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 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 the 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 a superior neutralizing antibody response to BA.1 vs NVX-CoV2373 (n = 274) at day 14 (geometric mean titer ratio, 1.6; 95% CI, 1.33-2.03). Seroresponse rates were 73.4% (91/124; 95% CI, 64.7-80.9) for NVX-CoV2515 vs 50.9% (59/116; 95% CI, 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 as compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT05372588).

Durability of Protection Against COVID-19 Through the Delta Surge for the NVX-CoV2373 Vaccine.

BACKGROUND: Protein-based vaccines for coronavirus disease 2019 (COVID-19) provide a traditional vaccine platform with long-lasting protection for non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogens and may complement messenger RNA vaccines as a booster dose. While NVX-CoV2373 showed substantial early efficacy, the durability of protection has not been delineated. METHODS: The PREVENT-19 vaccine trial used a blinded crossover design; the original placebo arm received NVX-CoV2373 after efficacy was established. Using novel statistical methods that integrate surveillance data of circulating strains with post-crossover cases, we estimated placebo-controlled vaccine efficacy and durability of NVX-CoV2373 against both pre-Delta and Delta strains of SARS-CoV-2. RESULTS: Vaccine efficacy against pre-Delta strains of COVID-19 was 89% (95% CI, 75-95%) and 87% (72-94%) at 0 and 90 days after 2 doses of NVX-CoV2373, respectively, with no evidence of waning (P = .93). Vaccine efficacy against the Delta strain was 88% (71-95%), 82% (56-92%), and 77% (44-90%) at 40, 120, and 180 days, respectively, with evidence of waning (P < .01). In sensitivity analyses, the estimated Delta vaccine efficacy at 120 days ranged from 66% (15-86%) to 89% (74-95%) per various assumptions of the surveillance data. CONCLUSIONS: NVX-CoV2373 has high initial efficacy against pre-Delta and Delta strains of COVID-19 with little evidence of waning for pre-Delta strains through 90 days and moderate waning against Delta strains over 180 days.

The Novavax Heterologous COVID Booster Demonstrates Lower Reactogenicity Than mRNA: A Targeted Review.

COVID-19 continues to be a global health concern and booster doses are necessary for maintaining vaccine-mediated protection, limiting the spread of SARS-CoV-2. Despite multiple COVID vaccine options, global booster uptake remains low. Reactogenicity, the occurrence of adverse local/systemic side effects, plays a crucial role in vaccine uptake and acceptance, particularly for booster doses. We conducted a targeted review of the reactogenicity of authorized/approved mRNA and protein-based vaccines demonstrated by clinical trials and real-world evidence. It was found that mRNA-based boosters show a higher incidence and an increased severity of reactogenicity compared with the Novavax protein-based COVID vaccine, NVX-CoV2373. In a recent NIAID study, the incidence of pain/tenderness, swelling, erythema, fatigue/malaise, headache, muscle pain, or fever was higher in individuals boosted with BNT162b2 (0.4 to 41.6% absolute increase) or mRNA-1273 (5.5 to 55.0% absolute increase) compared with NVX-CoV2373. Evidence suggests that NVX-CoV2373, when utilized as a heterologous booster, demonstrates less reactogenicity compared with mRNA vaccines, which, if communicated to hesitant individuals, may strengthen booster uptake rates worldwide.

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.

Acute Adverse Events at a Mass Vaccination Site after the Third and Fourth COVID-19 Vaccinations in Japan.

The third and fourth doses of the vaccine against coronavirus disease 2019 (COVID-19) were widely administered in Japan since December 2021. Currently, however, data are scarce regarding acute adverse events with the third and fourth doses. The present study reports the profiles of acute adverse events after the third and fourth COVID-19 vaccine doses, seen at the site of a mass vaccination center in Japan. Between December 2021 and July 2022, 267,515 individuals received the third, and 32,934 received the fourth COVID-19 vaccine dose at the mass vaccination center, of whom 442 recipients of the third (0.19%), and 22 recipients of the fourth (0.07%) dose reported acute adverse events and were examined by doctors on site. The most common diagnosis was vasovagal syncope/presyncope (incidence: 0.01-0.10%), followed by other miscellaneous complaints, acute allergic reactions (0.05-0.005%), and anaphylaxis (< 0.005%). Vasovagal syncope/presyncope occurred most frequently in recipients in those in their 20s, whereas acute allergic reactions were most frequent in those in their 40s. Both reactions were more frequent in women than men. The peak occurrence of vasovagal syncope/presyncope was earlier than 15 min after the injection, whereas that of acute allergic reaction was later than 15 min after the injection. The incidence of acute allergic reactions appeared to differ between various vaccine manufacturers, whereas that of vasovagal syncope/presyncope did not. These real-world data may benefit the safe and efficient implementation of mass vaccination campaigns for citizens who want to receive COVID-19 vaccines now and in the future.

Altered IgG4 Antibody Response to Repeated mRNA versus Protein COVID Vaccines.

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 Fcγ-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, FcγRIIa binding), antibody-dependent cellular cytotoxicity (ADCC, FcγRIIIa 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 Fcγ effector responses. Conversely, repeated NVX-CoV2373 vaccination uniquely enhanced IgG3 responses which are known to exhibit strong affinity for FcγRIIIa 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.

Safety and immunogenicity of the NVX-CoV2373 vaccine as a booster in adults previously vaccinated with the BBIBP-CorV vaccine.

This phase 3 observer-blind, randomized, controlled study was conducted in adults ≥18 years of age to assess the safety and immunogenicity of NVX-CoV2373 as a heterologous booster compared to BBIBP-CorV when utilized as a homologous booster. Approximately 1000 participants were randomly assigned in a 1:1 ratio to receive a single dose of NVX-CoV2373 or BBIBP-CorV after prior vaccination with 2 or 3 doses of BBIBP-CorV. Solicited adverse events (AEs) were collected for 7 days after vaccination. Unsolicited AEs were collected for 28 days following the booster dose and serious adverse and adverse events of special interest (AESI) were collected throughout the study. Anti-spike IgG and neutralizing antibodies against SARS-CoV-2 were measured at baseline, day 14, day 28, and day 180. The study achieved its primary non-inferiority endpoint and also demonstrated statistically higher neutralization responses when NVX-CoV2373 was utilized as a heterologous booster compared with BBIBP-CorV as a homologous booster. Both vaccines had an acceptably low reactogenicity profile, and no new safety concerns were found. Heterologous boosting with NVX-CoV2373 was a highly immunogenic and safe vaccine regimen in those previously vaccinated with BBIBP-CorV.

Cost-effectiveness analysis of NVX-CoV2373 COVID-19 vaccination for elderly people in Japan.

Background: NVX-CoV2373 is one of the vaccines marketed for COVID-19 prevention in Japan. Information on its cost-effectiveness is important for making well-informed decisions on the future of Japan's COVID-19 vaccination programme from the public healthcare payer's perspective. The aim of this study was to evaluate the cost-effectiveness of NVX-CoV2373 vaccination in the elderly Japanese population. Methods: Two analysis populations that included elderly Japanese individuals (aged ≥ 65 years) were defined in this study: those who had not received a COVID-19 vaccine or had not completed a primary vaccination series (i.e., first two vaccinations) with an approved COVID-19 vaccine (analysis population 1), and those who had received two primary vaccinations with an approved COVID-19 vaccine (analysis population 2). A literature-informed Markov model for each analysis population was developed to evaluate the cost-effectiveness of vaccination with NVX-CoV2373 against no vaccination with NVX-CoV2373 from the public healthcare payer's perspective as a base-case analysis and from the societal perspective as a scenario analysis. Vaccine efficacy was estimated from a phase 3 study of NVX-CoV2373 (EudraCT number: 2020-004123-16). Cost-effectiveness was assessed using a willingness-to-pay threshold of Japanese yen (JPY) 5 million per quality-adjusted life-year (QALY). Deterministic and probabilistic sensitivity analyses were also performed. Results: For analysis population 1, NVX-CoV2373 primary and booster vaccinations would reduce costs by JPY 37,647 and prolong QALYs by 0.01601. Therefore, NVX-CoV2373 primary and booster vaccinations were considered to be dominant over no vaccination. For analysis population 2, an NVX-CoV2373 booster vaccination would increase costs by JPY 5010 and prolong QALYs by 0.00550, with the incremental cost-effectiveness ratio of JPY 910,566 per QALY gained. Conclusions: Our analyses suggest that a vaccination strategy with NVX-CoV2373 is cost-effective in the elderly population (aged ≥ 65 years) of Japan.

One-year follow-up of the immunogenicity and safety of a primary series of the NVX-CoV2373 (TAK-019) vaccine in healthy Japanese adults: Final report of a phase I/II randomized controlled trial.

BACKGROUND: In the interim report of this phase I/II randomized, placebo-controlled trial in Japanese adults, a two-dose primary series of NVX-CoV2373 (5 µg SARS-CoV-2 recombinant nanoparticle spike protein [rS]; 50 µg Matrix-M) administered 21 days apart induced robust anti-SARS-CoV-2 immune responses up to day 50 and had an acceptable safety profile. METHODS: Following the double-blind phase of this study (day 1-50), participants were informed about their assignment to NVX-CoV2373 or placebo, and their reconsent was required for continuation in the open-label phase (day 51-387). This final report evaluated immunogenicity on days 202 and 387, and safety findings from the 1-year follow-up. RESULTS: In total, 131/150 participants in the NVX-CoV2373 arm and 4/50 in the placebo arm completed the study. The most common reason for discontinuation was because the participant requested a publicly available COVID-19 vaccine. At 6 months and 1 year after the second vaccine dose, both the geometric mean titres of anti-SARS-CoV-2 rS serum immunoglobulin G and serum neutralizing antibodies against the SARS-CoV-2 ancestral strain were numerically higher than before the second dose. There were no deaths, adverse events (AEs) leading to participant withdrawal, or AEs of special interest throughout the trial. During follow-up, 2.0 % (1/50) of participants in the placebo arm reported COVID-19 approximately 1 month after the second vaccine dose (serious AE requiring hospitalisation, already presented in the interim report) and 2.7 % (4/150) in the NVX-CoV2373 arm after approximately 10 months (mild [2/4] or moderate [2/4] in severity). DISCUSSION: A primary series of NVX-CoV2373 induced persistent immune responses up to 1 year after the second dose. The vaccine was well tolerated and had an acceptable safety profile. We believe our findings offer important insights for determining dosing intervals between primary and booster vaccinations.

Reactogenicity Differences between Adjuvanted, Protein-Based and Messenger Ribonucleic Acid (mRNA)-Based COVID-19 Vaccines.

Participants in studies investigating COVID-19 vaccines commonly report reactogenicity events, and concerns about side effects may lead to a reluctance to receive updated COVID-19 vaccinations. A real-world, post hoc analysis, observational 2019nCoV-406 study was conducted to examine reactogenicity within the first 2 days after vaccination with either a protein-based vaccine (NVX-CoV2373) or an mRNA vaccine (BNT162b2 or mRNA-1273) in individuals who previously completed a primary series. Propensity score adjustments were conducted to address potential confounding. The analysis included 1130 participants who received a booster dose of NVX-CoV2373 (n = 303) or an mRNA vaccine (n = 827) during the study period. Within the first 2 days after vaccination, solicited systemic reactogenicity events (adjusted) were reported in 60.5% of participants who received NVX-CoV2373 compared with 84.3% of participants who received an mRNA vaccine; moreover, 33.9% and 61.4%, respectively, reported ≥3 systemic reactogenicity symptoms. The adjusted mean (95% CI) number of systemic symptoms was 1.8 (1.6-2.0) and 3.2 (3.0-3.4), respectively. Local reactogenicity events (adjusted) were reported in 73.4% and 91.7% of participants who received NVX-CoV2373 and mRNA vaccines, respectively; the adjusted mean (95% CI) number of local symptoms was 1.5 (1.33-1.61) and 2.4 (2.31-2.52), respectively. These results support the use of adjuvanted, protein-based NVX-CoV2373 as an immunization option with lower reactogenicity than mRNAs.

Characteristics and Outcomes for Recipients of NVX-CoV2373: A Real-World Retrospective Study in Germany.

Real-world evidence supports SARS-CoV-2 vaccination strategies during the COVID-19 pandemic. This real-world retrospective study utilized the German Disease Analyzer database to characterize recipients of NVX-CoV2373 and explore vaccination outcomes. Recipients (≥12 years) of NVX-CoV2373 as a primary series or booster in Germany were vaccinated between March and December 2022. Outcomes included demographics and clinical characteristics of recipients, tolerability/reactogenicity-related events within 7 and 14 days post-vaccination, and protection from COVID-19. Overall, there were 597 recipients (mean age ~60 years) of NVX-CoV2373; 81% were vaccinated by a general practitioner, and 68% had a Standing Committee on Vaccination (STIKO) high-risk factor. The most common baseline comorbidities were chronic neurological (36%) and chronic intestinal (21%) diseases. Among recipients with metabolic disease (~11%), 65% had diabetes. Tolerability/reactogenicity-related symptoms were recorded in ~1% of recipients. There were no sick-leave notes associated with NVX-CoV2373. After 10 months (median, 7 months) of follow-up, 95% (95% CI, 93-95) of recipients were estimated to be protected from COVID-19. Outcomes were similar across the primary series, booster, and STIKO populations. Tolerability and COVID-19 protection support the use of NVX-CoV2373 as a primary/booster vaccination for all authorized populations, including high-risk.

Immunogenicity and safety of a second heterologous booster dose of NVX-CoV2373 (TAK-019) in healthy Japanese adults who had previously received a primary series of COVID-19 mRNA vaccine: Interim analysis report of a phase 3 open-label trial.

BACKGROUND: The phase 3, single-arm, open-label TAK-019-3001 study assessed two heterologous booster doses of NVX-CoV2373 administered 5 months apart in healthy Japanese adults who had completed a primary series of a COVID-19 mRNA vaccine 6-12 months previously. In the main part of this study, a first booster induced rapid and robust anti-SARS-CoV-2 immune responses, addressing waning immunity in participants. METHODS: This interim analysis evaluated the immunogenicity and safety of a second booster in the extension part of this study including comparisons with the first booster. Immunogenicity was assessed on extension day (ED) 1 (before vaccination) and ED15. Solicited and unsolicited adverse events occurring in the 7 and 28 days, respectively, after vaccination were assessed. RESULTS: Of the 150 participants who received a first NVX-CoV2373 booster, 129 were administered a second booster on ED1. Participant characteristics were consistent between the main and extension parts of the study. Titres of anti-SARS-CoV-2 rS serum immunoglobulin G and serum neutralizing antibodies against the SARS-CoV-2 ancestral strain at ED15 were 4.0- and 3.0-fold higher, respectively, than those observed 5 months after the first booster on ED1, and 3.0- and 1.4-fold higher, respectively, than those observed 14 days after the first booster on day 15. The proportions of participants who experienced solicited local and systemic adverse events (AEs) in the 7 days after the second booster were 73.6 % and 51.2 %, respectively: most were of grade 2 severity or lower. Seven percent of participants experienced unsolicited AEs in the 28 days after the second booster: all were unrelated to the treatment. There were no deaths or AEs leading to study discontinuation. DISCUSSION: A second heterologous NVX-CoV2373 booster in healthy Japanese adults induced more robust anti-SARS-CoV-2 immune responses than the first booster. The second booster was well tolerated. No new safety concerns were identified.

Risk of SARS-CoV-2 breakthrough infection following NVX-CoV2373 and BNT162b2 vaccinations in Korean Adults: A population-based observational study.

South Korea experienced a low prevalence of SARS-CoV-2 until the emergence of the omicron in early 2022, triggering a major community epidemic. To evaluate effectiveness of NVX-CoV2373 and BNT162b2 vaccines in Korean population, we conducted an observational study utilizing individual-level case data on laboratory-confirmed SARS-CoV-2 infection, along with vaccination record. A total of 47,078 recipients of NVX-CoV2373 vaccine and 7,561 recipients of BNT162b2 vaccine were eligible for the study. Thirty days post-second doses, COVID-19 rates were 7.9% (595 out of 7561) of NVX-CoV2373 recipients and 8.6 % (647 out of 7561) of BNT162b2 recipients experienced COVID-19. NVX-CoV2373 rates increased to 9.8 % and 11.2 % at 60 and 90 days, while BNT162b2 rates were 10.5 % and 11.3 % at the same intervals. The 22-weeks risk ratios for recipients of the NVX-CoV2373 vaccine as compared with recipients of the BNT162b2 vaccine were 1.11 (95 % CI, 0.99 to 1.25) for laboratory-confirmed SARS-CoV-2 infection. Continued monitoring is essential to evaluate the duration of protection across different vaccine platforms and schedules.

Burden and Impact of Reactogenicity among Adults Receiving COVID-19 Vaccines in the United States and Canada: Results from a Prospective Observational Study.

As SARS-CoV-2 variants continue to emerge, vaccination remains a critical tool to reduce the COVID-19 burden. Vaccine reactogenicity and the impact on work productivity/daily activities are recognized as contributing factors to vaccine hesitancy. To encourage continued COVID-19 vaccination, a more complete understanding of the differences in reactogenicity and impairment due to vaccine-related side effects across currently available vaccines is necessary. The 2019nCoV-406 study (n = 1367) was a prospective observational study of reactogenicity and associated impairments in adults in the United States and Canada who received an approved/authorized COVID-19 vaccine. Compared with recipients of mRNA COVID-19 booster vaccines, a smaller percentage of NVX-CoV2373 booster recipients reported local and systemic reactogenicity. This study's primary endpoint (percentage of participants with ≥50% overall work impairment on ≥1 of the 6 days post-vaccination period) did not show significant differences. However, the data suggest that NVX-CoV2373 booster recipients trended toward being less impaired overall than recipients of an mRNA booster; further research is needed to confirm this observed trend. The results of this real-world study suggest that NVX-CoV2373 may be a beneficial vaccine option with limited impact on non-work activities, in part due to the few reactogenicity events after vaccination.

Neurovascular Adverse Effects of Sars-Cov-2 Vaccination.

The global deployment of SARS-CoV-2 vaccines has been pivotal in curbing the COVID-19 pandemic, reducing morbidity and mortality associated with the virus. While most of these vaccines have demonstrated high efficacy and overall safety, emerging reports have highlighted potential neurovascular adverse effects, albeit uncommon, associated with these vaccinations. This review aims to assess and summarize the current knowledge on the neurovascular complications arising post-SARS-CoV-2 vaccination. We conducted an extensive literature review, focusing on clinical studies and case reports to identify reported neurovascular events, such as ischemic stroke, cerebral sinus venous thrombosis, intracerebral hemorrhage, pituitary apoplexy and primary CNS angiitis Despite the relative rarity of these events, their impact on affected individuals underscores the importance of ongoing surveillance, early detection, and management strategies. We aim to provide healthcare professionals with the latest evidence on neurovascular adverse effects, facilitating informed decision-making in the context of SARS-CoV-2 vaccination programs. Furthermore, we highlight areas requiring further research to understand the pathophysiology of these adverse events better and to develop targeted prevention and treatment strategies.

NVX-CoV2373 induces humoral and cellular immune responses that are functionally comparable to vector and mRNA-based vaccines.

Background: After licensing of the protein-based vaccine NVX-CoV2373, three technically different vaccines against the SARS-CoV-2 became available for application to the human population - and for comparison of efficacies. Methods: We here recruited 42 study participants who had obtained one initial dose of NVX-CoV2373 and analyzed their immune responses in contrast to 37 study participants who had obtained either the vector vaccine AZD1222 or the mRNA vaccine BNT162b2 a year earlier. 32 participants also donated blood before first vaccination to serve as a vaccine-naive control. In detail, we investigated and quantified at day 21 and approximately six months after primary immunization the amounts of vaccine-specific antibodies produced, their neutralization capacity, their quality in terms of binding different epitopes and their efficiency in inducing various isotypes. Cellular immunity and intracellular cytokine production following in vitro re-stimulation with BNT162b2 vaccine was analyzed via ELISpot or via flow cytometry. Results: Our results show that even though vaccination including the mRNA vaccine yielded best results in almost any aspect of antibody levels and binding efficiency, the neutralization capacities against the wild-type Wuhan strain and the Omicron BA.1 variant early and at six months were comparable among all three vaccination groups. As for the T cells, we observed a prevailing CD8 response at three weeks which turned into a predominant CD4 memory at six months which has not yet been observed for AZD1222 and BNT162b2. While additional infection with SARS-CoV-2 resulted in a boost for the humoral response, T cell memory appeared rather unaffected. Conclusion: Whether any of these differences translate into real world protection from infection, mitigation of severe disease courses and prevention of long/post COVID will need to be investigated in the future.

Safety and immunogenicity of SII-NVX-CoV2373 (COVID-19 vaccine) in adults in a phase 2/3, observer-blind, randomised, controlled study.

Background: NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine is manufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. Methods: This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort by ELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Findings: Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13-22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. Interpretation: SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. Funding: SIIPL, Indian Council of Medical Research, Novavax.

Cytokine and Chemokine Production in Mice Inoculated with NVX-CoV2373 (Nuvaxovid®) in Comparison with Omicron BA.4/5 Bivalent BNT162b2 (Comirnaty®).

A recombinant SARS-CoV-2 spike protein vaccine (NVX-CoV2373) has been licensed and has a lesser incidence of adverse events. To know the immunological mechanisms of adverse events, the production of cytokines and chemokines was investigated in mice inoculated with NVX-CoV2373. Serum IL-6 was detected on Day 1 of the first and second doses and the IFN-γ, IL-4, IL-10, TNF-α, and IL-6 levels increased on Day 1 of the second dose at the inoculation site. The enhanced production of the inflammatory chemokines (CCL2), homeostatic chemokine (CXCL13), and Th2 chemokine (CCL17) was observed at the inoculation site on Day 1 of the second dose. These findings were compared with data obtained following inoculation with BNT162b2 bivalent vaccine containing omicron BA.4/5. Significantly lower levels of inflammatory chemokines were detected on Day 1 after the first dose of NVX-CoV2373 in sera and inoculation site than those following inoculation with bivalent BNT162b2 (p < 0.01), reflecting a lower incidence of adverse events after immunization with NVX-CoV2373 in humans. NVX-CoV2373 induced significantly higher concentrations of IFN-γ, TNF-α, and IL-10 at the inoculation site obtained on Day 1 of the second dose (p < 0.05). Significant higher levels of Th2 chemokines, CCL11 and CCL17, were induced at the inoculation site on Day 1 of the second dose (p < 0.01) and they explain the booster IgG EIA antibody response after the second dose of NVX-CoV2373.

Immunogenicity and safety of NVX-CoV2373 as a booster: A phase 3 randomized clinical trial in adults.

BACKGROUND: To combat the SARS-CoV-2 pandemic, multiple vaccines using different manufacturing platforms have been developed, including NVX-CoV2373 (an adjuvanted recombinant protein vaccine). As SARS-CoV-2 variants have emerged, some of which evade vaccine-induced immunity, introduction of vaccine booster doses has become critical. Employing different vaccine types for primary series vaccination and boosting could expand vaccine coverage and access. This study assessed whether NVX-CoV2373 would induce robust responses when used as a booster. METHODS: The 2019nCoV-307 study was a phase 3, randomized, observer-blinded trial evaluating immunogenicity and safety of NVX-CoV2373 in previously vaccinated adults aged 18-49 years in the United States (NCT05463068). Participants were randomized 1:1:1 to receive one intramuscular injection of NVX-CoV2373 from one of three different manufacturing lots. Immunogenicity was assessed by immunoglobulin G (IgG) and neutralizing antibodies (NAb). These responses were compared for the three lots, and for participants with primary series with or without a prior booster dose of the mRNA-1273, BNT162b2, Ad26.COV2.S, or NVX-CoV2373 COVID-19 vaccines. RESULTS: A total of 911 participants were randomized between July 11 and 13, 2022, with 905 being assessed for safety and 848 for immunogenicity. Immunogenicity of NVX-CoV2373 met prespecified equivalence criteria between lots, and the booster dose was well-tolerated. NVX-CoV2373 induced robust IgG and NAb responses when used as a first or later booster dose, regardless of primary series vaccine type. Seroconversion rates were also similar across previous vaccine types. Induced antibodies were strongly reactive, even to the immune-evasive Omicron BA.1 and BA.5 variants. CONCLUSIONS: NVX-CoV2373 showed consistent immunogenicity between lots, with no new safety signals identified. Use of NVX-CoV2373 as a booster dose (first or later) is supported.

NVX-CoV2373 vaccine efficacy against hospitalization: A post hoc analysis of the PREVENT-19 phase 3, randomized, placebo-controlled trial.

PREVENT-19, the pivotal phase 3 trial of the Novavax adjuvanted, recombinant spike protein COVID-19 vaccine (NVX-CoV2373), demonstrated that the vaccine was well tolerated and efficacious (vaccine efficacy, VE = 90%) for the prevention of symptomatic COVID-19. In the trial, participants were randomly assigned in a 2:1 ratio to receive 2 doses of NVX-CoV2373 or placebo 21 days apart. Throughout the study, the predominant SARS-CoV-2 variant was alpha, but additional variants were in circulation (i.e., beta, gamma, epsilon, and iota). VE among the per-protocol efficacy analysis population was calculated according to pre-specified disease severity (mild, moderate, or severe) criteria, but the impact on the risk of COVID-19-associated hospitalization was not specifically investigated. During this analysis period (January 25, 2021, to April 30, 2021 [95 days]), 4 hospitalizations occurred among the 77 events analyzed for the primary endpoint using the per-protocol population, 0 among vaccine recipients and 4 among placebo recipients, yielding a post hoc VE against hospitalization of 100% (95% CI: 28.8, 100). Among an expanded efficacy population, also identified post hoc, which included COVID-19-associated hospitalizations without a requirement for diagnostic polymerase chain reaction testing performed at the study central laboratory, 12 total hospitalizations were identified, 0 among vaccine recipients and 12 among placebo recipients, yielding a post hoc VE against hospitalization of 100% (95% CI: 83.1, 100). These additional data from the PREVENT-19 trial provide relevant public health information concerning the attributes of NVX-CoV2373.