ABSTRACT
Background: Additional safe and effective vaccines are needed to control the COVID-19 pandemic.Methods: HERALD is an ongoing phase 2b/3 randomised, observer-blinded, placebo-controlled clinical trial in ten countries in Europe and Latin America. SARS-CoV-2 naïve adults were randomised 1:1 to receive two doses of CVnCoV mRNA vaccine candidate or placebo 28 days apart. Primary efficacy analysis included symptomatic COVID-19 more than 14 days after second dose. Solicited adverse events (AEs) were assessed in phase 2b participants and unsolicited AEs in all participants. The study is registered at ClinicalTrials.gov (NCT04652102).Findings: Between 11 December 2020 and 12 April 2021, 39 680 participants were randomised and 39 529 received CVnCoV (19 783) or placebo (19 746). Overall VE was 48·2% (95% CI: 31·0–61·4; 83/12 851 vs. 145/12 221 in CVnCoV and placebo recipients, respectively). Overall VE against moderate-to-severe COVID-19 was 70·7% (95% CI: 42·5–86·1; 12/12 851 vs. 37/12 211, respectively). In participants aged 18–60 years VE was 52·5% (95% CI: 36·2–64·8; 71/11 532 vs. 136/11 031, respectively). Too few cases occurred in participants aged ≥61 years (CVnCoV: 12, placebo: 9) precluding VE evaluation. Wild type SARS-CoV-2 was detected in 7/204 (3%) sequenced cases, with 14 variants being responsible for the other cases. Solicited adverse events, mostly systemic, were more common in CVnCoV recipients; 542/2002 CVnCoV recipients and 61/1980 placebo recipients reported grade 3 events. Unsolicited serious AEs were reported for 82/19 746 CVnCoV recipients and 66/19 746 placebo recipients; 8 and 2 SAEs, respectively were considered related to vaccination. Fatal SAEs were reported for 8 and 6 CVnCoV and placebo recipients.Interpretation: CVnCoV is efficacious in the prevention of COVID-19 of any severity and has an acceptable safety profile.Trial Registration: Study number: ClinicalTrials.gov Identifier: NCT04652102. Funding: This trial was funded by the German Federal Ministry of Education and Research (grant01KI20703), and CureVac AG.Declaration of Interest: MB declares institutional funding from CureVac during the conduct of this study, from Janssen Vaccines, molecular partners, and Merck outside of the submitted work, and consulting fees from Janssen Vaccines. EJLDB, and MFMR, TO and XSL declare institutional funding from CureVac during the conduct of this study. LE, and LG declare institutional funding from CureVac during the conduct of this study and outside of the submitted work. CFL declares institutional funding from CureVac during the conduct of this study, and outside of the submitted work, and is a member of WHO Covid-19 Vaccine Effectiveness Working Group and WHO Product Development for Vaccines Advisory Committee (PDVAC). CL declares institutional funding from CureVac during the conduct of this study, and is a member of the of German Society of Infection board. ILR declares institutional funding from CureVac during the conduct of this study and from J &J, and OSE Immunotherapeutics outside of the submitted work. PGK declares institutional funding from CureVac during the conduct of this study, and is a member of the scientific advisory board for the HERALD clinical trial. VVRH declares institutional funding from CureVac during the conduct of this study, and speakers fees from Gilead outside of the submitted work. HJ declares consultant fees from CureVac, is the Medical Responsible Person for the HERALD clinical trial, and is co-chair of DSMB for the HERALD clinical trial. AK and PM are employed by CureVac, and hold stock options. OSK declares consultant fees from CureVac during the conduct of this study, and is a member of the DSMB for a CVnCoV phase 1 trial. TV declares consultant fees from CureVac during the conduct of this study, and consultant fees from CureVac, AstraZeneca, Pfizer, Johnson&Johnson, and Moderna outside of the submitted work. LO is employed by CureVac, and holds stock options, and is the holder of a pending patent. The other authors declare no competing interests.Ethical Approval: The trial protocol and amendments have been approved by the appropriate independent ethics committee or institutional review board at each study centre