safety and immunogenicity of an inactivated recombinant newcastle disease virus vaccine CORD-Papers-2021-10-25 (Version 1)

Title: Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: Interim Results of a Randomised, Placebo-Controlled, Phase 1/2 Trial
Abstract: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy adults aged 18-59 years, non-pregnant and negative for SARS-CoV-2 antibodies were eligible. Participants were block randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 microgram (mcg) +/- CpG1018 (a toll-like receptor 9 agonist), 3 mcg +/- CpG1018, 10 mcg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enrolled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5.7% to 17.1% among vaccine groups and was 2.9% in controls; there was no vaccine-related serious adverse event. The immunogenicity of the 10 mcg formulation ranked best, followed by 3 mcg+CpG1018, 3 mcg, 1 mcg+CpG1018, and 1 mcg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122.23 IU/mL (1 mcg, 95% CI 86.40-172.91) to 474.35 IU/mL (10 mcg, 95% CI 320.90-701.19), with 93.9% to 100% of vaccine groups attaining a => 4-fold increase over baseline. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 mcg and 3 mcg+CpG1018 formulations advanced to phase 2.
Published: 9/20/2021
Journal: medRxiv : the preprint server for health sciences
DOI: 10.1101/2021.09.17.21263758
DOI_URL: http://doi.org/10.1101/2021.09.17.21263758
Author Name: Innis, B L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/innis_b_l
Author Name: Mercer, L D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mercer_l_d
Author Name: White, J A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/white_j_a
Author Name: Scharf, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/scharf_r
Author Name: Hjorth, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hjorth_r
Author Name: Lamola, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lamola_s
Author Name: Raghunandan, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/raghunandan_r
Author Name: Lal, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lal_m
Author Name: McLellan, J S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mclellan_j_s
Author Name: Hsieh, C L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hsieh_c_l
Author Name: Pitisuttithum, P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/pitisuttithum_p
Author Name: Luvira, V
Author link: https://covid19-data.nist.gov/pid/rest/local/author/luvira_v
Author Name: Muangnoicharoen, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/muangnoicharoen_s
Author Name: Lawpoolsri, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lawpoolsri_s
Author Name: Sivakorn, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sivakorn_c
Author Name: Phumratanaprapin, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/phumratanaprapin_w
Author Name: Kamolratanakul, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kamolratanakul_s
Author Name: Phonrat, B
Author link: https://covid19-data.nist.gov/pid/rest/local/author/phonrat_b
Author Name: Sabmee, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sabmee_y
Author Name: Thantamnu, N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/thantamnu_n
Author Name: Wirachwong, P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wirachwong_p
Author Name: Poopipatpol, K
Author link: https://covid19-data.nist.gov/pid/rest/local/author/poopipatpol_k
Author Name: Surichan, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/surichan_s
Author Name: Prangpratanporn, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/prangpratanporn_s
Author Name: Kaweepornpoj, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kaweepornpoj_r
Author Name: Theerasurakarn, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/theerasurakarn_s
Author Name: Narakorn, P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/narakorn_p
Author Name: Singchareon, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/singchareon_r
Author Name: Suthepakul, N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/suthepakul_n
Author Name: Puksuriwong, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/puksuriwong_s
Author Name: Vilasmongkolchai, T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/vilasmongkolchai_t
Author Name: Gagnon, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/gagnon_l
Author Name: Tran, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tran_s
Author Name: Khan, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/khan_s
Author Name: Krammer, F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/krammer_f
Author Name: Mena, I
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mena_i
Author Name: Garcia Sastre, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/garcia_sastre_a
Author Name: Sun, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sun_w
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: McCroskery, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mccroskery_s
sha: 726315945eb2e2fadc8f3a82c29fd34bacd76111
license: medrxiv
source_x: MedRxiv; Medline
source_x_url: https://www.medline.com/
pubmed_id: 34580673
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/34580673
url: http://medrxiv.org/cgi/content/short/2021.09.17.21263758v1?rss=1 https://www.ncbi.nlm.nih.gov/pubmed/34580673/ https://doi.org/10.1101/2021.09.17.21263758
has_full_text: TRUE
Keywords Extracted from Text Content: Saraburi SARS-CoV-2 2N H2SO4 GMFRs PBMCs Wisent Bioproducts GMFR Unmasked anti-human IFN-γ fluorescein isothiocyanate 32:7 IgG-Fc TH2) 326 T-helper cell Jackson ImmunoResearch 20·43-fold NT50 GMTs 12·82 HCS panel SARS-CoV-2 peptide pool 1 9·4 ≥10-fold Anti-human IFN-γ/IL-5 214 BNT162b2 participants FITC-HRP HCS medRxiv GMT human convalescent serum samples 199 B.1.351 rats T cell SARS-CoV-2 pseudotyped virus toll-like receptor 9 GMC pseudotyped anti-SARS-CoV-2 immunoglobulin COVID-19 allantoic fluids round-186 observer-blind eggs intramuscular 79·4 pseudotyped virus particles Cellular NT50 GMCs sucrose 320·90-306 701·19 CR3022 7 CO2 ≥4-fold post-second IFN-γ/IL-5 HXP-S reference 8 SARS-CoV-2 232 pseudotyped virus TH1 recipients Vaccine ≥38 COVID-19 vaccine luciferase medRxiv preprint 519 human vaccines. NCT04993209 IL-5 IgG NDV cytoplasmic tail mid-and high-dose 371 BAU/mL streptavidin-alkaline 218 phosphatase coronavirus disease 2019 immunoglobulin NT80 cells 265·89-478·88 GMCs serum anti-human IL-5 215 peripheral blood mononuclear cells SARS-CoV-2 184 3:3:1 HRP interferon-γ phosphate buffered 166 saline B·1·351 biotin P.1 humans 2-8°C PIMMCs IFN-γ Earle Brazil ( q1-q3 SARS-CoV-2 spike 339 B.1.351 (table 5 beta-propiolactone anti-human IFN-γ/IL-5 capture 210 antibodies MN908947 antigen blue TMB LLOQ oral B.1.617.2 NT50 coronavirus 2 IFN-327 3,3′,5,5′-172 tetramethylbenzidine cellular 7·49 2:2:1 SARS-CoV-2 S AEs CIs t-261 anti-Wuhan medRxiv preprint vaccine-induced T cell Nexelis SFU/10 6 cells B.1.315 12 204 horseradish peroxidase 199·08 BAU/mL human monoclonal antibody six-proline 97 blood human convalescent serum vaccine-368 SARS-CoV-2 spike glycoprotein S1 human vaccine TH2 357 convalescent sera Newcastle disease virus 83 Wuhan-1 LMICs SARS-CoV-2 spike peptide medRxiv preprint preprint sera medRxiv preprint Table 1 medRxiv preprint Table 5 hamsters 5 PBMCs 207 human IFN-γ/IL-5 double-colour filter-134 erythema saline GPO 344 JPT computer-117 B.1.351 and P.1 1:4000 medRxiv preprint 520 521 LakePharma peroxidase virus neutralising antibodies virus vaccine ≥40 122·23 ≥10 Blood samples sodium dodecyl sulphate 137 polyacrylamide gel TLR-9 340 NDV-377 HXP-S vaccine anti-SARS-CoV-2 Wuhan-Hu-1 NT50 ≥4
Extracted Text Content in Record: First 5000 Characters:There remains a shocking imbalance in the global distribution of coronavirus disease 2019 (COVID-19) 76 vaccines. 1 To achieve control of the COVID-19 pandemic in low-and middle-income countries (LMICs) 77 where most of the global population resides, there must be a great increase in sustainable supply of 78 affordable vaccines. The manufacturing capacity for egg-based inactivated influenza vaccines (IIV) is 79 among the largest in the world; these facilities, some in middle-income countries and operating for less 80 than six months per year, use locally produced embryonated eggs to make more than a billion doses 81 annually of affordable human vaccines. 2 To enable these manufacturers to respond to the COVID-19 82 pandemic, we developed a COVID-19 vaccine for production in eggs, based on a Newcastle disease virus 83 (NDV) expressing the ectodomain of a novel membrane-anchored, prefusion-stabilized severe acute 84 respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein construct, wherein virions are purified 85 and inactivated (NDV-HXP-S). 3-5 86 From September to November 2020, manufacturers in Thailand, Vietnam, and Brazil modified their IIV 87 manufacturing process to optimize production of beta-propiolactone (BPL)-inactivated NDV-HXP-S, 88 achieving high yields at pilot scale; the result was three similar processes. A preclinical evaluation of 89 their vaccine candidates, formulated with and without CpG1018, a toll-like receptor 9 agonist adjuvant 90 (Dynavax Technologies) 6 confirmed that they were highly immunogenic and protective in hamsters 5 with 91 no sign of toxicity in rats at the maximum human doses planned for evaluation (3 μg S protein+1·5 mg 92 CpG1018; 10 μg S protein). These results enabled all three manufacturers to initiate clinical 93 development of their vaccine candidates. Herein, we report interim safety and immunogenicity data 94 generated in the phase 1 portion of an adaptive phase 1/2 clinical trial evaluating the NDV-HXP-S 95 vaccine candidate developed by The Government Pharmaceutical Organization of Thailand (GPO). These 96 results provide the first evidence in humans that the NDV vector technology expressing a six-proline 97 prefusion-stabilized spike protein construct offers a unique platform for affordable manufacturing of a 98 well-tolerated and highly immunogenic COVID-19 vaccine. 99 Study design and participants 101 The phase 1 segment of a randomised, observer-blind, placebo-controlled, phase 1/2 trial was 102 Enrolled subjects were randomly assigned in sequence to one of 6 equal groups (vaccine containing 1 μg 115 S ± 1·5mg CpG1018 adjuvant, 3 μg S ± 1·5mg CpG1018 adjuvant, 10 μg S, or saline placebo). Subjects 116 were enrolled in stages, each including active treatment and placebo groups, using a computer-117 generated block randomisation sequence prepared by an independent statistician; an unblinded 118 pharmacist team dispensed each treatment according to the randomization sequence. The first 18 119 subjects (sentinel cohort) were enrolled to three sequential sentinel groups; 3:1, 1 μg and placebo; 120 3:3:1, 3 μg or 1 μg+CpG1018 and placebo; and 3:3:1, 10 μg or 3 μg+CpG1018 and placebo, After safety 121 data were reviewed for the sentinel groups, the next 192 subjects were randomised in 5-dose-cohorts; 122 32:6, 1 μg and placebo; 32:6, 3 μg and placebo; 32:6, 1 μg+CpG1018 and placebo; 32:7, 10 μg and 123 placebo; and 32:7, 3 μg+CpG1018 and placebo. All participants and personnel other than the unmasked 124 pharmacy team and vaccinators were masked to treatment. 125 Procedures 126 The recombinant NDV-HXP-S vaccine was manufactured according to current Good Manufacturing 127 Practice by the GPO in their Influenza Vaccine Plant (Saraburi, Thailand) using locally procured 128 embryonated eggs inoculated with a master virus seed made and extensively tested for adventitious 129 agents by the Icahn School of Medicine at Mount Sinai (New York, USA). After incubation for 72 hours at 130 37°C, eggs were chilled overnight at 4°C, then the allantoic fluids were harvested, clarified, and 131 concentrated. Recombinant virus particles were purified from the concentrated harvest by two 132 sequential continuous flow sucrose gradient centrifugations, diafiltered against phosphate-buffered 133 saline (PBS), inactivated by treatment with 1:4000 BPL for 24 hours at 4°C, and 0.2 micron filter-134 sterilized. Vaccine potency was measured by direct enzyme-linked immunosorbent assay (ELISA) using a 135 human monoclonal antibody (CR3022 7 ) to SARS-CoV-2 spike glycoprotein S1 (LakePharma Inc) and an 136 NDV-HXP-S standard that had been calibrated to a purified HXP-S reference 8 by sodium dodecyl sulphate 137 polyacrylamide gel electrophoresis (SDS-PAGE) densitometry. 138 Unmasked staff administered study treatments by intramuscular injection of 0·5 mL on study days 1 and 139 29. Blood samples were drawn and clinical assessments were done for safety and immunogenicity 140 endpoints b
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