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

BACKGROUND: NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America. METHODS: We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed. RESULTS: Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose. CONCLUSIONS: NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.).

Strong CD4+ T-Cell Responses to Ancestral and Variant Spike Proteins Are Established by NVX-CoV2373 Severe Acute Respiratory Syndrome Coronavirus 2 Primary Vaccination.

BACKGROUND: NVX-CoV2373 is an efficacious coronavirus disease 2019 (COVID-19) vaccine comprising full-length recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (rS) glycoprotein and Matrix-M adjuvant. Phase 2 of a randomized, placebo-controlled, phase 1/2 trial in healthy adults (18-84 years of age) previously reported good safety/tolerability and robust humoral immunogenicity. METHODS: Participants were randomized to placebo or 1 or 2 doses of 5-µg or 25-µg rS with 50 µg Matrix-M adjuvant 21 days apart. CD4+ T-cell responses to SARS-CoV-2 intact S or pooled peptide stimulation (with ancestral or variant S sequences) were measured via enzyme-linked immunosorbent spot assay and intracellular cytokine staining. RESULTS: A clearly discernable spike antigen-specific CD4+ T-cell response was induced after 1 dose, but markedly enhanced after 2 doses. Counts and fold increases in cells producing Th1 cytokines exceeded those secreting Th2 cytokines, although both phenotypes were clearly present. Interferon-γ responses to rS were detected in 93.5% of 2-dose 5-µg recipients. A polyfunctional CD4+ T-cell response was cross-reactive and of equivalent magnitude to all tested variants, including Omicron BA.1/BA.5. CONCLUSIONS: NVX-CoV2373 elicits a moderately Th1-biased CD4+ T-cell response that is cross-reactive with ancestral and variant S proteins after 2 doses. CLINICAL TRIALS REGISTRATION: NCT04368988.

Immunogenicity and safety of heterologous Omicron BA.1 and bivalent SARS-CoV-2 recombinant spike protein booster vaccines: a phase 3, randomized, clinical trial.

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.

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

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).

Induction of Cross-Reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-Cell Responses by a Recombinant Matrix-M-Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine.

BACKGROUND: Recurrent reports of suboptimal influenza vaccine effectiveness have renewed calls to develop improved, broadly cross-protective influenza vaccines. Here, we evaluated the safety and immunogenicity of a novel, saponin (Matrix-M)-adjuvanted, recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV). METHODS: We conducted a randomized, observer-blind, comparator-controlled (trivalent high-dose inactivated influenza vaccine [IIV3-HD] or quadrivalent recombinant influenza vaccine [RIV4]), safety and immunogenicity trial of qNIV (5 doses/formulations) in healthy adults ≥65 years. Vaccine immunogenicity was measured by hemagglutination-inhibition assays using reagents that express wild-type hemagglutination inhibition (wt-HAI) sequences and cell-mediated immune responses. RESULTS: A total of 1375 participants were randomized, immunized, and followed for safety and immunogenicity. Matrix-M-adjuvanted qNIV induced superior wt-HAI antibody responses against 5 of 6 homologous or drifted strains compared with unadjuvanted qNIV. Adjuvanted qNIV induced post-vaccination wt-HAI antibody responses at day 28 that were statistically higher than IIV3-HD against a panel of homologous or drifted A/H3N2 strains, similar to IIV3-HD against homologous A/H1N1 and B (Victoria) strains and similar to RIV4 against all homologous and drifted strains evaluated. The qNIV formulation with 75 µg Matrix-M adjuvant induced substantially higher post-vaccination geometric mean fold increases of influenza HA-specific polyfunctional CD4+ T cells compared with IIV3-HD or RIV4. Overall, similar frequencies of solicited and unsolicited adverse events were reported in all treatment groups. CONCLUSIONS: qNIV with 75 µg Matrix-M adjuvant was well tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses. Further investigation in a pivotal phase 3 trial is underway. CLINICAL TRIALS REGISTRATION: NCT03658629.

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.

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.

Safety and Immunogenicity of a Respiratory Syncytial Virus Fusion (F) Protein Nanoparticle Vaccine in Healthy Third-Trimester Pregnant Women and Their Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract disease and hospitalization worldwide. METHODS: Safety and immunogenicity of RSV fusion (F) protein nanoparticle vaccine or placebo were evaluated in 50 healthy third-trimester pregnant women. Assessments included vaccine tolerability and safety in women and infants, and RSV-specific antibody measures in women before and after vaccination, at delivery and post partum. RESULTS: The vaccine was well tolerated; no meaningful differences in pregnancy or infant outcomes were observed between study groups. RSV-specific antibody levels increased significantly among vaccine recipients, including responses competitive with well-described monoclonal antibodies specific for multiple RSV neutralizing epitopes. No significant antibody increase was seen among placebo recipients, although a shallow upward trend across the RSV season was noted. Transplacental antibody transfer was 90%-120% across assays for infants of vaccinated women. Women with an interval of ≥30 days between vaccination and delivery demonstrated higher placental antibody transfer rates than women with an interval <30 days. Half-lives of RSV-specific antibodies in infants approximated 40 days. There was no evidence of severe RSV disease in infants of vaccinated mothers. CONCLUSIONS: Data from this phase 2 study support a maternal immunization strategy to protect infants from RSV disease. CLINICAL TRIALS REGISTRATION: NCT02247726.

Ketalization of 2-heptanone to prolong its activity as mite repellant for the protection of honey bees.

BACKGROUND: 2-Heptanone is a volatile liquid known to be effective in protecting honey bees from parasitic mite infestations in hives. The present study aimed to show that chemical derivatives of 2-heptanone would release the ketone for a significantly longer time than it takes for the pure ketone to evaporate and preferably for as long as two brood cycles of a honey bee (42 days). RESULTS: A liquid ketal of 2-heptanone with glycerol (Glyc-Ket) and solid ketals of the ketone with polyvinyl alcohol (PVAl-Ket), containing different amounts of the ketone, were synthesized. The fully resolved 1 H and 13 C nuclear magenetic resonance (NMR) spectra of the ketals are discussed. In the case of the polymer, differential scanning calorimetry (DSC) of a ketal was also compared with the unketalized polyvinyl alcohol. The length of time for which 2-heptanone was released by the ketals was determined by gas chromatography-mass spectrometry of the headspace. In the case of Glyc-Ket, the concentration of the 2-heptanone in the liquid phase was also monitored by 1 H NMR spectroscopy. The deketalization was pH dependent, ranging between 2.0 and 2.5 for Glyc-Ket and between 2.0 and 3.5 for PVAl-Ket. CONCLUSION: Under bee hive conditions, the release of 55 mmol 2-heptanone from Glyc-Ket lasted for 42 days, whereas the release of the ketone from the PVAl-Ket with a similar amount of the ketone lasted for 23 days, versus a maximum of 17 days for an equivalent amount of the pure ketone. These ketals therefore have the potential to be effective mite repellants for the protection of honey bees. © 2019 Society of Chemical Industry.

Immunogenicity and safety of a respiratory syncytial virus fusion protein (RSV F) nanoparticle vaccine in older adults.

BACKGROUND: A preventative strategy for Respiratory Syncytial Virus (RSV) infection constitutes an under-recognized unmet medical need among older adults. Four formulations of a novel recombinant RSV F nanoparticle vaccine (60 or 90 µg RSV F protein, with or without aluminum phosphate adjuvant) administered concurrently with a licensed inactivated trivalent influenza vaccine (TIV) in older adult subjects were evaluated for safety and immunogenicity in this randomized, observer-blinded study. RESULTS: A total of 220 healthy males and females ≥ 60 years of age, without symptomatic cardiopulmonary disease, were vaccinated concurrently with TIV and RSV F vaccine or placebo. All vaccine formulations produced an acceptable safety profile, with no vaccine-related serious adverse events or evidence of systemic toxicity. Vaccine-induced immune responses were rapid, rising as early as 7 days post-vaccination; and were comparable in all formulations in terms of magnitude, with maximal levels attained within 28 (unadjuvanted) or 56 (adjuvanted) days post-vaccination. Peak anti-F protein IgG antibody levels rose 3.6- to 5.6-fold, with an adjuvant effect observed at the 60 µg dose, and a dose-effect observed between the unadjuvanted 60 and 90 µg regimens. The anti-F response persisted through 12 months post-vaccination. Palivizumab-competitive antibodies were below quantifiable levels (<33 µg/mL) at day 0. The rise of antibodies with specificity for Site II peptide, and the palivizumab-competitive binding activity, denoting antibodies binding at, or in proximity to, antigenic Site II on the F protein, closely paralleled the anti-F response. However, a larger proportion of antibodies in adjuvanted vaccine recipients bound to the Site II peptide at high avidity. Day 0 neutralizing antibodies were high in all subjects and rose 1.3- to 1.7-fold in response to vaccination. Importantly, the RSV F vaccine co-administered with TIV did not impact the serum hemagglutination inhibition antibody responses to a standard-dose TIV, and TIV did not impact the immune response to the RSV F vaccine. CONCLUSIONS: RSV F protein nanoparticle vaccine induced increases in measures of functional immunity to RSV in older adults and demonstrated an acceptable safety profile. Adjuvanted formulations provided additional immunogenicity benefit as compared to increasing antigen dose alone. This trial was registered with ClinicalTrials.gov number NCT01709019.

A Randomized, Blinded, Controlled, Dose-Ranging Study of a Respiratory Syncytial Virus Recombinant Fusion (F) Nanoparticle Vaccine in Healthy Women of Childbearing Age.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of infant morbidity and mortality. A recombinant RSV fusion protein nanoparticle vaccine (RSV F vaccine) candidate for maternal immunization was tested for safety and immunogenicity in women of childbearing age. METHODS: Three hundred thirty women (18-35 years) were randomized to receive 1 or 2 doses of RSV F vaccine (60 or 90 µg) with or without aluminum phosphate adjuvant, or placebo at days 0 and 28. Safety was evaluated over 180 days; immunogenicity and RSV infection rates were evaluated over 112 days. RESULTS: All vaccine formulations were well tolerated, without vaccine-related serious adverse events. Anti-F immunoglobulin G antibodies rose 6.5-15.6-fold, with significantly higher levels in 2-dose, adjuvanted regimens at day 56. Palivizumab-competitive antibody levels were undetectable at day 0 but increased up to 325 µg/mL at day 56. A 2.7- and 3.5-fold rise in RSV/A and RSV/B microneutralization antibodies were noted at day 56. Between days 56 and 112, 21% (12/56) of placebo recipients and 11% of vaccinees (26/244) showed evidence of a recent RSV infection (P = .04). CONCLUSIONS: The vaccine appeared safe, immunogenic, and reduced RSV infections. Further development as a vaccine for use in maternal immunization is warranted. CLINICAL TRIALS REGISTRATION: NCT01704365.

Controlled Release of Linalool Using Nanofibrous Membranes of Poly(lactic acid) Obtained by Electrospinning and Solution Blow Spinning: A Comparative Study.

The controlled-release of natural plant oils such as linalool is of interest in therapeutics, cosmetics, and antimicrobial and larvicidal products. The present study reports the release characteristics of linalool encapsulated at three concentrations (10, 15 and 20 wt.%) in poly(lactic acid) nanofibrous membranes produced by electrospinning and solution blow spinning (SBS) as well as the effect of linalool on fiber morphology and structural properties. PLA nanofibrous membranes were characterized by Scanning Electron Microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and contact angle measurements. The average diameters of the electrospun and solution blow spun nanofibers were similar, ranging from 176 to 240 nm. Linalool behaved as a plasticizer to PLA decreasing the glass transition temperature (Tg), melting point (Tm) and crystallization temperature (TC) of PLA. Curves of the release of linalool at 35 °C were non-linear, showing a clear biphasic pattern consistent with one or more Fickian release components. The time required to release 50% of linalool (t1/2) decreased with increasing linalool concentration. The range in t1/2 values for SBS nanofibers was higher (291-1645s) than the t1/2 values for electrospun fibers (76-575s).

Effect of Starch and Paperboard Reinforcing Structures on Insulative Fiber Foam Composites.

Single-use plastic foams are used extensively as interior packaging to insulate and protect items during shipment but have come under increasing scrutiny due to the volume sent to landfills and their negative impact on the environment. Insulative compression molded cellulose fiber foams could be a viable alternative, but they do not have the mechanical strength of plastic foams. To address this issue, a novel approach was used that combined the insulative properties of cellulose fiber foams, a binder (starch), and three different reinforcing paperboard elements (angular, cylindrical, and grid) to make low-density foam composites with excellent mechanical strength. Compression molded foams and composites had a consistent thickness and a smooth, flat finish. Respirometry tests showed the fiber foams mineralized in the range of 37 to 49% over a 46 d testing period. All of the samples had relatively low density (Dd) and thermal conductivity (TC). The Dd of samples ranged from 33.1 to 64.9 kg/m3, and TC ranged from 0.039 to 0.049 W/mk. The addition of starch to the fiber foam (FF+S) and composites not only increased Dd, drying time (Td), and TC by an average of 18%, 55%, and 5.5%, respectively, but also dramatically increased the mechanical strength. The FF+S foam and paperboard composites had 240% and 350% higher average flexural strength (σfM) and modulus (Ef), respectively, than the FF-S composites. The FF-S grid composite and all the FF+S foam and composite samples had equal or higher σfM than EPS foam. Additionally, FF+S foam and paperboard composites had 187% and 354% higher average compression strength (CS) and modulus (Ec), respectively, than the FF-S foam and composites. All the paperboard composites for both FF+S and FF-S samples had comparable or higher CS, but only the FF+S cylinder and grid samples had greater toughness (Ωc) than EPS foam. Fiber foams and foam composites are compatible with existing paper recycling streams and show promise as a biodegradable, insulative alternative to EPS foam internal packaging.

Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial.

BACKGROUND: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 µg SARS-CoV-2 recombinant spike protein and 50 µg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 µg of NVX-CoV2373 plus 2·5 µg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING: Novavax.

Immunogenicity and safety of a fourth homologous dose of NVX-CoV2373.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5 µg SARS-CoV-2 recombinant spike [rS] protein + 50 µg Matrix-M™ adjuvant; Novavax, Gaithersburg, MD) was evaluated to determine induction of cross-reactive antibodies to variants of concern. A phase II randomized study (NCT04368988) recruited participants in Australia and the United States to assess a primary series of NVX-CoV2373 followed by two booster doses (third and fourth doses at 6-month intervals) in adults 18-84 years of age. The primary series was administered when the SARS-CoV-2 ancestral strain was prevalent and the third and fourth doses while the Alpha and Delta variants were prevalent in AUS and US. 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 serum immunoglobulin G (IgG) and neutralization assays against ancestral SARS-CoV-2 strain and Omicron sublineages. Among 1283 enrolled participants, 258 were randomized to receive the two-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 4. Unsolicited AEs were reported in 9 % of participants after dose 4 (none of which were severe or serious). Anti-rS IgG levels and neutralization antibody titers increased following booster doses to a level approximately four-fold higher than that observed after the primary series, with a progressively narrowed gap in response between the ancestral strain and Omicron BA.5. A fourth dose of NVX-CoV2373 enhanced immunogenicity for ancestral and variant SARS-CoV-2 strains without increasing reactogenicity, indicating that updates to the vaccine composition may not be currently warranted.

Novavax NVX-COV2373 triggers neutralization of Omicron sub-lineages.

The SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern (VOC) and its sub-lineages (including BA.2, BA.4, BA.5, BA.2.12.1) contain spike mutations that confer high level resistance to neutralizing antibodies induced by vaccination with ancestral spike or infection with previously circulating variants. The NVX-CoV2373 vaccine, a protein nanoparticle vaccine containing the ancestral spike sequence, has value in countries with constrained cold-chain requirements. Here we report neutralizing titers following two or three doses of NVX-CoV2373. We show that after two doses, Omicron sub-lineages BA.1 and BA.4/BA.5 were resistant to neutralization by 72% (21/29) and 59% (17/29) of samples respectively. However, after a third dose of NVX-CoV2373, we observed high titers against Omicron BA.1 (GMT: 1,197) and BA.4/BA.5 (GMT: 582), with responses similar in magnitude to those triggered by three doses of an mRNA vaccine. These data are of particular relevance as BA.4/BA.5 is dominating in multiple locations, and highlight the potential utility of the NVX-CoV2373 vaccine as a booster in resource-limited environments.

Immunogenicity of NVX-CoV2373 in PREVENT-19: A Phase 3, Randomized, Placebo-Controlled Trial in Adults in the United States and Mexico.

Background: NVX-CoV2373, an adjuvanted, recombinant SARS-CoV-2 spike (rS) protein vaccine, consistently demonstrated protective efficacy against COVID-19 in clinical trials and has received regulatory authorizations or approvals worldwide. Methods: PREVENT-19 (NCT04611802) is a phase 3, randomized, observer-blinded, placebo-controlled trial evaluating safety, immunogenicity, and efficacy of NVX-CoV2373 in ≈30 000 participants ≥18 years in the United States and Mexico. Vaccine humoral immune response (ie, serum immunoglobulin [IgG] antibodies, hACE2 receptor binding inhibition antibodies, and neutralizing antibodies to SARS-CoV-2) (ancestral strain) was assessed in 1200 participants randomly selected and equally divided between participants 18-64 and ≥65 years. Results: In the per protocol analysis, NVX-CoV2373 induced vigorous serum antibody responses among the 1063 analyzed participants who were SARS-CoV-2 seronegative at baseline, received both doses of study treatment, and had serology results available 2 weeks after dose 2. Geometric mean (GM) responses in both younger and older adults were higher among recipients of vaccine versus placebo for IgG (64 259 vs 121 and 37 750 vs 133 ELISA units, respectively), hACE2 receptor binding inhibition GM titers (GMTs) (222 vs 5 and 136 vs 5, respectively), and neutralizing antibody GMTs (1303 vs 11 and 900 vs 11, respectively). Humoral responses were 30-40% lower in participants ≥65 years or HIV-positive; however, seroconversion rates were high and comparable between the age cohorts, regardless of HIV serostatus. Conclusions: NVX-CoV2373 elicited robust humoral immune responses against ancestral SARS-CoV-2 virus 2 weeks following the second vaccination in adult PREVENT-19 participants, consistent with previously reported high vaccine efficacy.

Safety, efficacy, and immunogenicity of the NVX-CoV2373 vaccine.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality worldwide. As SARS-CoV-2 moves into endemic status, vaccination remains a key element in protecting the health of individuals, societies, and economies worldwide. AREAS COVERED: NVX-CoV2373 (Novavax, Gaithersburg, MD) is a recombinant protein vaccine composed of SARS-CoV-2 spike trimer nanoparticles formulated with saponin-based Matrix-M™ adjuvant (Novavax, Gaithersburg, MD). NVX-CoV2373 is authorized for emergency use in adults and adolescents aged ≥12 years in the United States and numerous other countries. EXPERT OPINION: In clinical trials, NVX-CoV2373 showed tolerable reactogenicity and favorable safety profiles characterized by mostly mild-to-moderate adverse events of short duration and by low rates of severe and serious adverse events comparable to those seen with placebo. The two-dose primary vaccination series resulted in robust increases in anti-spike protein immunoglobulin G, neutralizing antibody titers, and cellular immune responses. NVX-CoV2373 vaccination was associated with complete protection against severe disease and a high (90%) rate of protection against symptomatic disease in adults, including symptomatic disease caused by SARS-CoV-2 variants. Additionally, the NVX-CoV2373 adjuvanted recombinant protein platform offers a means to address issues of COVID-19 vaccination hesitancy and global vaccine equity.