). In Panels A and B, boxes and horizontal bars represent IQR and median area under the curve, respectively. Whisker endpoints are equal to the maximum and minimum values below or above the median ± 1.5 times the IQR. (A) SARS-CoV-2 anti-spike IgG ELISA. (B) Wild-type SARS-CoV-2 MN. CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; EU, endotoxin unit; GMT, geometric mean titer; IC, inhibitory concentration; IgG, immunoglobulin G; IQR, interquartile range; MN, microneutralization; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig 4. Correlation between SARS-CoV-2 anti-spike IgG and neutralizing antibody responses.

Shown is a scattergram and correlation analysis of the neutralizing antibody titers and anti-spike IgG ELISA units for the 5-μg NVX-CoV2373 2-dose vaccine group (Group B) for younger adults 18 to 59 years (Panel A) and older adults 60 to 84 years (Panel B). Pearson correlations were calculated with 2-sided 95% CIs. The correlation plots were inclusive of paired specimens by the 2 assays at the Day 21 time point following first vaccination, as well as for paired results at the Day 35 time point following second vaccination. (A) 5 μg + Matrix-M1 (Group B)– 18–59 years [footnote for Fig 4A] * NCT04368988 –phase 1. (B) 5 μg Matrix-M1 (Group B)– 60–84 years. CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; EU, endotoxin unit; IC, inhibitory concentration; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.