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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 - 24/02/22

Doi : 10.1016/S1473-3099(21)00677-0 
Peter G Kremsner, ProfMD a, b, c, * , Rodolfo Andrés Ahuad Guerrero, MD d, Eunate Arana-Arri, PhD e, f, Gustavo Jose Aroca Martinez, MD g, Marc Bonten, ProfMD h, Reynaldo Chandler, MD i, Gonzalo Corral, MD j, Eddie Jan Louis De Block, MD k, Lucie Ecker, MD l, Julian Justin Gabor, MD a, Carlos Alberto Garcia Lopez, MD m, Lucy Gonzales, MD n, María Angélica Granados González, MSc o, Nestor Gorini, MD p, Martin P Grobusch, ProfFRCP b, c, q, Adrian D Hrabar, MD r, Helga Junker, MD s, Alan Kimura, MD s, Claudio F Lanata, ProfMD l, t, u, Clara Lehmann, ProfMD v, Isabel Leroux-Roels, MD w, Philipp Mann, MD s, Michel Fernando Martinez-Reséndez, MD x, Theresa J Ochoa, MD y, z, aa, Carlos Alberto Poy, MD ab, Maria Jose Reyes Fentanes, MD ac, Luis Maria Rivera Mejia, ProfMD ad, Vida Veronica Ruiz Herrera, MD ae, Xavier Sáez-Llorens, MD af, ag, ah, Oliver Schönborn-Kellenberger, MSc ai, Mirjam Schunk, MD aj, Alexandra Sierra Garcia, MD ak, Itziar Vergara, PhD al, am, Thomas Verstraeten, MD an, Marisa Vico, MD ao, Lidia Oostvogels, MD s, *
on behalf of the

HERALD Study Group

  Members are listed in the Supplementary Material
Luciano Lovesio, Fabián Diez, Franco Grazziani, Maria Cristina Ganaha, Viviana Judith Zalatnik, Ricardo Julio Dittrich, Lidia Espínola, Sandra Lambert, Andrea Longhi, Claudia Vecchio, María Mastruzzo, Alberto Fernandez, Silvina Borchowiek, Roberto Potito, Rodolfo Andres Ahuad Guerrero, Fernando Martin Guardiani, Sofia Castella, Monica Foccoli, Aldana Pedernera, Ariel Braida, Virginia Durigan, Carolina Martella, Antonela Bobat, Bruno Emilio Boggia, Sergio Andrés Nemi, Javier Gerardo Tartaglione, Fabián César Piedimonte, Jessie De Bie, Humberto Reynales Londoño, Paula Andrea Rodríguez Ordoñez, Johanna Marcela García Cruz, Leonardo Bautista Toloza, Margot Cecilia Ladino González, Adriana Pilar Zambrano Ochoa, Iñigo Prieto Pradera, Daniela Torres Hernandez, Diana Patricia Mazo Elorza, Maria Fernanda Collazos Lennis, Beatriz Vanegas Dominguez, Lina Marianur Solano Mosquera, Rolf Fendel, Wim Alexander Fleischmann, Erik Koehne, Andrea Kreidenweiss, Carsten Köhler, Meral Esen, Carola Horn, Sandra Eberts, Arne Kroidl, Kristina Huber, Verena Thiel, Sonia Mazara Rosario, Gilda Reyes, Laura Rivera, Yeycy Donastorg, Flavia Lantigua, Dania Torres Almanzar, Rosalba Candelario, Lourdes Peña Mendez, Nadia Rosario Gomez, Antonio Portolés-Pérez, Ana Ascaso del Río, Leonor Laredo Velasco, Maria Jesus Bustinduy Odriozola, Igor Larrea Arranz, Luis Ignacio Martínez Alcorta, María Isabel Durán Laviña, Natale Imaz-Ayo, Susana Meijide, Aitor García-de-Vicuña, Ana Santorcuato, Mikel Gallego, Gloria Mayela Aguirre-García, Jocelyn Olmos Vega, Pablo González Limón, Andrea Vázquez Villar, Jaime Chávez Barón, Felipe Arredondo Saldaña, Juan de Dios Luján Palacios, Laura Julia Camacho Choza, Eduardo Gabriel Vázquez Saldaña, Sandra Janeth Ortega Dominguez, Karen Sofia Vega Orozco, Ivonne Aimee Torres Quiroz, Alejandro Martinez Avendaño, Javier Herrera Sanchez, Esperanza Guzman, Laura Castro Castrezana, Guillermo Miguel Ruiz Palacios y Santos, Ronald Frank Jacobus de Winter, Hanna K de Jonge, Jenny L Schnyder, Wim Boersma, Lisa Hessels, Remco Djamin, Simone van der Sar, Rodrigo DeAntonio, Moisés Peña, Gabriel Rebollon, Marianela Rojas, Johnny Escobar, Bruno Hammerschlag Icaza, Digna Y Wong T, Paulo Barrera Perigault, Sergio Ruiz, Milagros Chan, Dommie Janneth Arias Hoo, Ana I Gil, Carlos R Celis, Maria Pia Balmaceda, Omar Flores, Mayra Ochoa, Bia Peña, Carolina de la Flor, Camille María Webb, Enrique Cornejo, Fatima Sanes, Valerie Mayorga, Gladys Valdiviezo, Suzanne Pamela Ramírez Lamas, Gustavo Alberto Grandez Castillo, Javier R Lama, Milagros Erika Matta Aguirre, Lesly Angela Arancibia Luna, Óscar Carbajal Paulet, José Zambrano Ortiz, Anais Camara, Fernanda Guzman Quintanilla, Carmen Diaz-Parra, Jose Morales-Oliva, Rubelio E Cornejo, Sheby A Ricalde, Jhonny Vidal, Luis Rios Nogales, Darline Cheatham-Seitz, Giorgia Gregoraci, Alain Brecx, Lisa Walz, Dominik Vahrenhorst, Tobias Seibel, Gianluca Quintini

a Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany 
b Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon 
c German Center for Infection Research, Tübingen, Germany 
d Corporacion Medica de General San Martin, Buenos Aires, Argentina 
e Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain 
f Scientific Coordination Unit, Cruces University Hospital, Osakidetza, Barakaldo, Spain 
g Postgraduate School of Nephrology, Clínica de la Costa y Universidad Simón Bolívar, Barranquilla, Colombia 
h Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht University, Utrecht, Netherlands 
i Cevaxin, Panama City, Panama 
j Instituto de Investigaciones Clinicas de Mar del Plata, Mar del Plata, Argentina 
k Cohezio, Brussels, Belgium 
l Instituto de Investigación Nutricional, Lima, Peru 
m Unidad de Medicina Especializada, San Juan del Río, Mexico 
n Clinica Medica San Martin, Ica, Peru 
o Centro de Atención e Investigación Médica, Bogotá, Colombia 
p Haematology and Haemotherapy Diagnosis and Treatment Unit, Hospital Zonal General de Agudos Descentralizado Evita Pueblo de Berazategui, Buenos Aires, Argentina 
q Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Amsterdam University Medical Center, Amsterdam Public Health, Amsterdam Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands 
r Instituto de Investigaciones Clínicas Quilmes, Hudson, Argentina 
s CureVac, Tübingen, Germany 
t School of Medicine, Vanderbilt University, Nashville, TN, USA 
u Department of Epidemiology, London School of Hygiene & Tropical Medicine, London, UK 
v Infection Protection Centre (ISZ) & Infection Outpatient Clinic, Innere Medizin I, Uniklinik Köln, Cologne, Germany 
w Center for Vaccinology, Ghent University Hospital, Ghent, Belgium 
x School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, Mexico 
y Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru 
z Facultad de Medicina, Universidad Peruana Cayetano Heredia, Lima, Peru 
aa Center for Infectious Diseases, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA 
ab Sanatorio Parque, Rosario, Argentina 
ac PanAmerican Clinical Research México, Juriquilla, Mexico 
ad Fundacion Dominicana de Perinatologia, Hospital Universitario Maternidad Nuestra Senora de la Altagracia, Santo Domingo, Dominican Republic 
ae PanAmerican Clinical Research, Guadalajara, Mexico 
af Clinical Research Department, Panama City, Panama 
ag Cevaxin Research Center, Panama City, Panama 
ah Senacyt, Panama City, Panama 
ai Cogitars, Heidelberg, Germany 
aj Division of Infectious Diseases and Tropical Medicine, LMU Klinikum, Munich, Germany 
ak Centro de estudios en Infectologia Pediatrica, Cali, Colombia 
al Primary Care Group, Biodonostia Institute for Health Research, Donostia-San Sebastián, Spain 
am Research Network in Health Services in Chronic Diseases, Baracaldo, Spain 
an P95 Pharmacovigilance and Epidemiology Services, Leuven, Belgium 
ao Instituto de Investigaciones Clínicas Zárate, Buenos Aires, Argentina 

* Correspondence to: Prof Peter G Kremsner, Institute of Tropical Medicine, University of Tübingen, Tübingen 72074, Germany Institute of Tropical Medicine University of Tübingen Tübingen 72074 Germany

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Summary

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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Vol 22 - N° 3

P. 329-340 - mars 2022 Retour au numéro
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