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Background The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. Methods Adults aged 18–84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. Results Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%–88.8%). Vaccine efficacy was 100% (95% CI, 17.9%–100.0%) against severe disease and 76.3% (95% CI, 57.4%–86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein–specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. Conclusions A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. Clinical Trials Registration EudraCT, 2020-004123-16.

As the COVID-19 pandemic continues, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge. Immunogenicity evaluation of vaccines and identification of correlates of protection for vaccine effectiveness is critical to aid the development of vaccines against emerging variants. Anti-recombinant spike (rS) protein immunoglobulin G (IgG) quantitation in the systemic circulation (serum/plasma) is shown to correlate with vaccine efficacy. Thus, an enzyme-linked immunosorbent assay (ELISA)-based binding assay to detect SARS-CoV-2 (ancestral and variant strains) anti-rS IgG in human serum samples was developed and validated. This assay successfully met acceptance criteria for inter/intra-assay precision, specificity, selectivity, linearity, lower/upper limits of quantitation, matrix effects, and assay robustness. The analyte in serum was stable for up to 8 freeze/thaw cycles and 2 years in −80 °C storage. Similar results were observed for the Beta, Delta, and Omicron BA.1/BA.5/XBB.1.5 variant-adapted assays. Anti-rS IgG assay results correlated significantly with neutralization and receptor binding inhibition assays. In addition, usage of international reference standards allows data extrapolation to WHO international units (BAU/mL), facilitating comparison of results with other IgG assays. This anti-rS IgG assay is a robust, high-throughput method to evaluate binding IgG responses to S protein in serum, enabling rapid development of effective vaccines against emerging COVID-19 variants.

Omicron SARS-CoV-2 variants escape vaccine-induced neutralizing antibodies and cause nearly all current COVID-19 cases. Here, we compared the efficacy of three booster vaccines against Omicron BA.5 challenge in rhesus macaques: mRNA-1273, the Novavax ancestral spike protein vaccine (NVX-CoV2373), or Omicron BA.1 spike protein version (NVX-CoV2515). All three booster vaccines induced a strong BA.1 cross-reactive binding antibody and changed immunoglobulin G dominance from IgG1 to IgG4 in the serum. All three booster vaccines also induced strong and comparable neutralizing antibody responses against multiple variants of concern, including BA.5 and BQ.1.1, along with long-lived plasma cells in the bone marrow. The ratio of BA.1 to WA-1 spike-specific antibody-secreting cells in the blood was higher in NVX-CoV2515 animals compared to NVX-CoV2373 animals, suggesting a better recall of BA.1 specific memory B cells by the BA.1 spike-specific vaccine compared to the ancestral spike-specific vaccine. Further, all three booster vaccines induced low levels of spike-specific CD4 but not CD8 T cell responses in the blood. Following challenge with SARS-CoV-2 BA.5 variant, all three vaccines showed strong protection in the lungs and controlled virus replication in the nasopharynx. In addition, both Novavax vaccines blunted viral replication in nasopharynx at day 2. The protection against SARS-CoV-2 BA.5 infection in the upper respiratory airways correlated with binding, neutralizing, and ADNP activities of the serum antibody. These data have important implications for COVID-19 vaccine development, as vaccines that lower nasopharyngeal virus may help to reduce transmission.

Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

BackgroundThe recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported.MethodsAdults aged 18–84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses.ResultsOf 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%–88.8%). Vaccine efficacy was 100% (95% CI, 17.9%–100.0%) against severe disease and 76.3% (95% CI, 57.4%–86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein–specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups.ConclusionsA 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated.

Background Respiratory syncytial virus (RSV) can cause serious lung infections in young children and there is currently no available vaccine. Methods We used complementary statistical frameworks to analyze 4 RSV serology measurements in mothers and their infants in South Africa who participated in a phase 3 maternal immunization trial of an RSV F protein nanoparticle vaccine as correlates of risk and of protection against different RSV disease endpoints. Results We found evidence to support each antibody measurement—encompassing RSV-neutralizing antibodies and F surface glycoprotein-binding antibodies—as an inverse correlate of risk of RSV-associated acute lower respiratory tract infection with severe hypoxia in at least 1 framework, with vaccine-induced fold-rise from the maternal enrollment to day 14 samples of anti-F immunoglobulin G (IgG) binding antibodies having the most consistent evidence. This evidence includes a significant association of fold-rise anti-F IgG with vaccine efficacy (VE); achieving a baseline covariate-adjusted VE of 75% requires a vaccine-induced maternal anti-F IgG fold-rise of around 16. Neither multivariable logistic regression nor superlearning analyses showed benefit to including multiple time points or assays in the same model, suggesting a parsimonious correlate. Post hoc exploratory analyses supported adherence of vaccine-induced maternal anti-F IgG fold-rise to the Prentice criteria for a valid surrogate endpoint. Conclusions Our results suggest that the vaccine induced protective anti-F antibody responses. If this finding is confirmed, VE could potentially be augmented by increasing these responses.

Background We developed a COVID-Influenza Combination (CIC) vaccine, comprising recombinant SARS-CoV-2 Spike (rS) and quadrivalent influenza hemagglutinin (HA) protein nanoparticles (qNIV), and Matrix-MTM adjuvant. rS/Matrix-M previously demonstrated efficacy against COVID-19 in Phase 3 trials, while qNIV/Matrix-M previously demonstrated induction of broadly cross-reactive antibodies. Here we report preliminary safety and immunogenicity results of a first-ever Phase 1/2 CIC dose-finding trial. Methods Seropositive (COVID-19 vaccinated ≥ 8 weeks prior) participants (N=642) aged 50-70 years were randomized equally, to receive two intramuscular doses, 56 days apart, to 1 of 14 different dose/formulations of CIC using a design of experiments approach (dose range: rS 2.5-22.5ug, HA 5-60ug; and 50ug Matrix-M), or to 1 of 2 reference formulations of either standalone rS with Matrix-M [2 doses] or qNIV with Matrix-M [1 dose only]. Pre- and post-vaccination (Days 0, 28, 56, 70, 84, 182) immunogenicity assessments including SARS-CoV-2 anti-S IgG and influenza HAI antibodies to vaccine-homologous strains. Reactogenicity was assessed 7 days following each dose, and safety outcomes assessed through Day 70. Multiple regression was used to create predictive models to assess antibody response surfaces and for dose optimization. Results All CIC formulations were well tolerated, with a reactogenicity and safety profile generally comparable to standalone rS or qNIV. Regression modelling of post-first dose responses revealed that both rS and HA antigens in a CIC formulation modestly interfered with each other, however, interference was overcome with dose adjustment across a range of rS/HA doses. Specifically, higher rS dose ( >20ug), in a dose dependent fashion, overcame HA interference, closely matching standalone rS IgG reference responses (GMEU 16,818), whereas lower, intermediate HA dose overcame rS interference, closely matching standalone HA reference HAI responses for H3N2 (GMT 145), H1N1 (GMT 134), and B-Victoria (GMT 66); while modestly (at least 34%) lower than the reference B-Yamagata response (GMT 101). Conclusion CIC formulations were well tolerated and immunogenic, with various dose combinations achieving response comparable to standalone vaccines. Disclosures Vivek Shinde, MD, MPH, Novavax Inc.: Stocks/Bonds Wayne Woo, MS, Novavax Inc.: Stocks/Bonds Sharon Liu, n/a, Novavax Inc.: Stocks/Bonds Sara Cook, n/a, Novavax Inc.: Stocks/Bonds Zenaida Santiago, n/a, Novavax Inc.: Stocks/Bonds Susan Neal, n/a, Novavax Inc.: Stocks/Bonds Joyce S. Plested, n/a, Novavax Inc.: Stocks/Bonds Tim Vincent, n/a, Novavax Inc.: Stocks/Bonds Mingzhu Zhu, n/a, Novavax Inc.: Stocks/Bonds Shane Cloney-Clark, n/a, Novavax Inc.: Stocks/Bonds Iksung Cho, MS, Novavax Inc.: Stocks/Bonds Lou Fries, n/a, Novavax Inc.: Stocks/Bonds Greg Glenn, n/a, Novavax Inc.: Stocks/Bonds.

BACKGROUND: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1-2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission. METHODS: In this phase 2a-b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)-negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection. RESULTS: Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, -0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups. CONCLUSIONS: The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399.).

SummaryBackgroundThe safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines has not yet been reported.MethodsA sub-study on influenza vaccine co-administration was conducted as part of the phase 3 randomized trial of the safety and efficacy of NVX-CoV2373. The first ∼400 participants meeting main study entry criteria and with no contraindications to influenza vaccination were invited to join the sub-study. After randomization in a 1:1 ratio to receive NVX-CoV2373 (n=217) or placebo (n=214), sub-study participants received an age-appropriate, licensed, open-label influenza vaccine with dose 1 of NVX-CoV2373. Reactogenicity was evaluated via electronic diary for 7 days post-vaccination in addition to monitoring for unsolicited adverse events (AEs), medically-attended AEs (MAAEs), and serious AEs (SAEs). Influenza haemagglutination inhibition and SARS-CoV-2 anti-spike IgG assays were performed. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed. Comparisons were made between sub-study and main study participants.FindingsSub-study participants were younger, more racially diverse, and had fewer comorbid conditions than main study participants. Reactogenicity events more common in the co-administration group included tenderness (70.1% vs 57.6%) or pain (39.7% vs 29.3%) at injection site, fatigue (27.7% vs 19.4%), and muscle pain (28.3% vs 21.4%). Rates of unsolicited AEs, MAAEs, and SAEs were low and balanced between the two groups. Co-administration resulted in no change to influenza vaccine immune response, while a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. Vaccine efficacy in the sub-study was 87.5% (95% CI: -0.2, 98.4) while efficacy in the main study was 89.8% (95% CI: 79.7, 95.5).InterpretationThis is the first study to demonstrate the safety, immunogenicity, and efficacy profile of a COVID-19 vaccine when co-administered with seasonal influenza vaccines. The results suggest concomitant vaccination may be a viable immunisation strategy.FundingThis study was funded by Novavax, Inc.Research in ContextEvidence before this studyWe searched PubMed for research articles published from December 2019 until 1 April 2021 with no language restrictions for the terms “SARS-CoV-2”, “COVID-19”, “vaccine”, “co-administration”, and “immunogenicity”. There were no peer-reviewed publications describing the simultaneous use of any SARS-CoV-2 vaccine and another vaccine. Several vaccine manufacturers had recent publications on phase 3 trials results (Pfizer/BioNTech, Moderna, AstraZeneca, Janssen, and the Gamaleya Research Institute of Epidemiology and Microbiology). Neither these publications nor their clinical trials’ protocols (when publicly available) described co-administration and they often had trial criteria specifically excluding those with recent or planned vaccination with any licenced vaccine near or at the time of any study injection.Added value of this studyImmune interference and safety are always a concern when two vaccines are administered at the same time. This is the first study to demonstrate the safety and immunogenicity profile and clinical vaccine efficacy of a COVID-19 vaccine when co-administered with a seasonal influenza vaccine.Implications of all the available evidenceThis study provides much needed information to help guide national immunisation policy decision making on the critical issue of concomitant use of COVID-19 vaccines with influenza vaccines.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally. As SARS-CoV-2 has transmitted from person to person, variant viruses have emerged with elevated transmission rates and higher risk of infection for vaccinees. We present data showing that a recombinant prefusion-stabilized Spike (rS) protein based on the B.1.351 sequence (rS-B.1.351) was highly immunogenic in mice and produced neutralizing antibodies against SARS-CoV-2/WA1, B.1.1.7, and B.1.351. Mice vaccinated with our prototype vaccine NVX-CoV2373 (rS-WU1) or rS-B.1.351 alone, in combination, or as a heterologous prime boost, were protected when challenged with live SARS-CoV-2/B.1.1.7 or SARS-CoV-2/B.1.351. Virus titer was reduced to undetectable levels in the lungs post-challenge in all vaccinated mice, and Th1-skewed cellular responses were observed. A strong anamnestic response was demonstrated in baboons boosted with rS-B.1.351 approximately one year after immunization with NVX-CoV2373 (rS-WU1). An rS-B.1.351 vaccine alone or in combination with prototype rS-WU1 induced protective antibody- and cell-mediated responses that were protective against challenge with SARS-CoV-2 variant viruses.

dscCfaE is a recombinant form of the CFA/I tip adhesin CfaE, expressed by a large proportion of enterotoxigenic E. coli (ETEC). It is highly immunogenic by the intranasal route in mice and Aotus nancymaae, protective against challenge with CFA/I+ ETEC in an A. nancymaae challenge model, and antibodies to dscCfaE passively protect against CFA/I+ ETEC challenge in human volunteers. Here, we show that transcutaneous immunization (TCI) with dscCfaE in mice resulted in strong anti-CfaE IgG serum responses, with a clear dose-response effect. Co-administration with heat-labile enterotoxin (LT) resulted in enhanced immune responses over those elicited by dscCfaE alone and strong anti-LT antibody responses. The highest dose of dscCfaE administered transcutaneously with LT elicited strong HAI titers, a surrogate for the neutralization of intestinal adhesion. Fecal anti-adhesin IgG and IgA antibody responses were also induced. These findings support the feasibility of TCI for the application of an adhesin-toxin based ETEC vaccine.

BackgroundCovid-19 vaccines are urgently needed, especially against emerging variants. NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 rS) nanoparticle vaccine containing trimeric full-length SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant.MethodsA phase 3, randomized, observer-blinded, placebo-controlled trial was conducted in adults 18-84 years old who received two intramuscular 5-µg doses, 21 days apart, of NVX-CoV2373 or placebo (1:1) across 33 sites in the United Kingdom. The primary efficacy endpoint was virologically confirmed symptomatic Covid-19 with onset 7 days after second vaccination in serologically negative participants.ResultsA total of 15,187 participants were randomized, of whom 7569 received NVX-CoV2373 and 7570 received placebo; 27.2% were 65 years or older, 44.7% had comorbidities and 4.2% had baseline serological evidence of SARS-CoV-2. There were 10 cases of Covid-19 among NVX-CoV2373 recipients and 96 cases among placebo recipients, with symptom onset at least 7 days after second vaccination; NVX-CoV2373 was 89.7% (95% confidence interval, 80.2 to 94.6) effective in preventing Covid-19, with no hospitalizations or deaths reported. There were five cases of severe Covid-19, all in the placebo group. Post hoc analysis revealed efficacies of 96.4% (73.8 to 99.5) and 86.3% (71.3 to 93.5) against the prototype strain and B.1.1.7 variant, respectively. Vaccine efficacy was similar across subgroups, including participants with comorbidities and those ≥65 years old. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.ConclusionA two-dose regimen of NVX-CoV2373 conferred 89.7% protection against a blend of prototype and variant Covid-19, demonstrated high efficacy against the B.1.1.7 variant, and had a reassuring safety profile.(Funded by Novavax, Inc. EudraCT number, 2020-004123-16).

The 2019 outbreak of a severe respiratory disease caused by an emerging coronavirus, SARS-CoV-2, has spread globally with high morbidity and mortality. Co-circulating seasonal influenza has greatly diminished recently, but expected to return with novel strains emerging, thus requiring annual strain adjustments. We have developed a recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV) produced using an established recombinant insect cell expression system to produce nanoparticles. Influenza qNIV adjuvanted with Matrix-M was well-tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses in Phase 1, 2, and 3 trials. We also developed a full-length SARS-CoV-2 spike protein vaccine which is stable in the prefusion conformation (NVX-CoV2373) using the same platform technology. In phase 3 clinical trials, NVX-CoV2373 is highly immunogenic and protective against the prototype strain and B.1.1.7 variant. Here we describe the immunogenicity and efficacy of a combination quadrivalent seasonal flu and COVID-19 vaccine (qNIV/CoV2373) in ferret and hamster models. The combination qNIV/CoV2373 vaccine produces high titer influenza hemagglutination inhibiting (HAI) and neutralizing antibodies against influenza A and B strains. The combination vaccine also elicited antibodies that block SARS-CoV-2 spike protein binding to the human angiotensin converting enzyme-2 (hACE2) receptor. Significantly, hamsters immunized with qNIV/CoV2373 vaccine and challenged with SARS-CoV-2 were protected against weight loss and were free of replicating SARS-CoV-2 in the upper and lower respiratory tract with no evidence of viral pneumonia. This study supports evaluation of qNIV/CoV2373 combination vaccine as a preventive measure for seasonal influenza and CoVID-19.HighlightsCombination qNIV/CoV2373 vaccine induced protective hemagglutination inhibition (HAI) responses to seasonal influenza A and B unchanged when formulated with recombinant spike.Combination qNIV/CoV2373 vaccine maintained clinical and virologic protection against experimental challenge with SARS-CoV-2.Combination qNIV/CoV2373 vaccine showed no clinical or histological sign of enhanced disease following experimental challenge with SARS-CoV-2.Combination qNIV/CoV2373 vaccine induced antibodies against SARS-CoV-2 neutralizing epitopes common between US-WA and B.1.352 variant.

The respiratory syncytial virus (RSV) fusion (F) protein/polysorbate 80 (PS80) nanoparticle vaccine is the most clinically advanced vaccine for maternal immunization and protection of newborns against RSV infection. It is composed of a near-full-length RSV F glycoprotein, with an intact membrane domain, formulated into a stable nanoparticle with PS80 detergent. To understand the structural basis for the efficacy of the vaccine, a comprehensive study of its structure and hydrodynamic properties in solution was performed. Small-angle neutron scattering experiments indicate that the nanoparticle contains an average of 350 PS80 molecules, which form a cylindrical micellar core structure and five RSV F trimers that are arranged around the long axis of the PS80 core. All-atom models of full-length RSV F trimers were built from crystal structures of the soluble ectodomain and arranged around the long axis of the PS80 core, allowing for the generation of an ensemble of conformations that agree with small-angle neutron and X-ray scattering data as well as transmission electron microscopy (TEM) images. Furthermore, the hydrodynamic size of the RSV F nanoparticle was found to be modulated by the molar ratio of PS80 to protein, suggesting a mechanism for nanoparticle assembly involving addition of RSV F trimers to and growth along the long axis of the PS80 core. This study provides structural details of antigen presentation and conformation in the RSV F nanoparticle vaccine, helping to explain the induction of broad immunity and observed clinical efficacy. Small-angle scattering methods provide a general strategy to visualize surface glycoproteins from other pathogens and to structurally characterize nanoparticle vaccines.

Structure of a vaccine candidate Much effort is being targeted at developing vaccines that will provide protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A trimeric spike protein that decorates the virus is a primary target of the host immune system and the focus of vaccine development. Bangaru et al. present the structure of a leading vaccine candidate: a full-length spike protein with some modifications aimed at enhancing stability that is formulated in polysorbate 80 detergent. The study confirms that the full-length immunogen is in a stable prefusion conformation and provides a basis for understanding immune responses to the vaccine. Science, this issue p. 1089, Cryo-EM and glycan analysis of a leading SARS-CoV-2 subunit vaccine candidate reveals a stable prefusion conformation of the spike immunogen., Vaccine efforts to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the current coronavirus disease 2019 (COVID-19) pandemic, are focused on SARS-CoV-2 spike glycoprotein, the primary target for neutralizing antibodies. We performed cryo–election microscopy and site-specific glycan analysis of one of the leading subunit vaccine candidates from Novavax, which is based on a full-length spike protein formulated in polysorbate 80 detergent. Our studies reveal a stable prefusion conformation of the spike immunogen with slight differences in the S1 subunit compared with published spike ectodomain structures. We also observed interactions between the spike trimers, allowing formation of higher-order spike complexes. This study confirms the structural integrity of the full-length spike protein immunogen and provides a basis for interpreting immune responses to this multivalent nanoparticle immunogen.

Influenza viruses frequently acquire mutations undergoing antigenic drift necessitating annual evaluation of vaccine strains. Highly conserved epitopes have been identified in the hemagglutinin (HA) head and stem regions, however, current influenza vaccines induce only limited responses to these conserved sites. Here, we describe a novel seasonal recombinant HA nanoparticle influenza vaccine (NIV) formulated with a saponin-based adjuvant, Matrix-M™. NIV induced hemagglutination inhibition (HAI) and microneutralizing (MN) antibodies against a broad range of influenza A(H3N2) subtypes. In a comparison of NIV against standard-dose and high-dose inactivated influenza vaccines (IIV and IIV-HD, respectively) in ferrets NIV elicited HAI and MN responses exceeding those induced by IIV-HD against homologous A(H3N2) by 7 fold, A(H1N1) by 26 fold, and B strain viruses by 2 fold. NIV also induced MN responses against all historic A/H3N2 strains tested, spanning more than a decade of viral evolution from the 2000-2017 influenza seasons whereas IIV and IIV-HD induced HAI and MN responses were largely directed against the homologous A(H3N2), A(H1N1), and B virus strains. NIV induced superior protection compared to IIV and IIV-HD in ferrets challenged with a homologous or 10-year drifted influenza A(H3N2) strain. HAI positive and HAI negative neutralizing monoclonal antibodies derived from mice immunized with NIV were active against homologous and drifted influenza A(H3N2) strains. Taken together these observations suggest that NIV can induce responses to one or more highly conserved HA head and stem epitopes and result in highly neutralizing antibodies against both homologous and drift strains.

Globally, human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infection in infants and young children. There are no licensed vaccines despite the high worldwide disease burden. RSV fusion (F) glycoprotein vaccine is the most advanced candidate for maternal immunization. In this report, a baboon maternal immunization model was used to assess the immunogenicity and protection of infants against pulmonary challenge with human RSV/A. Vaccination in the third trimester produced high anti-RSV F IgG titers and virus-neutralizing antibodies. Infants born to immunized females had high levels of serum RSV antibodies that were comparable to maternal levels at birth and persisted for over 50 days with a half-life of 14–24 days. Furthermore, infants from immunized females and challenged with RSV/A were healthy, developed less severe disease, and had only mild pulmonary inflammatory changes whereas infants born to non-vaccinated females developed more severe disease with marked to moderate interstitial pneumonia, pulmonary edema, and bronchiolar obstruction. These results support the further development of the RSV F vaccine for maternal immunization.

Human respiratory syncytial virus (RSV) is a cause of lower respiratory tract infection in infants, young children, and older adults. There is no licensed vaccine and prophylactic treatment options are limited. The RSV fusion (F) glycoprotein is a target of host immunity and thus a focus for vaccine development. F-trimers are metastable and undergo significant rearrangements from the prefusion to a stable postfusion structure with neutralizing epitopes on intermediate structures. We hypothesize that vaccine strategies that recapitulate the breathable F quaternary structure, and provide accessibility of B-cells to epitopes on intermediate conformations, may collectively contribute to protective immunity, while rigid prefusion F structures restrict access to key protective epitopes. To test this hypothesis, we used the near full-length prefusogenic F as a backbone to construct three prefusion F variants with substitutions in the hydrophobic head cavity: (1) disulfide bond mutant (DS), (2) space filling hydrophobic amino acid substitutions (Cav1), and (3) DS, Cav1 double mutant (DS-Cav1). In this study, we compared the immunogenicity of prefusogenic F to prefusion F variants in two animal models. Native prefusogenic F was significantly more immunogenic, producing high titer antibodies to prefusogenic, prefusion, and postfusion F structures, while animals immunized with DS or DS-Cav1 produced antibodies to prefusion F. Importantly, prefusogenic F elicited antibodies that target neutralizing epitopes including prefusion-specific site zero (&Oslash, ) and V and conformation-independent neutralizing sites II and IV. Immunization with DS or DS-Cav1 elicited antibodies primarily to prefusion-specific sites &Oslash, and V with little or no antibodies to other key neutralizing sites. Animals immunized with prefusogenic F also had significantly higher levels of antibodies that cross-neutralized RSV A and B subtypes, while immunization with DS or DS-Cav1 produced antibodies primarily to the A subtype. We conclude that breathable trimeric vaccines that closely mimic the native F-structure, and incorporate strategies for B-cell accessibility to protective epitopes, are important considerations for vaccine design. F structures locked in a single conformation restrict access to neutralizing epitopes that may collectively contribute to destabilizing F-trimers important for broad protection. These results also have implications for vaccine strategies targeting other type 1 integral membrane proteins.

Background RSV is the leading cause of infant LRTI and hospitalization worldwide. The greatest burden of severe disease is in term infants Method After dose-finding studies in 1,050 women, we studied vaccine safety and immunogenicity in a Phase 2 trial in 50 healthy third trimester pregnant women. Safety was assessed in mothers and infants, focusing on pregnancy and peri-partum outcomes. We measured binding and functional RSV antibodies in mothers at baseline, day 14, delivery, and days 35 and 180 post-partum, in cord blood, and in infant sera on days 14, 35, 60, and 180 of life. Anti-F antibody specificities were probed with biolayer interferometry and monoclonal antibodies (mabs) to known epitopes. Result In Phase 2, RSV F nanoparticle vaccine was immunogenic, safe, and well-tolerated in pregnant women. Anti-F IgG and neutralizing antibodies were elicited. Increases in antibodies competitive with mabs to neutralizing epitope sites Ø, VIII, II, and IV, and also the p27 domain displayed by the pre-fusogenic F protein, were present in maternal and infant sera of vaccinated subject pairs. Transplacental transfer of RSV antibodies was more efficient (110 to 120%) in women immunized >30 days before delivery compared with those vaccinated later; RSV antibody t1/2 ranged from 30 to 41 days in infants. We have subsequently enrolled 4,636 pregnant women and their infants in a global observer-blind, randomized, placebo-controlled Phase 3 trial assessing efficacy against medically significant RSV LRTI. In November 2017, an informational analysis performed by an independent statistician, the sponsor remaining blinded, yielded a posterior probability of ≥90% that efficacy was >0%. Conclusion RSV F nanoparticle vaccine is immunogenic in pregnancy, and neutralizing antibodies, including those competing for pre-and post-fusion F epitopes, are transferred efficiently transplacentally. An analysis of Phase 3 efficacy against medically signifcant infant RSV LRTI is projected for Q1, 2019. Disclosures L. Fries, Novavax: Employee and Shareholder, Salary. D. N. Thomas, Novavax: Employee, Salary. G. Smith, Novavax: Employee and Shareholder, Salary. J. Plested, Novavax: Employee, Salary. P. Piedra, Novavax: Collaborator, Consultant, Research Contractor and Scientific Advisor, Consulting fee, contract fees for immunologic assays and Research support. N. Patel, Novavax: Employee and Shareholder, Salary. I. Cho, Novavax: Employee and Shareholder, Salary. G. Glenn, Novavax: Employee and Shareholder, Salary.

Maternal immunization is an effective strategy to prevent and/or minimize the severity of infectious diseases in pregnant women and their infants. Based on the success of vaccination programs to prevent maternal and neonatal tetanus, maternal immunization has been well received in the United States and globally as a promising strategy for the prevention of other vaccine-preventable diseases that threaten pregnant women and infants, such as influenza and pertussis. Given the promise for reducing the burden of infectious conditions of perinatal significance through the development of vaccines against relevant pathogens, the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) sponsored a series of meetings to foster progress toward clinical development of vaccines for use in pregnancy. A multidisciplinary group of stakeholders convened at the NIH in December 2013 to identify potential barriers and opportunities for scientific advancement in maternal immunization.