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      Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine

      , M.D., , Ph.D., , M.D., , Ph.D., , Ph.D., , Ph.D., , Ph.D., , Ph.D., , M.D., , M.D., , M.D., , D.O., , M.D., , M.D., , M.D., , M.D., , M.D., , Ph.D., , M.D., , Ph.D., , Ph.D., , M.D., , Ph.D., , M.D., , M.D., , M.D., , Ph.D.

      The New England Journal of Medicine

      Massachusetts Medical Society

      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_6Keyword part (keyword): Viral Infections , 18, Infectious Disease, Keyword part (code): 18_6Keyword part (keyword): Viral Infections, 18_6, Viral Infections

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          Abstract

          Background

          Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein.

          Methods

          In this multicenter, placebo-controlled, phase 1–2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×10 10 viral particles (low dose) or 1×10 11 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule.

          Results

          After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 224 to 354), regardless of vaccine dose or age group, and reached 100% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 14, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3.

          Conclusions

          The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.)

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          Most cited references 17

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

            Abstract Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. Methods We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. Results After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. Conclusions The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).
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              Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

              Summary Background The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R 2=0·67 by Marburg VN; p<0·001). Interpretation ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. Funding UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                13 January 2021
                Affiliations
                From Janssen Vaccines and Prevention, Leiden, the Netherlands (J. Sadoff, M.L.G., G. Shukarev, A.M.G., J. Stoop, S.T., E.C., G. Scheper, J. Hendriks, M.D., J.V.H., H.S.); Janssen Research and Development, Beerse (D.H., C.T., F.S.), Janssen Clinical Pharmacology Unit, Merksem (W.V.D.), the Center for Vaccinology, Ghent University, Gent (I.L.-R.), SGS Life Sciences (P.-J.B.) and the Center for the Evaluation of Vaccination, University of Antwerp (P.V.D.), Antwerp, and the Center for Clinical Pharmacology, University Hospitals Leuven, Leuven (J. de Hoon) — all in Belgium; Optimal Research, Melbourne, FL (M.K.); the Alliance for Multispecialty Research, Knoxville, TN (W.S.); the Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston (K.E.S., D.H.B.); and the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle (S.C.D.R., K.W.C., M.J.M.).
                Author notes
                Address reprint requests to Dr. Schuitemaker at Janssen Vaccines and Prevention, Newtonweg 1, Leiden 2301CA, the Netherlands, or at hschuite@ 123456its.jnj.com .

                Drs. Sadoff and Le Gars contributed equally to this article.

                Article
                NJ202101130000003
                10.1056/NEJMoa2034201
                7821985
                33440088
                Copyright © 2021 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

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                Funding
                Funded by: Biomedical Advanced Research and Development Authority of the Department of Health and Human Services, FundRef ;
                Award ID: HHS0100201700018C
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                2021-01-13T17:00:00-05:00
                2021
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