Safety and immunogenicity of a measles-vectored SARS-CoV-2 vaccine candidate, V591 / TMV-083, in healthy adults: results of a randomized, placebo-controlled Phase I study
Odile Launay, Cécile Artaud, Marie Lachâtre, Mohand Ait-Ahmed, Jelle Klein, Liem Binh Luong Nguyen, Christine Durier, Bastiaan Jansen, Yvonne Tomberger, Nathalie Jolly, Anna Grossmann, Houda Tabbal, Jérémy Brunet, Marion Gransagne, Zaineb Choucha, Damien Batalie, Ana Delgado, Matthias Müllner, Roland Tschismarov, Pieter-Jan Berghmans, Annette Martin, Katrin Ramsauer, Nicolas Escriou, Christiane Gerke, Odile Launay, Cécile Artaud, Marie Lachâtre, Mohand Ait-Ahmed, Jelle Klein, Liem Binh Luong Nguyen, Christine Durier, Bastiaan Jansen, Yvonne Tomberger, Nathalie Jolly, Anna Grossmann, Houda Tabbal, Jérémy Brunet, Marion Gransagne, Zaineb Choucha, Damien Batalie, Ana Delgado, Matthias Müllner, Roland Tschismarov, Pieter-Jan Berghmans, Annette Martin, Katrin Ramsauer, Nicolas Escriou, Christiane Gerke
Abstract
Background: V591 (TMV-083) is a live recombinant measles vector-based vaccine candidate expressing a pre-fusion stabilized SARS-CoV-2 spike protein.
Methods: We performed a randomized, placebo-controlled Phase I trial with an unblinded dose escalation and a double-blind treatment phase at 2 sites in France and Belgium to evaluate the safety and immunogenicity of V591. Ninety healthy SARS-CoV-2 sero-negative adults (18-55 years of age) were randomized into 3 cohorts, each comprising 24 vaccinees and 6 placebo recipients. Participants received two intramuscular injections of a low dose vaccine (1 × 105 median Tissue Culture Infectious Dose [TCID50]), one or two injections of a high dose vaccine (1 × 106 TCID50), or placebo with a 28 day interval. Safety was assessed by solicited and unsolicited adverse events. Immunogenicity was measured by SARS-CoV-2 spike protein-binding antibodies, neutralizing antibodies, spike-specific T cell responses, and anti-measles antibodies. ClinicalTrials.gov, NCT04497298.
Findings: Between Aug 10 and Oct 13, 2020, 148 volunteers were screened of whom 90 were randomized. V591 showed a good safety profile at both dose levels. No serious adverse events were reported. At least one treatment-related adverse event was reported by 15 (20.8%) participants receiving V591 vs. 6 (33.3%) of participants receiving placebo. Eighty-one percent of participants receiving two injections of V591 developed spike-binding antibodies after the second injection. However, neutralizing antibodies were detectable on day 56 only in 17% of participants receiving the low dose and 61% receiving the high dose (2 injections). Spike-specific T cell responses were not detected. Pre-existing anti-measles immunity had a statistically significant impact on the immune response to V591, which was in contrast to previous results with the measles vector-based chikungunya vaccine.
Interpretation: While V591 was generally well tolerated, the immunogenicity was not sufficient to support further development.
Funding: Themis Bioscience GmbH, a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA; Coalition for Epidemic Preparedness Innovations (CEPI).
Keywords: COVID-19; SARS-CoV-2; measles vector; vaccine.
Conflict of interest statement
Declaration of interests KR, RT, YT, AG, MM are employees of Themis Bioscience GmbH, a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. KR, RT, MM possess stock options of Merck & Co. A patent application including the design of V591 has been filed by the Institut Pasteur and is part of a licensing agreement between the Institut Pasteur and Themis/MSD, NE and CG are inventors. CIC Cochin-Pasteur, SGS, INSERM, Bioaster received payment to conduct the study. All other authors declare no conflict of interest.
Copyright © 2022 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, The Author(s). Published by Elsevier B.V. All rights reserved.
Figures
References
- World Health Organization. WHO COVID-19 Dashboard. (accessed July 22, 2021).
- World Health Organization. Draft landscape of COVID-19 candidate vaccines. (accessed July 22, 2021).
- Shrotri M, Swinnen T, Kampmann B, Parker EPK. An interactive website tracking COVID-19 vaccine development. Lancet Glob Health. 2021;9(5):e590–e5e2.
- Haas EJ, Angulo FJ, McLaughlin JM, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet. 2021;397(10287):1819–1829.
- Angeli F, Spanevello A, Reboldi G, Visca D, Verdecchia P. SARS-CoV-2 vaccines: Lights and shadows. Eur J Intern Med. 2021;88:1–8.
- Combredet C, Labrousse V, Mollet L, et al. A molecularly cloned Schwarz strain of measles virus vaccine induces strong immune responses in macaques and transgenic mice. J Virol. 2003;77(21):11546–11554.
- Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!) Lancet. 2017;389(10068):505–518.
- Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99–111.
- Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet. 2021;397(10275):671–681.
- Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396(10249):479–488.
- Singh M, Cattaneo R, Billeter MA. A recombinant measles virus expressing hepatitis B virus surface antigen induces humoral immune responses in genetically modified mice. J Virol. 1999;73(6):4823–4828.
- Brandler S, Ruffié C, Combredet C, et al. A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus. Vaccine. 2013;31(36):3718–3725.
- Lorin C, Segal L, Mols J, et al. Toxicology, biodistribution and shedding profile of a recombinant measles vaccine vector expressing HIV-1 antigens, in cynomolgus macaques. Naunyn Schmiedebergs Arch Pharmacol. 2012;385(12):1211–1225.
- Escriou N, Callendret B, Lorin V, et al. Protection from SARS coronavirus conferred by live measles vaccine expressing the spike glycoprotein. Virology. 2014;452-453:32–41.
- Malczyk AH, Kupke A, Prüfer S, et al. A highly immunogenic and protective Middle East respiratory syndrome coronavirus vaccine based on a recombinant measles virus vaccine platform. J Virol. 2015;89(22):11654–11667.
- Gerke C, Frantz PN, Ramsauer K, Tangy F. Measles-vectored vaccine approaches against viral infections: a focus on Chikungunya. Expert Rev Vaccines. 2019;18(4):393–403.
- Nürnberger C, Bodmer BS, Fiedler AH, Gabriel G, Mühlebach MD. A measles virus-based vaccine candidate mediates protection against zika virus in an allogeneic mouse pregnancy model. J Virol. 2019;93(3) e01485-18.
- Mateo M, Reynard S, Carnec X, et al. Vaccines inducing immunity to Lassa virus glycoprotein and nucleoprotein protect macaques after a single shot. Sci Transl Med. 2019;11(512):eaaw3163.
- Ramsauer K, Schwameis M, Firbas C, et al. Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial. Lancet Infect Dis. 2015;15(5):519–527.
- Reisinger EC, Tschismarov R, Beubler E, et al. Immunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active-controlled phase 2 trial. Lancet. 2018;392(10165):2718–2727.
- Kirchdoerfer RN, Wang N, Pallesen J, et al. Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis. Sci Rep. 2018;8(1):15701.
- Ujike M, Huang C, Shirato K, Makino S, Taguchi F. The contribution of the cytoplasmic retrieval signal of severe acute respiratory syndrome coronavirus to intracellular accumulation of S proteins and incorporation of S protein into virus-like particles. J Gen Virol. 2016;97(8):1853–1864.
- Grzelak L, Temmam S, Planchais C, et al. A comparison of four serological assays for detecting anti-SARS-CoV-2 antibodies in human serum samples from different populations. Sci Transl Med. 2020;12(559) eabc3103.
- Bewley KR, Coombes NS, Gagnon L, et al. Quantification of SARS-CoV-2 neutralizing antibody by wild-type plaque reduction neutralization, microneutralization and pseudotyped virus neutralization assays. Nat Protoc. 2021;16:3114–3140.
- Hodcroft EB. CoVariants: SARS-CoV-2 Mutations and Variants of Interest. 2021. (accessed Oct 22, 2021).
- World Health Organization WHO position on measles vaccines. Vaccine. 2009;27(52):7219–7221.
- Menni C, Klaser K, May A, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis. 2021;21(7):939–949.
- Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021;27:1205–1211.
- Vanhoutte F, Liu W, Wiedmann RT, et al. Safety and immunogenicity of the measles vector-based SARS-CoV-2 vaccine candidate V591, in adults: results from a Phase 1/2 randomised, double-blind, placebo-controlled, dose-ranging trial. EBioMedicine. 2021 in press.
- Walsh EE, Frenck RW, Jr, Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med. 2020;383:2439–2450.
- Lu M, Dravid P, Zhang Y, et al. A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike. Proc Natl Acad Sci U S A. 2021;118(12)
- Hörner C, Schürmann C, Auste A, et al. A highly immunogenic and effective measles virus-based Th1-biased COVID-19 vaccine. Proc Natl Acad Sci U S A. 2020;117(51):32657–32666.
- Pinschewer DD. Virally vectored vaccine delivery: medical needs, mechanisms, advantages and challenges. Swiss Med Wkly. 2017;147:w14465.
Source: PubMed