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Cited by 172SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesVaccine Coverage and Hesitancy

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial

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Kremsner, Peter G, Ahuad Guerrero, Rodolfo Andrés, Arana-Arri, Eunate, Aroca Martinez, Gustavo Jose, Bonten, Marc, Chandler, Reynaldo, Corral, Gonzalo, De Block, Eddie Jan Louis +169 more·2022·The Lancet Infectious Diseases
DOI 10.1016/s1473-3099(21)00677-0PMC PMC8610426
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Abstract

Background Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate.Methods HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 μg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing.Findings Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group.Interpretation CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates.Funding German Federal Ministry of Education and Research and CureVac.

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  • In phase II clinical trials, 228 COVID-19 cases were reported, 204 were sampled for whole-genome sequencing, only 3% had wild-type SARS-CoV-2, and 14 variants were identified in the remaining patients.

    “In phase II clinical trials, 228 COVID-19 cases were reported, from which 204 have been sampled for whole-genome sequencing, which showed that only 3% of the patients had been infected by wild-type SARS-CoV-2, whereas 14 variants have been identified in the remaining patients.425”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [425]

  • Preliminary results from phase IIb/III clinical trials showed overall efficacy of CVnCoV was 48.2%, which failed to meet prespecified success criteria.

    “Preliminary results from phase IIb/III clinical trials showed that the overall efficacy of the vaccine was 48.2% (Table 5), which failed to meet prespecified success criteria.425”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [425]

  • The low performance of CVnCoV in phase II clinical trials has been attributed to the rise of multiple SARS-CoV-2 variants.

    “The low performance of CVnCoV in phase II clinical trials has been attributed to the rise of multiple SARS-CoV-2 variants.”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [425]

  • In the phase IIb/III trial, CVnCoV using a prime-boost regimen with 12 μg 4 weeks apart had only 48% efficacy for the prevention of COVID-19 at any severity in all age groups among 39,680 participants.

    “later in the phase IIb/III trial, using a p-b regimen with 12 μg 4 weeks apart, only 48% efficacy was disclosed for the prevention of COVID-19 at any severity in all age groups among 39,680 participants,130”

    From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [130]

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Authors
Kremsner, P. G., Ahuad Guerrero, R. A., Arana-Arri, E., Aroca Martinez, G. J., Bonten, M., Chandler, R., Corral, G., De Block, E. J. L., Ecker, L., Gabor, J. J., Garcia Lopez, C. A., Gonzales, L., Granados González, M. A., Gorini, N., Grobusch, M. P., Hrabar, A. D., Junker, H., Kimura, A., Lanata, C. F., Lehmann, C., Leroux-Roels, I., Mann, P., Martinez-Reséndez, M. F., Ochoa, T. J., Poy, C. A., Reyes Fentanes, M. J., Rivera Mejia, L. M., Ruiz Herrera, V. V., Sáez-Llorens, X., Schönborn-Kellenberger, O., Schunk, M., Sierra Garcia, A., Vergara, I., Verstraeten, T., Vico, M., Oostvogels, L., Lovesio, L., Diez, F., Grazziani, F., Ganaha, M. C., Zalatnik, V. J., Dittrich, R. J., Espínola, L., Lambert, S., Longhi, A., Vecchio, C., Mastruzzo, M., Fernandez, A., Borchowiek, S., Potito, R., Ahuad Guerrero, R. A., Guardiani, F. M., Castella, S., Foccoli, M., Pedernera, A., Braida, A., Durigan, V., Martella, C., Bobat, A., Boggia, B. E., Nemi, S. A., Tartaglione, J. G., Piedimonte, F. C., De Bie, J., Reynales Londoño, H., Rodríguez Ordoñez, P. A., García Cruz, J. M., Bautista Toloza, L., Ladino González, M. C., Zambrano Ochoa, A. P., Prieto Pradera, I., Torres Hernandez, D., Mazo Elorza, D. P., Collazos Lennis, M. F., Vanegas Dominguez, B., Solano Mosquera, L. M., Fendel, R., Fleischmann, W. A., Koehne, E., Kreidenweiss, A., Köhler, C., Esen, M., Horn, C., Eberts, S., Kroidl, A., Huber, K., Thiel, V., Mazara Rosario, S., Reyes, G., Rivera, L., Donastorg, Y., Lantigua, F., Torres Almanzar, D., Candelario, R., Peña Mendez, L., Rosario Gomez, N., Portolés-Pérez, A., Ascaso del Río, A., Laredo Velasco, L., Bustinduy Odriozola, M. J., Larrea Arranz, I., Martínez Alcorta, L. I., Durán Laviña, M. I., Imaz-Ayo, N., Meijide, S., García-de-Vicuña, A., Santorcuato, A., Gallego, M., Aguirre-García, G. M., Olmos Vega, J., González Limón, P., Vázquez Villar, A., Chávez Barón, J., Arredondo Saldaña, F., Luján Palacios, J. D. D., Camacho Choza, L. J., Vázquez Saldaña, E. G., Ortega Dominguez, S. J., Vega Orozco, K. S., Torres Quiroz, I. A., Martinez Avendaño, A., Herrera Sanchez, J., Guzman, E., Castro Castrezana, L., Ruiz Palacios y Santos, G. M., de Winter, R. F. J., de Jonge, H. K., Schnyder, J. L., Boersma, W., Hessels, L., Djamin, R., van der Sar, S., DeAntonio, R., Peña, M., Rebollon, G., Rojas, M., Escobar, J., Hammerschlag Icaza, B., Wong T, D. Y., Barrera Perigault, P., Ruiz, S., Chan, M., Arias Hoo, D. J., Gil, A. I., Celis, C. R., Balmaceda, M. P., Flores, O., Ochoa, M., Peña, B., de la Flor, C., Webb, C. M., Cornejo, E., Sanes, F., Mayorga, V., Valdiviezo, G., Ramírez Lamas, S. P., Grandez Castillo, G. A., Lama, J. R., Matta Aguirre, M. E., Arancibia Luna, L. A., Carbajal Paulet, Ó., Zambrano Ortiz, J., Camara, A., Guzman Quintanilla, F., Diaz-Parra, C., Morales-Oliva, J., Cornejo, R. E., Ricalde, S. A., Vidal, J., Rios Nogales, L., Cheatham-Seitz, D., Gregoraci, G., Brecx, A., Walz, L., Vahrenhorst, D., Seibel, T., & Quintini, G.
Affiliations
  • Centre de Recherche Médicales de Lambaréné (GA)
  • Utrecht University (NL)
  • CEVAXIN (PA)
  • Instituto de Investigación Nutricional (PE)
  • University of Tübingen (DE)
  • Hospital Zonal General De Agudos Descentralizado "Evita Pueblo" (AR)
  • CureVac (Germany) (DE)
  • Vanderbilt University (US)
  • University Hospital Cologne (DE)
  • Universidad Peruana Cayetano Heredia (PE)
  • LMU Klinikum (DE)
  • Biogipuzkoa Health Research Institute (ES)
  • Tecnológico de Monterrey (MX)
Corresponding author
Kremsner, Peter G
ORCID
Venue
The Lancet Infectious Diseases
Publisher
Elsevier BV
Published
2022-03
Volume
22
Issue
3
Pages
329-340
ISSN
1473-3099 (ISSN-L)
DOI
10.1016/s1473-3099(21)00677-0
PMC
PMC8610426
OpenAlex
W3215521526
Cited by
172
References
30
Citations by year
2026: 9 · 2025: 27 · 2024: 34 · 2023: 40 · 2022: 55 · 2021: 7
FWCI
10.74
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Infectious Diseases (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Universidad Peruana Cayetano Heredia Institutional Repository (submittedVersion, cc-by-nc-nd)
Funders
  • Gilead Sciences
  • Bundesministerium für Bildung und Forschung (01KI20703)
  • Johnson and Johnson
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Social Sciences › Health › Vaccine Coverage and Hesitancy
Keywords
COVID-19 mRNA vaccine, COVID-19 vaccine efficacy, vaccine safety, age-stratified analysis, adverse events, COVID-19 pandemic
MeSH terms
SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, Adult, Aged, Double-Blind Method, Europe, Female, Humans, Latin America, Male, Middle Aged, Vaccination, Vaccines, Synthetic

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