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Different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373) in younger and older adults: A phase 2 randomized placebo-controlled trial

['Neil Formica', 'Novavax', 'Inc.', 'Gaithersburg', 'Maryland', 'United States Of America', 'Raburn Mallory', 'Gary Albert', 'Michelle Robinson', 'Joyce S. Plested']

Date: 2021-10

Abstract Background NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. Methods and findings The phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose. Reactogenicity occurred less frequently and was of lower intensity in older participants. Both 2-dose regimens of 5-μg and 25-μg NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 μg, geometric mean titers (GMTs) for IgG anti-spike protein were 65,019 (95% confidence interval (CI) 55,485 to 76,192) and 28,137 (95% CI 21,617 to 36,623) EU/mL and for wild-type virus neutralizing antibody (with an inhibitory concentration of 50%—MN 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. Conclusions The study confirmed the phase 1 findings that the 2-dose regimen of 5-μg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 μg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies. Trial registration ClinicalTrials.gov NCT04368988.

Author summary Why was this study done? This study was designed to identify which dosing regimen of NVX-CoV2373 (1 or 2 doses of either 5 μg or 25 μg) was immunogenic and associated with a safety and tolerability profile that was acceptable to move forward into late-phase efficacy studies. What did the researchers do and find? Participants (n = 1,288) in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo.

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.

The 2-dose regimen of 5-μg NVX-CoV2373 was found to be immunogenic and well tolerated in both younger and older adults. What do these findings mean? These findings support the use of the lower-dose regimen in late-phase efficacy studies.

Citation: Formica N, Mallory R, Albert G, Robinson M, Plested JS, Cho I, et al. (2021) Different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373) in younger and older adults: A phase 2 randomized placebo-controlled trial. PLoS Med 18(10): e1003769. https://doi.org/10.1371/journal.pmed.1003769 Academic Editor: Maheshi N. Ramasamy, University of Oxford, UNITED KINGDOM Received: March 29, 2021; Accepted: August 13, 2021; Published: October 1, 2021 Copyright: © 2021 Formica et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. Funding: Funding support for the study was provided from the Coalition of Epidemic Preparedness Innovations (CEPI) (https://cepi.net) to Novavax Inc. and not to any individual authors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Authors RM, GA, JSP, IC, AR, FD, MR and GG all state to be employees and/or stock owners at Novavax. Dr. NF reports through my personal consulting company vehicle I consult for a variety of pre and post-licensure clinical development and medical affairs activities for other vaccine pharmaceutical and biotech companies. In the area of coronavirus vaccines I have a current consulting contract for post-licensure COVID vaccine support for approval and implementation of rollout of the AstraZeneca/Oxford COVID vaccine in Australia and New Zealand. Dr. GG reports grants from CEPI during the conduct of the study; personal fees and other from Novavax, grants from Bill and Melinda Gates Foundation, grants from Department of Defense, grants from Operation Warp Speed, other from RA Capital outside the submitted work. Abbreviations: ADE, antibody-dependent enhancement; AE, adverse event; CI, confidence interval; COVID-19, coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay; FDA, Food and Drug Administration; GMFR, geometric mean fold rise; GMT, geometric mean titer; hACE2, human angiotensin-converting enzyme 2; IgG, immunoglobulin G; LLOQ, lower limit of quantification; MN, microneutralization; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; PIMMC, potential immune-mediated medical condition; rSARS-CoV-2, recombinant severe acute respiratory coronavirus 2; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

Introduction The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to spread rapidly throughout the world, with over 174 million confirmed cases and over 3.7 million deaths globally as of June 11, 2021 [1]. Mutated SARS-CoV-2 variants with enhanced transmissibility emerged and established themselves as clinically dominant in the United Kingdom and South Africa in late 2020 and have been spreading globally. Therefore, there is a growing health and economic need for safe and efficacious vaccines to help prevent the spread of SARS-CoV2 and its variants throughout the world. NVX-CoV2373 contains Matrix-M1 adjuvant [2] and a recombinant SARS-CoV-2 (rSARS-CoV-2) [3] protein, constructed from the full-length (i.e., including the transmembrane domain), wild-type SARS-CoV-2 spike glycoprotein. Viral attachment to the human angiotensin-converting enzyme 2 (hACE2) receptor of host cells is mediated by SARS-CoV2 spike protein and serves as a target for development of antibodies and vaccines [4,5]. Targeting the SARS-CoV-2 spike protein has been shown to be highly effective in preventing COVID-19 in clinical trials, which has formed the basis for emergency use of several vaccine candidates [6,7]. The phase 1 component of the phase 1 to 2 trial showed that 2-dose regimens of 5-μg and 25-μg rSARS-CoV-2 with 50-μg Matrix-M1 adjuvant (mixed prior to use) in participants 18 to 59 years were well tolerated and immunogenic as seen by increases in immunoglobulin G (IgG) anti-spike antibodies and neutralizing antibodies with an inhibitory concentration of >99% (MN >99% ), which exceed levels seen in a panel of COVID-19 convalescent serum samples [3]. Importantly, the Matrix-M1 adjuvant was dose sparing and induced CD4+ effector memory T-cell responses that were biased toward a Th1 phenotype, which may play a role in reducing the theoretical possibility of antibody-dependent enhancement (ADE) of SARS-CoV-2 infection [8]. Here, we report on the phase 2 safety and immunogenicity, evaluating 1- or 2-dose regimens for 2 antigen dose levels. This descriptive study was designed to generate data supporting selection of a preferred dose regimen in both younger and older adults for evaluation in clinical endpoint studies. The phase 2 study does not include any participants from the phase 1 component of the study.

Methods Trial design and oversight Our phase 2 trial was conducted at 9 sites in Australia and 8 sites in the United States. Eligible participants were men and nonpregnant women 18 to 84 years of age with a body mass index (the weight in kilograms divided by the square of the height in meters) of 17 to 35. Participants with a range of underlying medical conditions could be enrolled if the conditions were judged clinically to be stable, and, therefore, the study population was inclusive of potentially more comorbid conditions than would normally be enrolled in a phase 2 study to allow a more generalizable population to be enrolled for expected priority population groups for vaccination. Details of the trial design, eligibility criteria, conduct, oversight, and analyses are provided in the protocol and statistical analysis plan (included in the Supporting information). All participants provided written informed consent prior to trial enrollment. Up to 750 participants were planned to be randomized in each country (150 participants per treatment group) to decrease the risk that study recruitment or implementation in either country might be difficult due to outbreak restrictions or vaccine and sample transportation challenges. Eligible participants were randomly assigned (1:1:1:1:1) in a blinded manner to 1 of 4 vaccine groups (Groups B, C, D, and E) or placebo (Group A) according to pregenerated randomization schedules and were stratified by age (ages 18 to 59 and 60 to 84 years) and study site (Fig 1). As a safety measure, enrollment of older participants was initially limited to approximately 50 participants in each of the 4 vaccine and placebo groups until reactogenicity was observed for 5 days after which safety monitoring committee review confirmed further enrollment could continue. PPT PowerPoint slide

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TIFF original image Download: Fig 1. CONSORT flow diagram. Notes: Study treatments Dose 1 / Dose 2: Group A: placebo / placebo; Group B: 5-μg SARS-CoV-2 rS + M1 / 5-μg SARS-CoV-2 rS + M1; Group C: 5-μg SARS-CoV-2 rS + M1 / placebo; Group D: 25-μg SARS-CoV-2 rS + M1 / 25-μg SARS-CoV-2 rS + M1; Group E: 25-μg SARS-CoV-2 rS + M1 / placebo (M1 = 50-μg Matrix M1 adjuvant). Details of the analysis sets are included in the Supporting methods section. https://doi.org/10.1371/journal.pmed.1003769.g001 Each participant received 2 intramuscular injections of 5-μg (low-dose) or 25-μg (high-dose) NVX-CoV2373 and/or 0.9% sodium chloride placebo in a 1-dose (5 μg or 25 μg followed by placebo) or 2-dose (5 μg followed by 5 μg or 25 μg followed by 25 μg) regimen, 21 days apart. Both dose regimens included 50 μg of the Matrix-M1 adjuvant. Participants and trial site personnel managing the conduct of the trial remained blinded to vaccine assignment. Vaccination pause rules were in place to monitor participants’ safety (see Supporting appendix). The trial was designed by Novavax (Gaithersburg, Maryland, USA), with funding support from the Coalition for Epidemic Preparedness Innovations. The trial protocol was approved by the Alfred Hospital Human Research Ethics Committee (Melbourne, Australia) and Advarra Central Institutional Review Board (Columbia, Maryland, USA) and was performed in accordance with the International Conference on Harmonisation, Good Clinical Practice guidelines; ClinicalTrials.gov number: NCT04368988. Safety oversight for the older adult lead-in enrollment cohort and specific vaccination pause rules were supported by an independent safety monitoring committee. The authors assume responsibility for the accuracy and completeness of the data and analyses, as well as for the fidelity of the trial. Trial procedures: Safety assessments Reactogenicity was self-reported by participants using an electronic smartphone-based diary with daily electronic prompts for completion each evening, starting on the day of vaccination (Day 0) and for 6 subsequent days (for a total of 7 days). Predefined solicited local (injection site) reactogenicity included pain, tenderness, erythema, and swelling; systemic reactogenicity included fever, nausea or vomiting, headache, fatigue, malaise, myalgia, and arthralgia. Reactogenicity severity was graded according to the Food and Drug Administration (FDA) toxicity grading scale with minor modifications (Table A in S1 Text) [9]. Unsolicited adverse events (AEs) were assessed at each study visit and coded by preferred term and system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, and summarized by trial vaccine, clinical severity (mild, moderate, and severe), and causality (not related and related). Definitions for AEs of special interest relevant to COVID-19 [10,11] (Table B in S1 Text) and potential immune-mediated medical conditions (PIMMCs) (Table C in S1 Text) are included in the Supporting information. Immunogenicity assessments An enzyme-linked immunosorbent assay (ELISA) (Novavax, Gaithersburg, Maryland, USA) was used to measure IgG anti-spike protein levels specific for rSARS-CoV-2 protein antigens from all participants with evaluable samples at Days 0 (baseline), 21, and 35, with seropositivity defined as a titer above the lower limit of quantification (LLOQ; 200 ELISA units per milliliter). A microneutralization (MN) assay (360biolabs, Melbourne, Australia) with an inhibitory concentration of 50% (MN 50% ) was used to measure neutralizing antibodies specific to wild-type virus SARS-CoV-2 at the same time points from a nonrandomized subgroup of approximately 250 participants (25 participants per treatment group per age group) with seropositivity defined as titer above the LLOQ (titer of 20). Although nonrandomized, the MN subset was selected (by an unblinded study statistician) to be approximately balanced by treatment group and age group from participants enrolled earlier in the study until the subgroup quota was met. Details of assays are included in the Supporting methods section. An ad hoc analysis was conducted, comparing the neutralizing antibody response to a sample serum panel from a clinical case series of 60 convalescent sera samples from cases with polymerase chain reaction (PCR)-confirmed asymptomatic to severe symptoms of COVID-19 from Baylor College of Medicine (Houston, Texas, USA). Three samples were from pediatric cases, 13 (22%) of samples were from adults 18 to 49 years, 13 (22%) from adults 50 to 64 years, and 31 (52%) from older adults 65 to 79 years. In terms of clinical disease severity, 11 (18%) were from asymptomatic/mild cases (identified through contact/exposure assessment), 30 (50%) were from mild/moderate cases (outpatient cases/discharged cases from the emergency department), and 19 (32%) were from moderate/severe cases (hospitalized cases/intensive care unit cases). Statistical analysis The decision on which dosing regimen of NVX-CoV2373 to move forward into late-phase studies in both younger and older adult participants was based on the totality of the immunogenicity and safety data rather than any individual measurement and was not based on formal statistical comparisons of treatments. With a minimum of approximately 150 participants in each treatment group (in either country), there was a greater than 99.9% probability of observing at least 1 participant with an AE if the true incidence of the AE was 5% and a 77.9% probability if the true incidence of the AE was 1%. For immunogenicity endpoints, power estimates based on a range of assumptions for potential immunogenicity endpoint scenarios were made and are included in the statistical analysis plan. Most endpoints were summarized using descriptive statistics, with 95% confidence intervals (CIs) added based on the t-distribution of the log-transformed values. This Set included all participants who received at least 1 dose of study vaccine or placebo. Immunogenicity Analysis Sets are described in the protocol and statistical analysis plan. Any participant who tested SARS-CoV-2 positive by qualitative PCR testing from screening and prior to the immunogenicity assessment for a particular time point were excluded from the Per-Protocol Analysis Set for that time point as were participants who had major protocol deviations that might affect their immune responses.

Discussion Based on the totality of the safety and immunogenicity data through at least Day 35 from this phase 2 study, the 2-dose regimen of 5-μg NVX-CoV2373 administered 21 days apart was determined to be the preferred dose regimen for phase 3 development and potential licensure in both younger and older adults. Following first vaccination, both dose levels of NVX-CoV2373 were well tolerated, but there was a higher incidence of local reactogenicity (any solicited local AE) with the higher dose for all participants; however, anti-spike protein binding IgG levels and neutralizing antibody responses were similar by dose level. Following second vaccination, both dose levels of NVX-CoV2373 remained generally well tolerated despite increased frequencies and intensities of local and systemic reactogenicity in both younger and older adults, with higher incidence of overall solicited local and systemic AEs seen with the higher-dose level. Most solicited AEs were of mild or moderate grade severity, and grade 3 or higher solicited AEs were uncommon. NVX-CoV2373 induced robust levels of anti-spike protein binding IgG levels and neutralizing antibodies in both younger and older adults, with seroconversion rates of at least 96% achieved with similar immune responses between the 2 dose levels. Notably, in both age groups, there was a high correlation between “binding” antibodies (anti-spike IgG) and neutralizing antibodies (Fig 4), suggesting that the anti-spike immunity was predominantly functional, as indicated by neutralization. Based on the antibody responses, the low-dose, 2-immunization regimen of 5-μg NVX-CoV2373 was selected to move into later phase development. The study is ongoing, with immune persistence being assessed at approximately 6 months, with subsequent booster doses administered to some study subgroups. Cell-mediated immune responses in a subset of participants by analysis of peripheral blood mononuclear cells (PBMCs) for T-cell responses are also underway and will be published once complete. PPT PowerPoint slide

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TIFF original image Download: Fig 4. Correlation between SARS-CoV-2 anti-spike IgG and neutralizing antibody responses. Shown is a scattergram and correlation analysis of the neutralizing antibody titers and anti-spike IgG ELISA units for the 5-μg NVX-CoV2373 2-dose vaccine group (Group B) for younger adults 18 to 59 years (Panel A) and older adults 60 to 84 years (Panel B). Pearson correlations were calculated with 2-sided 95% CIs. The correlation plots were inclusive of paired specimens by the 2 assays at the Day 21 time point following first vaccination, as well as for paired results at the Day 35 time point following second vaccination. (A) 5 μg + Matrix-M1 (Group B)– 18–59 years [footnote for Fig 4A] * NCT04368988 –phase 1. (B) 5 μg Matrix-M1 (Group B)– 60–84 years. CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; EU, endotoxin unit; IC, inhibitory concentration; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. https://doi.org/10.1371/journal.pmed.1003769.g004 The 2-dose regimen of 5-μg NVX-CoV2373 is being investigated in a phase 2a/b study in South Africa [NCT04533399] and 2 large phase 3 studies in the UK [NCT04583995] and the US [NCT04611802]. To date, the phase 2a/b has reported that among 2,684 baseline seronegative participants (94% HIV–negative and 6% HIV–positive), that vaccine efficacy was 49.4%, 95% CI, 6.1 to 72.8). Vaccine efficacy among HIV–negative participants was 60.1% (95% CI, 19.9 to 80.1). This vaccine efficacy is predominantly against the B.1.351 variant, with 38/41 (92.7%) of sequenced samples being the B.1.351 variant [13]. As expected, we found lower frequencies of local and systemic reactogenicity and lower anti-spike protein binding IgG and neutralizing antibody responses in older adults. These findings are consistent with other SARS-CoV-2 vaccines [6,7]. Despite the lower immune response in older adults, seroconversion rates after the 2-dose regimen of 5-μg NVX-CoV2373 were 97% for anti-spike protein binding IgG and 100% for neutralizing antibodies, which reflected increases from baseline of >250-fold and >95-fold, respectively. Additionally, in both younger and older adults, neutralizing antibody titers exceeded those seen in a sample of convalescent sera from a clinical case series of asymptomatic, outpatient, and hospitalized patients. The safety and tolerability data from this study are also consistent with that gathered from over 14,000 participants [14–21], including over 4,300 participants who received the Matrix-M1 adjuvant [18–21], enrolled in previous noncoronavirus nanoparticle trials. These studies included children, pregnant women, and older adults with an age range from 5 months to 85 years of age and indicate that vaccines based on the nanoparticle/Matrix-M1 adjuvant technology have an acceptable safety profile to date. 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. Other limitations include restricted eligibility criteria that excluded advanced age participants (85 years and older) and persons with severe comorbidities and immunocompromised persons, although this phase 2 study was more permissive of inclusion of persons with clinically stable comorbidities than would normally be the case for a phase 2 study, given the pandemic situation to broaden the generalizability of the results. Another limitation was the lack of formal statistical inference to assess superiority or noninferiority of the 2 vaccine regimens. There is not currently an established immune correlate of protection to establish the clinical significance of the immunogenicity results; however, clinical endpoint studies underway by Novavax and other companies for a variety of SARS-CoV-2 vaccine candidates have been demonstrating that multiple vaccines targeting immune responses directed against the spike protein of SARS-CoV-2 are demonstrating substantial initial vaccine efficacy with acceptable safety/tolerability profiles in adults and/or older adults against the vaccine strains included [6,7,13,22–25]. In settings where mass vaccination programs have been implemented for some of the first licensed vaccines, vaccine effectiveness studies have begun to demonstrate effectiveness estimates that are similar to clinical efficacy results from phase 3 studies [26,27]. The emergence of SARS-CoV-2 variants circulating in countries concurrently during some clinical efficacy studies have allowed some vaccines to report efficacy against emerging variants [13,22,28,29]. The data from this phase 2 study indicate that the Matrix-M1 adjuvanted rSARS-CoV-2 nanoparticle vaccine was highly immunogenic and well tolerated in younger and older participants.

Supporting information S1 CONSORT Checklist. https://doi.org/10.1371/journal.pmed.1003769.s001 (DOC) S1 Text. Table A. Toxicity grading scales for solicited local and systemic adverse events—modified from FDA toxicity grading scale for clinical abnormalities. Table B. Adverse events of special interest relevant to COVID-19. Table C. Potential immune-mediated medical conditions. Fig A. Vaccine regimens and key trial assessments. Table D. Overall summary of solicited and unsolicited adverse events following vaccination of SARS-CoV-2 rS with Matrix-M1 adjuvant in adult participants 18 to 84 years of age (Safety Analysis Set). Table E. Percentage of all participants (18 to 84 years) experiencing solicited local and systemic adverse events by symptom, vaccination dose, vaccine group, and maximum toxicity grade (Safety Analysis Set). Table F. Percentage of younger adults (18 to 59 years) experiencing solicited local and systemic adverse events by symptom, vaccination dose, vaccine group, and maximum toxicity grade (Safety Analysis Set). Table G. Percentage of older adults (60 to 84 years) experiencing solicited local and systemic adverse events by symptom, vaccination dose, vaccine group, and maximum toxicity grade (Safety Analysis Set). Table H. Unsolicited adverse events by system organ class and preferred term reported in 1% or more participants in any group through 35 days after first vaccination (Safety Analysis Set). https://doi.org/10.1371/journal.pmed.1003769.s002 (DOCX)

Acknowledgments We thank all of the study participants who volunteered for this study. Editorial assistance on the preparation of this manuscript was provided by Phase Five Communications, supported by Novavax, Inc. Disclosure forms provided by the authors are available with the full text of this article at the PLOS Medicine website. We acknowledge the contributions of the 2019nCoV-101 Study Group: Mark Adams, Mark Arya, Eugene Athan, Ira Berger, Paul Bradley, Richard Glover II, Paul Griffin, Joshua Kim, Scott Kitchener, Terry Klein, Amber Leah, Charlotte Lemech, Jason Lickliter, Mary Beth Manning, Fiona Napier-Flood, Paul Nugent, Susan Thackwray, and Mark Turner. We also acknowledge the contributions to the Part 2 of the study by Cheryl Keech, the clinical lead when the Part 1 of the 2019nCoV-101 Study started.

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