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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. 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-[mu]g or 25-[mu]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. 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-[mu]g and 25-[mu]g NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 [mu]g, 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%-MN.sub.50%) 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. The study confirmed the phase 1 findings that the 2-dose regimen of 5-[mu]g NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 [mu]g was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies.

A recombinant SARS-CoV-2 spike protein nanoparticle vaccine delivered in the deltoid muscle on days 0 and 21 was found to be immunogenic at both 5 μg and 25 μg doses. When given with a saponin-based adjuvant, both doses were equally immunogenic, with little or no reactogenicity, and elicited neutralizing antibody titers higher than those in convalescent serum.

Authorities globally recommended a monovalent omicron XBB.1.5-based COVID-19 vaccine for the 2023–24 season. The Novavax COVID-19 vaccine, NVX-CoV2601, contains XBB.1.5 recombinant spike protein, based on an authorised prototype vaccine (NVX-CoV2373) technology. We aimed to determine whether a single dose of NVX-CoV2601 versus NVX-CoV2373 (from a previous study [2019nCoV-311 part 2]) produced superior neutralising antibody (nAb) responses, and non-inferior seroresponse rates to XBB.1.5, after three or more previous mRNA-based COVID-19 vaccinations. In part 1 of this single-arm, phase 2/3 study (2019nCoV-313), participants aged 18 years or older who had been previously vaccinated with three or more doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) were enrolled across 30 US centres (research groups and universities) located across 20 states. Participants received one intramuscular injection of NVX-CoV2601 (5 μg XBB.1.5 spike plus 50 μg Matrix-M adjuvant). Coprimary endpoints were superiority of baseline-adjusted nAb geometric mean XBB.1.5 titres (adjusted GMTs), with superiority declared when the lower bound of the 95% CI for the GMT ratio (GMTR) was greater than 1, and non-inferiority of seroresponse rates, with non-inferiority declared when the lower bound of the 95% CI for the seroresponse rate difference was greater than –10%, on day 28; comparisons were made for NVX-CoV2601 administered in this study versus NVX-CoV2373 administered in part 2 (group G) of the 2019nCoV-311 study. Coprimary endpoints were assessed in the per-protocol immunogenicity set (ie, all participants who received study vaccine, underwent 28 days of follow-up, had day 0 and day 28 samples available, and had no major protocol deviations). Safety was a secondary endpoint and included assessments of solicited treatment-emergent adverse events up to 7 days and unsolicited treatment-emergent adverse events up to 28 days after vaccination in the safety analysis set (ie, all participants who received study vaccine). Here we report the prespecified interim analysis of immunogenicity and safety up to day 28. This study is registered with ClinicalTrials.gov, NCT05975060, and is now complete. Between Sept 7 and Sept 8, 2023, 380 individuals were screened, of whom 332 were enrolled and received study vaccine. At the 28-day interim analysis database lock (Jan 17, 2023), the per-protocol analysis sets included 309 (93%) of 332 NVX-CoV2601 recipients and 227 (90%) of 252 NVX-CoV2373 recipients. Mean age of NVX-CoV2601 recipients was 52·1 years (SD 16·1); 192 (62%) of 309 were female and 117 (38%) were male. Mean age of NVX-CoV2373 recipients was 42·2 years (13·4); 128 (56%) of 227 were female and 99 (44%) were male. At day 28, the baseline-adjusted nAb GMT for NVX-CoV2601 was 905·9 (95% CI 807·1–1016·8) and for NVX-CoV2373 was 156·6 (137·0–179·0); the between-group adjusted GMTR was 5·8 (95% CI 4·9–6·9). In the per-protocol immunogenicity set, seroresponse rates were 64% (196 of 305) among recipients of NVX-CoV2601 and 7% (16 of 227) among recipients of NVX-CoV2373, with a seroresponse rate difference of 57% (95% CI 51–63). In the NVX-CoV2601 group, within 7 days, solicited local treatment-emergent adverse events were reported in 189 (57%) of 332 participants (including one [<1%] grade 3 or worse event; tenderness) and solicited systemic treatment-emergent adverse events were reported in 158 (48%) participants (including four [1%] participants with one or more grade 3 events; malaise [n=3], headache [n=2], fatigue [n=1], and muscle pain [n=1]). The most common solicited treatment-emergent adverse events were tenderness (171 [52%]) and pain (98 [30%]) at the injection site, fatigue (97 [29%]), and muscle pain (97 [29%]). Up to day 28, unsolicited adverse events considered related to study vaccination in the NVX-CoV2601 group occurred in five (2%) participants (one for each of asthma, axillary pain, diarrhoea, hypertension [which was medically attended], and presyncope). No serious adverse events due to study product, adverse events of special interest, or deaths due to study product occurred, and no study discontinuations due to treatment-emergent adverse events occurred. The coprimary endpoints were met, and NVX-CoV2601 was well tolerated. These interim data support NVX-CoV2601 use per guidance for XBB.1.5-directed COVID-19 vaccines and demonstrate the adaptability of this vaccine platform for updated SARS-CoV-2 spike proteins. Novavax.

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 individuals made CD4+ T cell responses after 1 and 2 doses of NVX-CoV2373, and a subset of individuals made CD8+ T cell responses. Characterization of the vaccine-elicited CD8+ T cells demonstrated IFN-γ production. Characterization of the vaccine-elicited CD4+ T cells revealed both circulating T follicular helper (cTfh) cells and Th1 cells (IFN-γ+, TNF-α+, 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 that utilizes Matrix-M adjuvant.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 individuals made CD4+ T cell responses after 1 and 2 doses of NVX-CoV2373, and a subset of individuals made CD8+ T cell responses. Characterization of the vaccine-elicited CD8+ T cells demonstrated IFN-γ production. Characterization of the vaccine-elicited CD4+ T cells revealed both circulating T follicular helper (cTfh) cells and Th1 cells (IFN-γ+, TNF-α+, 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 that utilizes Matrix-M adjuvant.

Improved seasonal influenza vaccines for older adults that can induce broadly cross-reactive antibodies and enhanced T-cell responses, particularly against A H3N2 viruses, while avoiding egg-adaptive antigenic changes, are needed. We aimed to show that the Matrix-M-adjuvanted quadrivalent nanoparticle influenza vaccine (qNIV) was immunologically non-inferior to a licensed, standard-dose quadrivalent inactivated influenza vaccine (IIV4) in older adults. This was a phase 3 randomised, observer-blinded, active-comparator controlled trial done across 19 US community-based clinical research sites during the 2019–20 influenza season. Participants were clinically stable and community-dwelling, aged at least 65 years, and were randomised in a 1:1 ratio using an interactive web response system to receive a single intramuscular dose of qNIV or IIV4. The primary objective was to describe safety and show that qNIV was immunologically non-inferior to IIV4. The primary outcomes were adverse events by treatment group and comparative haemagglutination-inhibiting antibody responses (assayed with egg-propagated virus) on day 28, summarised in terms of the ratio of geometric mean titres (GMTRqNIV/IIV4) and seroconversion rate (SCR) difference between participants receiving qNIV or IIV4 for all four vaccine homologous influenza strains. The immunogenicity outcome was measured in the per-protocol population. Non-inferiority was shown if the lower bound of the two-sided 95% CI on the GMTRqNIV/IIV4 was at least 0·67 and the lower bound of the two-sided 95% CI on the SCR difference -was at least −10%. The study is registered with clinicaltrials.gov, NCT04120194, and is active and not recruiting. 2742 adults were assessed for eligibility and 2654 were enrolled and randomised between Oct 14, 2019, and Oct 25, 2019; 1333 participants were randomised to the qNIV group and 1319 to the IIV4 group (two participants withdrew consent before being assigned to a group). qNIV showed immunological non-inferiority to IIV4: GMTRqNIV/IIV4 for the four vaccine homologous influenza strains was A/Brisbane 1·09 (95% CI 1·03 to 1·15), A/Kansas 1·19 (1·11 to 1·27), B/Maryland 1·03 (0·99 to 1·07), and B/Phuket 1·23 (1·16 to 1·29); and SCR difference was A/Brisbane 5·0 (95% CI 1·9 to 8·1), A/Kansas 7·3 (3·6 to 11·1), B/Maryland 0·5 (−1·9 to 2·9), and B/Phuket 8·5 (5·0 to 11·9). 659 (49·4%) of 1333 of participants in the qNIV group and 551 (41·8%) of 1319 participants in the IIV4 group had at least one treatment-emergent adverse event. More solicited adverse events were reported by participants in the qNIV group (551 [41·3%] of 1333) than in the IIV4 group (420 [31·8%] of 1319), and were comprised primarily of mild to moderate transient injection site pain (341 [25·6%] in the qNIV group vs 212 [16·1%] in the IIV4 group). qNIV was well tolerated and produced qualitatively and quantitatively enhanced humoral and cellular immune response in older adults compared with IIV4. qNIV might enhance the effectiveness of seasonal influenza vaccination, and future studies to show clinical efficacy are planned. Novavax.

Emerging SARS-CoV-2 variants and evidence of waning vaccine efficacy present substantial obstacles towards controlling the COVID-19 pandemic. Booster doses of SARS-CoV-2 vaccines might address these concerns by amplifying and broadening the immune responses seen with initial vaccination regimens. We aimed to assess the immunogenicity and safety of a homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373). This secondary analysis of a phase 2, randomised study assessed a single booster dose of a SARS-CoV-2 recombinant spike protein vaccine with Matrix-M adjuvant (NVX-CoV2373) in healthy adults aged 18–84 years, recruited from 17 clinical centres in the USA and Australia. Eligible participants had a BMI of 17–35 kg/m2 and, for women, were heterosexually inactive or using contraception. Participants who had a history of SARS-CoV or SARS-CoV-2, confirmed diagnosis of COVID-19, serious chronic medical conditions, or were pregnant or breastfeeding were excluded. Approximately 6 months following their primary two-dose vaccination series (administered day 0 and day 21), participants who received placebo for their primary vaccination series received a placebo booster (group A) and participants who received NVX-CoV2373 for their primary vaccination series (group B) were randomly assigned (1:1) again, via centralised interactive response technology system, to receive either placebo (group B1) or a single booster dose of NVX-CoV2373 (5 μg SARS-CoV-2 rS with 50 μg Matrix-M adjuvant; group B2) via intramuscular injection; randomisation was stratified by age and study site. Vaccinations were administered by designated site personnel who were masked to treatment assignment, and participants and other site staff were also masked. Administration personnel also assessed the outcome. The primary endpoints are safety (unsolicited adverse events) and reactogenicity (solicited local and systemic) events and immunogenicity (serum IgG antibody concentrations for the SARS-CoV-2 rS protein antigen) assessed 14 days after the primary vaccination series (day 35) and 28 days following booster (day 217). Safety was analysed in all participants in groups A, B1, and B2, according to the treatment received; immunogenicity was analysed in the per-protocol population (ie, participants in groups A, B1, and B2) who received all assigned doses and who did not test SARS-CoV-2-positive or received an authorised vaccine, analysed according to treatment assignment). This trial is registered with ClinicalTrials.gov, NCT04368988. 1610 participants were screened from Aug 24, 2020, to Sept 25, 2020. 1282 participants were enrolled, of whom 173 were assigned again to placebo (group A), 106 were re-randomised to NVX-CoV2373–placebo (group B1), and 104 were re-randomised to NVX-CoV2373–NVX-CoV2373 (group B2); after accounting for exclusions and incorrect administration, 172 participants in group A, 102 in group B1, and 105 in group B2 were analysed for safety. Following the active booster, the proportion of participants with available data reporting local (80 [82%] of 97 participants had any adverse event; 13 [13%] had a grade ≥3 event) and systemic (75 [77%] of 98 participants had any adverse event; 15 [15%] had a grade ≥3 event) reactions was higher than after primary vaccination (175 [70%] of 250 participants had any local adverse event, 13 [5%] had a grade ≥3 event; 132 [53%] of 250 had any systemic adverse event, 14 [6%] had a grade ≥3 event). Local and systemic events were transient in nature (median duration 1·0–2·5 days). In the per-protocol immunogenicity population at day 217 (167 participants in group A, 101 participants in group B1, 101 participants in group B2), IgG geometric mean titres (GMT) had increased by 4·7-fold and MN50 GMT by 4·1-fold for the ancestral SARS-CoV-2 strain compared with the day 35 titres. Administration of a booster dose of NVX-CoV2373 resulted in an incremental increase in reactogenicity. For both the prototype strain and all variants evaluated, immune responses following the booster were similar to or higher than those associated with high levels of efficacy in phase 3 studies of the vaccine. These data support the use of NVX-CoV2373 in booster programmes. Novavax and the Coalition for Epidemic Preparedness Innovations.

We evaluated the immunogenicity and safety of a dose of NVX-CoV2705, a JN.1 subvariant SARS CoV-2 rS vaccine, in adults previously vaccinated with authorized/approved COVID-19 vaccines. Study 2019nCoV-315 is a Phase 3, open-label, single-arm study to evaluate the safety and immunogenicity of a single dose of NVX-CoV2705 in previously COVID-19–vaccinated adult participants ≥18 years of age in the United States. Participants received one dose of NVX-CoV2705. The primary immunogenicity endpoint was the geometric mean titer (GMT) of serum neutralizing antibodies against the SARS-CoV-2 Omicron JN.1 variant at Day 28 following study vaccination and seroresponse rate (SRR) in ID50 titers for the JN.1 subvariant assessed at Day 28 following study vaccination. Primary safety endpoints include local and systemic solicited adverse events (AEs) up to Day 6 post-vaccination, unsolicited AEs up to Day 28, and treatment-related MAAEs, AESIs, and SAEs through Day 180. Exploratory endpoints also provided additional data for circulating variants. Between October 14, 2024, and October 15, 2024, 66 participants were screened and 60 enrolled. A total of 58 participants were included in the Per-Protocol Analysis Set. GMTs increased from 138.6 (95 % CI: 88.0, 218.2) to 671.4 (95 % CI: 437.0, 1031.6) from baseline to Day 28, respectively. In addition, GMTs increased ≥3.8-fold (GMFR) from baseline (Day 0) to Day 28 for currently circulating or emerging Omicron subvariants JN.1, LP.8.1, KP.2, KP.3, KP.3.1.1, MC.1, XEC, MC.10.1, LF.7, LF.7.2.1, LF.7.7.2, NB.1.8.1, and XFC, with an acceptable safety profile after single dose vaccination. A single dose of NVX-CoV2705 induced a rapid and robust anti–SARS-CoV-2 immune response against the Omicron JN.1 and other circulating variants and had an acceptable safety profile. https://clinicaltrials.gov/study/NCT06409663

Most of the population has been infected with SARS-CoV-2 and, thus, is primed by natural exposure. As such, it was assessed whether a single dose of the monovalent XBB.1.5 vaccine, NVX-CoV2601, elicited a comparable immune response to XBB.1.5 in seropositive unvaccinated participants to that in previously vaccinated participants, thereby allowing the former to forego a two-dose primary series. In this phase 2/3, open-label, single-arm study (2019nCoV-313/NCT05975060 [group 2]), vaccine-naive participants ≥18 years with previous SARS-CoV-2 infection received one dose of NVX-CoV2601. This analysis compared the 28-day immunogenicity and safety of NVX-CoV2601 in vaccine-naive and previously vaccinated (≥3 prior mRNA-based vaccines, from 2019nCoV-313 group 1) participants. Noninferiority of neutralizing antibody (nAb) response in vaccine-naive versus vaccinated participants was the primary objective. The day-28 geometric mean titer (GMT) ratio (GMTR) and seroresponse rate (SRR; percentage of participants with a ≥4-fold rise in antibody response from baseline) were measured, and safety was assessed. Of the participants enrolled from September 11 to November 15, 2023, per-protocol sets included 306/338 (90.5%) vaccine-naive and 309/332 (93.1%) vaccinated participants. At day 28, adjusted GMTs (95% CI) against XBB.1.5 in the vaccine-naive and vaccinated groups were 1491.5 (1277.5–1741.4) and 841.4 (723.9–978.0), respectively. The vaccine-naive–vaccinated nAb GMTR was 1.8 (95% CI 1.43–2.20) and SRRs were 74.3% and 64.3% for vaccine-naive and vaccinated participants, respectively (SRR difference: 10.0 [95% CI 2.6–17.4]). No new safety signals or events of special interest were reported. A single dose of NVX-CoV2601 in vaccine-naive participants with a history of SARS-CoV-2 infection elicited a robust neutralizing antibody response that was noninferior to that observed in vaccinated participants. The vaccine was well-tolerated. These data support the use of NVX-CoV2601 as a single dose, regardless of prior vaccination history. NCT05975060. •Single-dose XBB.1.5-based protein vaccine, NVX-CoV2601, was well-tolerated.•NVX-CoV2601 elicited robust immunogenicity, regardless of prior vaccination status.•Immune responses were noninferior in previously unvaccinated vs previously vaccinated.•Cross-reactive immunogenicity to SARS-CoV-2 variants was observed.

Boosters of adjuvanted NVX-CoV2373 protein vaccine led to increasing neutralizing titers of antibody specific for the ancestral strain and omicron variants. Whether the elicited antibodies protect against infection is unclear.

•A fourth dose of NVX-CoV2373 did not increase local/systemic reactogenicity.•A fourth dose of NVX-CoV2373 enhanced immune response to SARS-CoV-2 variants.•An NVX-CoV2373 fourth dose induced robust immunogenicity in those aged 18–84 years.•Correlates of protection imply post-boost efficacy of ≥ 82% for Omicron variants. 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.