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

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 × 10 5 median Tissue Culture Infectious Dose [TCID 50 ]), one or two injections of a high dose vaccine (1 × 10 6 TCID 50 ), 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.

Versatility of live-attenuated measles viruses as platform technology for recombinant vaccines

“…However, the picture became different for the MeV-vectors targeting SARS-CoV-2. Here, pre-formed anti-measles immunity negatively correlated with anti-COVID-19 responses 35 . This may indicate that the impact of anti-measles immunity on clinical efficacy of MeV-derived vaccine vectors is dependent of the antigen (native CHIKV-E vs. stabilized SARS-CoV-2 S), the way the antigen is presented by the vaccine (VLPs vs. cell-associated), or some other parameters yet to be defined.…”

“… Trial number Virus Disease Phase Institution Status Refs. EudraCT 2013-001084-23 MV-CHIK Chikungunya fever I Themis Biosciences Completed 93 NCT01320176 MV1-F4-CT1 AIDS I Institut Pasteur Completed NCT02861586 MV-CHIK Chikungunya fever II Themis Biosciences Completed 91 , 98 NCT02996890 MV-ZIKA Zika fever I Themis Biosciences Completed NCT03028441 MV-CHIK Chikungunya fever I NIAID Completed NCT03101111 MV-CHIK Chikungunya fever II Themis Biosciences, Walter Reed Army Institute of Research Completed, results posted NCT03635086 MV-CHIK Chikungunya fever II Themis Biosciences Completed, results posted NCT03807843 MV-CHIK Chikungunya fever II Themis Biosciences, Walter Reed Army Institute of Research Completed, results posted NCT04033068 MV-ZIKA-RSP Zika fever I Themis Biosciences Completed, results posted NCT04055454 MV-LASV Lassa fever I Themis Biosciences Completed NCT04497298 TMV-083 / V-591 COVID-19 I Institut Pasteur, Themis Biosciemces, CEPI Completed …”

“…While proof of efficacy has been demonstrated for only one of the experimental vaccine candidates targeting a disease transmitted by direct contact, MV-SHIV 78 , all but one of the experimental vaccines targeting diseases transmitted via the respiratory route or arthropod vectors have yielded evidence of protection in animal models. For the respiratory group, the COVID-19 vaccine candidate has entered clinical development 35 , 36 , as has the LASV vaccine candidate (Table 3 ). More impressively, the most clinically advanced group is those vaccines targeting arboviral pathogens, with the MV-ZIKA vaccine having undergone testing in phase I (NCT02996890, NCT04033068), and MV-CHIK having succeeded in phase II clinical trials 91 ready to enter phase III (Table 3 and Fig.…”

“…If these trials are successful, marketing authorization could be expected. Interest of key players of the pharmaceutical industry in this technology became evident at least when Merck Sharp & Dohme acquired Vienna-based Themis Biosciences 92 , who have been driving clinical development of the MeV-derived vaccines against CHIKV 68 , 93 , ZIKV (NCT02996890, NCT04033068), and SARS-CoV-2 35 , 36 . Moreover, the very first project funded by the Coalition for Epidemic Preparedness Innovations (CEPI) focused on the development of MeV-derived vaccines against LASV and MERS-CoV 94 and financed the development of the LASV vaccine into clinical evaluation (Table 3 , NCT04055454).…”

Concentrating all helper protein functions on a single entity allows rescue of recombinant measles virus by transfection of just two plasmids

“…In addition, clinical trials using MeV-derived recombinant MeV have been performed, and reached up to phase 2, awaiting a phase 3 trial to target Chikungunya virus (CHIKV) [4]. Moreover, MeV-derived vaccines have recently been tested against COVID-19 [5][6][7][8][9].…”