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
Subject(s)
COVID-19 , Lymphoproliferative DisordersABSTRACT
Background: Healthcare workers (HCWs) are at increased risk of SARS-CoV-2 infection. We assessed incidence of SARS-CoV-2 infection and COVID-19 before the roll out of COVID-19 vaccines in a cohort of HCWs in Mainz, Germany. Methods: Using prospective observational cohort design, antibody status was assessed at baseline and every 6 weeks (±2 weeks). Daily self-reported COVID-19 symptoms were collected using a smartphone application. Symptomatic HCWs were tested using RT-PCR. We estimated symptomatic and asymptomatic SARS-CoV-2 infection rates based on two case definitions of varying sensitivity and specificity. Results: 3664 HCWs were enrolled with a median follow-up of 101 days. The seroprevalence of anti-SARS-CoV-2 antibodies increased from 2.7% at baseline to 3.8%, with the number of seroconversions (65) outweighing seroreversions (26) by end of follow-up. Among HCWs who seroconverted, 12 (~19%) did not report any symptoms. The estimated incidence rate was 4.5 per 1000 person-months, but none the incident cases developed severe disease. Anti-SARS-CoV-2 antibodies fell below diagnostic cut-off value in a third of those positive at baseline and in one incident case. Conclusions: We observed increasing COVID-19 rates among HCWs during an accelerated community transmission period, with relatively lower rate of asymptomatic infections. Our findings indicate a relatively long-lasting humoral immune response following natural infection.
Subject(s)
COVID-19ABSTRACT
Background: Healthcare workers (HCWs) are at increased risk of SARS-CoV-2 infection. We followed a large cohort of HCWs in Germany to assess the incidence of SARS-CoV-2 infection and COVID-19 disease before the introduction of COVID-19 vaccines.Methods: We present interim data, collected from August 2020 to January 2021 in the ′CPMprevac′ study, an ongoing prospective observational cohort study including HCWs at the University Medical Centre of Mainz in Germany. Antibody status was assessed at baseline and every 6 weeks (±2 weeks). Daily self-reported COVID-19 symptoms were collected using a smartphone application, and symptomatic HCWs were tested using RT-PCR. We estimated the rates of symptomatic and asymptomatic SARS-CoV-2 infections. The rates of confirmed COVID-19 disease were estimated based on two case definitions of varying sensitivity and specificity.Findings: 3664 HCWs were enrolled in the study with a median follow-up of 101 days. The seroprevalence of anti-SARS-CoV-2 IgM and/or IgG increased from 2·7% at baseline to 3·8%, with the number of seroconversions (65) outweighing seroreversions (26) by the end of follow-up. Among HCWs who seroconverted, 12 (~19%) did not report any symptoms. The incidence rate was estimated to be 4·5 per 1000 person-months. Among the 53 incident cases, none developed severe COVID-19 disease, however, one subject (1·8%) was hospitalized. The most common symptom reported was smell or taste dysfunction, with or without other symptoms. With a median follow up of 100 days, anti-SARS-CoV-2 antibodies fell below diagnostic cut-off value in a third of those positive at baseline and in only one incident case.Interpretation: We observed increasing rates of COVID-19 disease infections among HCWs during a period of accelerated community transmission. The rate of asymptomatic infections, however, was lower than estimates from cross-sectional studies. Nearly one third of seropositive HCWs at baseline reverted by the end of follow-up, however, we did not detect evidence of reinfection.Registration: European Union’s electronic register of Post-Authorisation Studies (EU PAS register number EUPAS37174).Funding: This study was funded by CureVac AG, Tübingen, Germany.Declaration of Interests: Thomas Verstraeten is the managing director of P95, and also a paid consultant at CureVac AG, fulfilling the role of Safety Physician. Stephan Gehring and Frank Kowalzik are employees of UM Mainz and in addition paid for this study as Principal Investigator and Co-Investigator, respectively, by CureVac AG. Omar Okasha, Anirudh Thomer and Wendy Hartig-Merkel are paid employees of P95 and state no conflict of interest. Lidia Oostvogels is a paid employee of CureVac AG.Ethics Approval Statement: The study was approved by the relevant Independent Ethical Committee (IEC; Ethik-Kommission bei der Landesärztekammer Rheinland-Pfalz, Germany).
Subject(s)
COVID-19 , Taste DisordersABSTRACT
There is an urgent need for vaccines to counter the COVID-19 pandemic due to infections with severe acute respiratory syndrome coronavirus (SARS-CoV-2). Evidence from convalescent sera and preclinical studies has identified the viral Spike (S) protein as a key antigenic target for protective immune responses. We have applied an mRNA-based technology platform, RNActive(R), to develop CVnCoV which contains sequence optimized mRNA coding for a stabilized form of S protein encapsulated in lipid nanoparticles (LNP). Following demonstration of protective immune responses against SARS-CoV-2 in animal models we performed a dose-escalation phase 1 study in healthy 18-60 year-old volunteers. This interim analysis shows that two doses of CVnCoV ranging from 2 g to 12 g per dose, administered 28 days apart were safe. No vaccine-related serious adverse events were reported. There were dose-dependent increases in frequency and severity of solicited systemic adverse events, and to a lesser extent of local reactions, but the majority were mild or moderate and transient in duration. Immune responses when measured as IgG antibodies against S protein or its receptor-binding domain (RBD) by ELISA, and SARS-CoV-2-virus neutralizing antibodies measured by micro-neutralization, displayed dose-dependent increases. Median titers measured in these assays two weeks after the second 12 g dose were comparable to the median titers observed in convalescent sera from COVID-19 patients. Seroconversion (defined as a 4-fold increase over baseline titer) of virus neutralizing antibodies two weeks after the second vaccination occurred in all participants who received 12 g doses. Preliminary results in the subset of subjects who were enrolled with known SARS-CoV-2 seropositivity at baseline show that CVnCoV is also safe and well tolerated in this population, and is able to boost the pre-existing immune response even at low dose levels. Based on these results, the 12 g dose is selected for further clinical investigation, including a phase 2b/3 study that will investigate the efficacy, safety, and immunogenicity of the candidate vaccine CVnCoV.