Immunogenicity and safety of a 4th homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): a phase 2, randomized, placebo-controlled trial

BackgroundThe emergence of SARS-CoV-2 variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5{micro}g SARS-CoV-2 rS + 50{micro}g Matrix-M adjuvant) was evaluated to determine induction of cross-reactive antibodies to variants of concern. MethodsA phase 2 randomized study assessed a fourth dose of NVX-CoV2373 in adults 18-84 years of age (2-dose primary series followed by third and fourth doses at 6-month intervals). 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 neutralization assays against the ancestral SARS-CoV-2 strain and Omicron sublineages. Antigenic cartography assessed antigenic distances between ancestral and variant strains. ResultsAmong 1283 enrolled participants, 258 were randomized to receive the 2-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 four. Unsolicited AEs were reported in 9% of participants after dose 4 (none severe or serious). Neutralization antibody titers increased following booster doses. Antigenic cartography demonstrated reductions in antigenic distance between ancestral and variant SARS-CoV-2 strains with increased number of NVX-CoV2373 doses. ConclusionsA fourth dose of NVX-CoV2373 enhanced immunogenicity without increasing reactogenicity. Antigenic cartography demonstrated a more universal-like response against SARS-CoV-2 variants after a fourth dose of NVX-CoV2373, indicating that updates to the vaccine composition may not be warranted. Trial registration numberNCT04368988

Safety, Immunogenicity and Efficacy of NVX-CoV2373 in Adolescents in PREVENT-19: A Randomized, Phase 3 Trial

BACKGROUNDOver 20% of cases and 0.4% of deaths from Covid-19 occur in children. Following demonstration of safety and efficacy of the adjuvanted, recombinant spike protein vaccine NVX-CoV2373 in adults, the PREVENT-19 trial enrolled adolescents. METHODSSafety, immunogenicity, and efficacy of NVX-CoV2373 were evaluated in adolescents aged 12 to <18 years in an expansion of PREVENT-19, a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States. Participants were randomized 2:1 to two doses of NVX-CoV2373 or placebo 21 days apart, and followed for a median of 2 months after second vaccination. Primary end points were serologic non-inferiority of neutralizing antibody (NA) responses compared with young adults (18 to <26 years) in PREVENT-19, protective efficacy against laboratory-confirmed Covid-19, and assessment of reactogenicity/safety. RESULTSAmong 2,247 participants randomized between April-June 2021, 1,491 were allocated to NVX-CoV2373 and 756 to placebo. Post-vaccination, the ratio of NA geometric mean titers in adolescents compared to young adults was 1.5 (95% confidence interval [CI] 1.3 to 1.7). Twenty Covid-19 cases (all mild) occurred: 6 among NVX-CoV2373 and 14 among placebo recipients (vaccine efficacy [VE]: 79.5%, 95% CI, 46.8 to 92.1). All sequenced viral genomes (11/20) were identified as Delta variant (Delta variant VE: 82.0% [95% CI: 32.4 to 95.2]). Reactogenicity was largely mild-to-moderate, transient, and more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments. CONCLUSIONSNVX-CoV2373 was safe, immunogenic, and efficacious in the prevention of Covid-19 and those cases caused by the Delta variant in adolescents. (Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802).

Immunogenicity and Safety Following a Homologous Booster Dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): A Phase 2 Randomized Placebo-Controlled Trial

BackgroundEmerging SARS-CoV-2 variants and evidence of waning vaccine efficacy present significant obstacles toward controlling the COVID-19 pandemic. Booster doses of SARS-CoV-2 vaccines may address these concerns by both amplifying and broadening the immune responses seen with initial vaccination regimens. MethodsIn a phase 2 study, a single booster dose of a SARS-CoV-2 recombinant spike protein vaccine with Matrix-M adjuvant (NVX-CoV2373) was administered to healthy adult participants 18 to 84 years of age approximately 6 months following their primary two-dose vaccination series. Safety and immunogenicity parameters were assessed, including assays for IgG, MN50, and hACE2 receptor binding inhibition against the ancestral SARS-CoV-2 strain and select variants (B.1.351 [Beta], B.1.1.7 [Alpha], B.1.617.2 [Delta], and B.1.1.529 [Omicron]). This trial is registered with ClinicalTrials.gov, NCT04368988. FindingsAn incremental increase in the incidence of solicited local and systemic reactogenicity events was observed with subsequent vaccinations. Following the booster, incidence rates of local and systemic reactions were 82.5% (13.4% [≥] Grade 3) and 76.5% (15.3% [≥] Grade 3), respectively, compared to 70.0% (5.2% [≥] Grade 3) and 52.8% (5.6% [≥] Grade 3), respectively, following the primary vaccination series. Events were primarily mild or moderate in severity and transient in nature, with a median duration of 1.0 to 2.5 days. Immune responses seen 14 days following the primary vaccination series were compared with those observed 28 days following the booster (Day 35 and Day 217, respectively). For the ancestral SARS-CoV-2 strain, serum IgG geometric mean titers (GMTs) increased [~]4.7-fold from 43,905 ELISA units (EU) at day 35 to 204,367 EU at Day 217. Neutralization (MN50) assay GMTs showed a similar increase of [~]4.1-fold from 1,470 at day 35 to 6,023 at Day 217. A functional hACE2 receptor binding inhibition assay analyzing activity against ancestral and variant strains of SARS-CoV-2 at Day 189 vs Day 217 found 54.4-fold (Ancestral), 21.9-fold (Alpha), 24.5-fold (Beta), 24.4-fold (Delta), and 20.1-fold (Omicron) increases in titers. An anti-rS IgG activity assay comparing the same time points across the same SARS-CoV-2 strains found titers improved 61.2-fold, 85.9-fold, 65.0-fold, 92.5-fold, and 73.5-fold, respectively. InterpretationAdministration of a booster dose of NVX-CoV2373 approximately 6 months following the primary vaccination series resulted in an incremental increase in reactogenicity along with enhanced immune responses. For both the prototype strain and all variants evaluated, immune responses following the booster were notably higher than those associated with high levels of efficacy in phase 3 studies of the vaccine. FundingNovavax(R) and the Coalition for Epidemic Preparedness Innovations (CEPI(R)).

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico

BACKGROUNDVaccination using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein antigen has been effective in the prevention of coronavirus disease 2019 (Covid-19). NVX-CoV2373 is an adjuvanted, recombinant S protein nanoparticle vaccine that demonstrated clinical efficacy for prevention of Covid-19 in phase 2b/3 trials in the United Kingdom and South Africa. METHODSThis phase 3, randomized, observer-blinded, placebo-controlled trial evaluated the efficacy and safety of NVX-CoV2373 in adults [≥]18 years of age in the United States and Mexico during the first quarter of 2021. Participants were randomized in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary end point was vaccine efficacy (VE) against reverse transcriptase-polymerase chain reaction-confirmed Covid-19 in SARS-CoV-2-naive participants [≥]7 days after the second dose administration. RESULTSOf the 29,949 participants randomized between December 27, 2020, and February 18, 2021, 29,582 (median age: 47 years, 12.6% [≥]65 years) received [≥]1 dose: 19,714 received vaccine and 9868 placebo. In the per-protocol population, there were 77 Covid-19 cases; 14 among vaccine and 63 among placebo recipients (VE: 90.4%, 95% confidence interval [CI] 82.9 to 94.6, P<0.001). All moderate-to-severe cases occurred in placebo recipients, yielding VE of 100% (95% CI 87.0 to 100). Most sequenced viral genomes (48/61, 78.7%) were variants of concern (VOC) or interest (VOI), mainly represented by variant alpha/B.1.1.7 (31/35, 88.6% VOC identified). VE against any VOC/VOI was 92.6% (95% CI 83.6 to 96.7). Reactogenicity was mostly mild-to-moderate and transient, but more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments. CONCLUSIONSNVX-CoV2373 was well tolerated and demonstrated a high overall VE (>90%) for prevention of Covid-19, with most cases due to variant strains. (Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802.)

Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant

BackgroundThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use. MethodsIn this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 {micro}g recombinant spike protein with 50 {micro}g Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy [≥]7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants. ResultsA total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups. ConclusionsThe NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399)

Evaluation of a SARS-CoV-2 Vaccine NVX-CoV2373 in Younger and Older Adults

BackgroundNVX-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. MethodsThe phase 2 component of our randomized, placebo-controlled, phase 1-2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late phase studies in younger (18-59 years) and older (60-84 years) participants and was based on immunogenicity and safety data through day 35 (14 days after the second dose). Participants were randomly assigned to receive either one or two intramuscular doses of 5-{micro}g or 25-{micro}g 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. ResultsAfter randomization, approximately 250 participants each were assigned to one of four vaccine groups or placebo. Of these, approximately 45% were older participants. 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, and occurred less frequently and was of lower intensity in older participants. The two-dose regimen of 5-{micro}g NVX-CoV2373 induced robust geometric mean titer (GMT) IgG anti-spike protein (65,019 and 28,137 EU/mL) and wild-type virus neutralizing antibody (2201 and 981 titers) responses in younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in convalescent sera for both age groups. ConclusionsThe study confirmed that the two-dose regimen of 5-{micro}g NVX-CoV2373 is highly immunogenic and well tolerated in both younger and older participants. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number: NCT04368988).

SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines

The SARS-CoV-2 Spike glycoprotein mediates virus entry and is a major target for neutralizing antibodies. All current vaccines are based on the ancestral Spike with the goal of generating a protective neutralizing antibody response. Several novel SARS-CoV-2 variants with multiple Spike mutations have emerged, and their rapid spread and potential for immune escape have raised concerns. One of these variants, first identified in the United Kingdom, B.1.1.7 (also called VUI202012/01), contains eight Spike mutations with potential to impact antibody therapy, vaccine efficacy and risk of reinfection. Here we employed a lentivirus-based pseudovirus assay to show that variant B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (~2-fold), by serum samples from convalescent individuals and recipients of two different vaccines based on ancestral Spike: mRNA-1273 (Moderna), and protein nanoparticle NVX-CoV2373 (Novavax). Some monoclonal antibodies to the receptor binding domain (RBD) of Spike were less effective against the variant while others were largely unaffected. These findings indicate that B.1.1.7 is not a neutralization escape variant that would be a major concern for current vaccines, or for an increased risk of reinfection.

First-in-Human Trial of a SARS CoV 2 Recombinant Spike Protein Nanoparticle Vaccine

BackgroundNVX-CoV2373 is a recombinant nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins. We present the Day 35 primary analysis of our trial of NVX-CoV2373 with or without the saponin-based Matrix-M1 adjuvant in healthy adults. MethodsThis is a randomized, observer-blinded, placebo-controlled, phase 1 trial in 131 healthy adults. Trial vaccination comprised two intramuscular injections, 21 days apart. Primary outcomes were reactogenicity, safety labs, and immunoglobulin G (IgG) anti-spike protein response. Secondary outcomes included adverse events, wild-type virus neutralizing antibody, and T-cell responses. ResultsParticipants received NVX-CoV2373 with or without Matrix-M1 (n=106) or placebo (n=25). There were no serious adverse events. Reactogenicity was mainly mild in severity and of short duration (mean [≤]2 days), with second vaccinations inducing greater local and systemic reactogenicity. The adjuvant significantly enhanced immune responses and was antigen dose-sparing, and the two-dose 5g NVX-CoV2373/Matrix-M1 vaccine induced mean anti-spike IgG and neutralizing antibody responses that exceeded the mean responses in convalescent sera from COVID-19 patients with clinically significant illnesses. The vaccine also induced antigen-specific T cells with a largely T helper 1 (Th1) phenotype. ConclusionsNVX-CoV2373/Matrix-M1 was well tolerated and elicited robust immune responses (IgG and neutralization) four-fold higher than the mean observed in COVID-19 convalescent serum from participants with clinical symptoms requiring medical care and induced CD4+ T-cell responses biased toward a Th1 phenotype. These findings suggest that the vaccine may confer protection and support transition to efficacy evaluations to test this hypothesis. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).