ABSTRACT
Repeated mRNA SARS-CoV-2 vaccination has been associated with increases in the proportion of IgG4 in spike-specific antibody responses and concurrent reductions in Fc{gamma}-mediated effector functions that may limit control of viral infection. Here, we assessed anti-Spike total IgG, IgG1, IgG2, IgG3 and IgG4, and surrogate markers for antibody-dependent cellular phagocytosis (ADCP, Fc{gamma}RIIa binding), antibody-dependent cellular cytotoxicity (ADCC, Fc{gamma}RIIIa binding), and antibody-dependent complement deposition (ADCD, C1q binding) associated with repeated SARS-CoV-2 vaccination with NVX-CoV2373 (Novavax Inc., Gaithersburg, MD). The NVX-CoV2373 protein vaccine did not induce notable increases in spike-specific IgG4 or negatively impact surrogates for Fc{gamma} effector responses. Conversely, repeated NVX-CoV2373 vaccination uniquely enhanced IgG3 responses which are known to exhibit strong affinity for Fc{gamma}RIIIa and have previously been linked to potent neutralization of SARS-CoV-2. Subsequent investigations will help to understand the immunological diversity generated by different SARS-CoV-2 vaccine types and have the potential to reshape public health strategies.
Subject(s)
Immunologic Deficiency Syndromes , Virus Diseases , Drug-Related Side Effects and Adverse Reactions , Neural Tube DefectsABSTRACT
Background. Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone, or as a bivalent preparation in combination with the prototype vaccine (NVX CoV2373), to assess antibody responses to SARS-CoV-2. Methods. Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. Results. Of participants who received trial vaccine (N=829), those administered NVX-CoV2515 (n=286) demonstrated superior neutralizing antibody response to BA.1 versus NVX-CoV2373 (n=274) at Day 14 (geometric mean titer ratio [95% CI]: 1.6 [1.33, 2.03]). Seroresponse rates [n/N; 95% CI] were 73.4% [91/124; 64.7, 80.9] for NVX-CoV2515 versus 50.9% [59/116; 41.4, 60.3] for NVX-CoV2373. All formulations were similarly well-tolerated. Conclusions. NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373.
ABSTRACT
Background Due to waning immunity following primary immunization with Covid-19 vaccines, booster doses may be required. The present study assessed a heterologous booster of SII-NVX-CoV2373 (spike protein vaccine) in adults primed with viral vector and inactivated vaccines.Methods In this Phase 3, observer-blind, randomized, active controlled study, a total of 372 adults primed with ChAdOx1 nCoV-19 (n = 186) or BBV152 (n = 186) at least six months ago, were randomized to receive a booster of SII-NVX-CoV2373 or control vaccine. The control group received homologous booster of ChAdOx1 nCoV-19 or BBV152 depending upon the prime cohort. Anti-S IgG and neutralizing antibodies were assessed at baseline (day 1), day 29, day 91 and day 181 for immunogenicity assessments. Solicited reactions were collected for one week after vaccination. Unsolicited adverse events (AEs) were collected for 28 days while serious adverse events (SAE) and adverse events of special interest (AESI) were reported throughout the six-month study duration. (Identifier: CTRI/2022/04/042017)Results In both the ChAdOx1 nCoV-19 primed group and BBV152 primed group, 186 participants each received the study vaccines. In the ChAdOx1 nCoV-19 Prime cohort, at 28 days after the booster dose, there was a 3.9- to 5.1-fold-rise and 1.9- to 2.8-fold-rise in anti-S IgG and neutralizing antibody titres from the baseline in the SII-NVX-CoV2373 group and the ChAdOx1 nCoV-19 group, respectively. The same responses for the BBV152 prime cohort was 7.4- to 10.4-fold-rise and 1.5- to 2.5-fold-rise in the SII-NVX-CoV2373 group and the BBV152 group, respectively. There was 86.96% (95% CI 78.32, 93.07) to 94.57% (95% CI 87.77, 98.21) and 37.63% (95% CI 27.79, 48.28) to 79.57% (95% CI 69.95, 87.23) anti-S IgG and neutralizing antibody seroresponse (2-fold-rise from baseline) in the SII-NVX-CoV2373 group and ChAdOx1 nCoV-19 group, respectively. The same was 94.51% (95% CI 87.64, 98.19) to 98.90% (95% CI 94.03, 99.97) and 20.43% (95% CI 12.77, 30.05) to 74.19% (95% CI 64.08, 82.71) in the SII-NVX-CoV2373 group and BBV152 group, respectively. No SAE or AESI was caused by the study vaccines.Conclusion SII-NVX-CoV2373 showed a numerically higher boosting effect than homologous boosters in adults primed with ChAdOx1 nCoV-19 and BBV152. The vaccine was also safe and well tolerated.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , COVID-19ABSTRACT
Background The emergence of SARS-CoV-2 variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5g SARS-CoV-2 rS + 50g Matrix-M adjuvant) was evaluated to determine induction of cross-reactive antibodies to variants of concern. Methods A 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. Results Among 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. Conclusions A 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 number: NCT04368988
Subject(s)
Drug-Related Side Effects and Adverse ReactionsABSTRACT
BACKGROUND Over 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. METHODS Safety, 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. RESULTS Among 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. CONCLUSIONS NVX-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).
Subject(s)
COVID-19 , Drug Hypersensitivity , Communicable DiseasesABSTRACT
NVX-CoV2373 is an adjuvanted recombinant full-length SARS-CoV-2 spike trimer protein vaccine demonstrated to be protective against COVID-19 in efficacy trials. Here we demonstrate that vaccinated subjects made CD4+ T cell responses after one and two doses of NVX-CoV2373, and a subset of individuals made CD8+ T cell responses. Characterization of the vaccine-elicited CD8+ T cells demonstrated IFN{gamma} production. Characterization of the vaccine-elicited CD4+ T cells revealed both circulating T follicular helper cells (cTFH) and TH1 cells (IFN{gamma}, TNF, and IL-2) were detectable within 7 days of the primary immunization. Spike-specific CD4+ T cells were correlated with the magnitude of the later SARS-CoV-2 neutralizing antibody titers, indicating that robust generation of CD4+ T cells, capable of supporting humoral immune responses, may be a key characteristic of NVX-CoV2373 which utilizes Matrix-M adjuvant.
Subject(s)
COVID-19ABSTRACT
Background Emerging 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. Methods In 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. Findings An 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. Interpretation Administration 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.
Subject(s)
COVID-19ABSTRACT
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally. As SARS-CoV-2 has transmitted from person to person, variant viruses have emerged with elevated transmission rates and higher risk of infection for vaccinees. We present data showing that a recombinant prefusion-stabilized Spike (rS) protein based on the B.1.351 sequence (rS-B.1.351) was highly immunogenic in mice and produced neutralizing antibodies against SARS-CoV-2/WA1, B.1.1.7, and B.1.351. Mice vaccinated with our prototype vaccine NVX-CoV2373 (rS-WU1) or rS-B.1.351 alone, in combination, or as a heterologous prime boost, were protected when challenged with live SARS-CoV-2/B.1.1.7 or SARS-CoV-2/B.1.351. Virus titer was reduced to undetectable levels in the lungs post-challenge in all vaccinated mice, and Th1-skewed cellular responses were observed. A strong anamnestic response was demonstrated in baboons boosted with rS-B.1.351 approximately one year after immunization with NVX-CoV2373 (rS-WU1). An rS-B.1.351 vaccine alone or in combination with prototype rS-WU1 induced protective antibody- and cell-mediated responses that were protective against challenge with SARS-CoV-2 variant viruses.
Subject(s)
Coronavirus InfectionsABSTRACT
Background The 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. Methods In 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 micrograms recombinant spike protein with 50 micrograms Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy greater than or equal to 7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants. Results A 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. Conclusions The 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)
Subject(s)
Coronavirus Infections , HIV Infections , Infections , Immunologic Deficiency Syndromes , COVID-19ABSTRACT
Background NVX-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. Methods This 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. Results Participants 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. Conclusions NVX-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).