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Clinical Trial
. 2020 Dec 10;383(24):2320-2332.
doi: 10.1056/NEJMoa2026920. Epub 2020 Sep 2.

Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine

Cheryl Keech  1 , Gary Albert  1 , Iksung Cho  1 , Andreana Robertson  1 , Patricia Reed  1 , Susan Neal  1 , Joyce S Plested  1 , Mingzhu Zhu  1 , Shane Cloney-Clark  1 , Haixia Zhou  1 , Gale Smith  1 , Nita Patel  1 , Matthew B Frieman  1 , Robert E Haupt  1 , James Logue  1 , Marisa McGrath  1 , Stuart Weston  1 , Pedro A Piedra  1 , Chinar Desai  1 , Kathleen Callahan  1 , Maggie Lewis  1 , Patricia Price-Abbott  1 , Neil Formica  1 , Vivek Shinde  1 , Louis Fries  1 , Jason D Lickliter  1 , Paul Griffin  1 , Bethanie Wilkinson  1 , Gregory M Glenn  1
Affiliations
Clinical Trial

Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine

Cheryl Keech et al. N Engl J Med. .

Abstract

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

Methods: We initiated a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-μg and 25-μg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti-spike protein response (in enzyme-linked immunosorbent assay [ELISA] units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses (cytokine staining). IgG and microneutralization assay results were compared with 32 (IgG) and 29 (neutralization) convalescent serum samples from patients with Covid-19, most of whom were symptomatic. We performed a primary analysis at day 35.

Results: After randomization, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose-sparing, and induced a T helper 1 (Th1) response. The two-dose 5-μg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic Covid-19 patients (8344 and 983, respectively).

Conclusions: At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in Covid-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).

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Figures

Figure 1
Figure 1. Vaccine Regimens and Key Trial Assessments.
Shown are the planned randomization schema and associated vaccine regimens administered in the trial (Panel A), along with timing of the key safety and immunogenicity assessments (Panel B).
Figure 2
Figure 2. Solicited Local and Systemic Adverse Events.
The percentage of participants in each vaccine group (groups A, B, C, D, and E) with adverse events according to the maximum FDA toxicity grade (mild, moderate, or severe) during the 7 days after each vaccination is plotted for solicited local (Panel A) and systemic (Panel B) adverse events. There were no grade 4 (life-threatening) events. Participants who reported 0 events make up the remainder of the 100% calculation (not displayed). Excluded were the three sentinel participants in groups C (5 μg + Matrix-M1, 5 μg + Matrix-M1) and D (25 μg + Matrix-M1, 25 μg + Matrix-M1), who received the trial vaccine in an open-label manner (see Table S7 for complete safety data on all participants).
Figure 3
Figure 3. SARS-CoV-2 Anti-Spike IgG and Neutralizing Antibody Responses.
Shown are geometric mean anti-spike IgG enzyme-linked immunosorbent assay (ELISA) unit responses to recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) protein antigens (Panel A) and wild-type SARS-CoV-2 microneutralization assay at an inhibitory concentration greater than 99% (MN IC>99%) titer responses (Panel B) at baseline (day 0), 3 weeks after the first vaccination (day 21), and 2 weeks after the second vaccination (day 35) for the placebo group (group A), the 25-μg unadjuvanted group (group B), the 5-μg and 25-μg adjuvanted groups (groups C and D, respectively), and the 25-μg adjuvanted and placebo group (group E). Diamonds and whisker endpoints represent geometric mean titer values and 95% confidence intervals, respectively. The Covid-19 human convalescent serum panel includes specimens from PCR-confirmed Covid-19 participants, obtained from Baylor College of Medicine (29 specimens for ELISA and 32 specimens for MN IC>99%), with geometric mean titer values according to Covid-19 severity. The severity of Covid-19 is indicated by the colors of the dots for hospitalized patients (including those in intensive care), symptomatic outpatients (with samples collected in the emergency department), and asymptomatic patients who had been exposed to Covid-19 (with samples collected during contact and exposure assessment). Mean values (in black) for human convalescent serum are depicted next to (and of same color as) the category of Covid-19 patients, with the overall mean shown above the scatter plot (in black). For each trial vaccine group, the mean at day 35 is depicted above the scatterplot.
Figure 4
Figure 4. Correlation of Anti-Spike IgG and Neutralizing Antibody Responses.
Shown are scatter plots of 100% wild-type neutralizing antibody responses and anti-spike IgG ELISA unit responses at 3 weeks after the first vaccination (day 21) and 2 weeks after the second vaccination (day 35) for the two-dose 25-μg unadjuvanted vaccine (group B; Panel A), the combined two-dose 5-μg and 25-μg adjuvanted vaccine (groups C and D, respectively; Panel B), and convalescent serum from patients with Covid-19 (Panel C). In Panel C, the severity of Covid-19 is indicated by the colors of the dots for hospitalized patients (including those in intensive care), symptomatic outpatients (with samples collected in the emergency department), and asymptomatic patients who had been exposed to Covid-19 (with samples collected during contact and exposure assessment).
Figure 5
Figure 5. rSARS-CoV-2 CD4+ T-cell Responses with or without Matrix-M1 Adjuvant.
Frequencies of antigen-specific CD4+ T cells producing T helper 1 (Th1) cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 and for T helper 2 (Th2) cytokines interleukin-5 and interleukin-13 indicated cytokines from four participants each in the placebo (group A), 25-μg unadjuvanted (group B), 5-μg adjuvanted (group C), and 25-μg adjuvanted (group D) groups at baseline (day 0) and 1 week after the second vaccination (day 28) after stimulation with the recombinant spike protein. “Any 2Th1” indicates CD4+ T cells that can produce two types of Th1 cytokines at the same time. “All 3 Th1” indicates CD4+ T cells that produce IFN-γ, TNF-α, and interleukin-2 simultaneously. “Both Th2” indicates CD4+ T cells that can produce Th2 cytokines interleukin-5 and interleukin-13 at the same time.
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