Gale Smith

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).

Autographa californica nuclear polyhedrosis virus (AcNPV) was used as an expression vector for human beta interferon. By using specially constructed plasmids, the protein-coding sequences for interferon were linked to the AcNPV promoter for the gene encoding for polyhedrin, the major occlusion protein. The interferon gene was inserted at various locations relative to the AcNPV polyhedrin transcriptional and translational signals, and the interferon-polyhedrin hybrid genes were transferred to infectious AcNPV expression vectors. Biologically active interferon was produced, and greater than 95% was secreted from infected insect cells. A maximum of ca. 5 X 10(6) U of interferon activity was produced by 10(6) infected cells. These results demonstrate that AcNPV should be suitable for use as a eucaryotic expression vector for the production of products from cloned genes.

Abstract The COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd protection and control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) from the full-length spike (S) protein that is stable in the prefusion conformation. NVX-CoV2373 S form 27.2-nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicit high titer anti-S IgG that blocks hACE2 receptor binding, neutralize virus, and protects against SARS-CoV-2 challenge with no evidence of vaccine-associated enhanced respiratory disease. NVX-CoV2373 also elicits multifunctional CD4 + and CD8 + T cells, CD4 + follicular helper T cells (Tfh), and antigen-specific germinal center (GC) B cells in the spleen. In baboons, low-dose levels of NVX-CoV2373 with Matrix-M was also highly immunogenic and elicited high titer anti-S antibodies and functional antibodies that block S-protein binding to hACE2 and neutralize virus infection and antigen-specific T cells. These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2373 with Matrix-M (NCT04368988).