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

Kremsner, Peter G.; Guerrero, Rodolfo A. Ahuad; Arana-Arri, Eunate; Aroca, Gustavo; Bonten, Marc J. M.; Chandler, Reynaldo; Corral, Gonzalo; Block, Eddie Jan Louis De; Ecker, Lucie; Gabor, Julian; Lopez, Carlos; Gonzales, Lucy A. De; González, María Angélica Granados; Gorini, Nestor; Grobusch, Martin P.; Hrabar, Adrian D.; Junker, Helga; Kimura, Alan; Lanata, Claudio F.; Lehmann, Clara; Leroux-Roels, Isabel; Mann, Philipp; Martínez‐Reséndez, Michel F.; Ochoa, Theresa J.; Poy, Carlos; Fentanes, Maria Jose Reyes; Mejia, Luis Maria Rivera; Herrera, Vida Veronica Ruiz; Sáez-Llorens, Xavier; Schönborn‐Kellenberger, Oliver; Schunk, Mirjam; Garcia, Alexandra Sierra; Vergara, Itziar; Verstraeten, Thomas; Vico, Marisa; Oostvogels, Lidia; Lovesio, Luciano; Diez, Fabián; Grazziani, Franco Sebastián; Ganaha, María Cristina; Zalatnik, Viviana Judith; Dittrich, Ricardo Julio; Espinola, Lidia; Lambert, Sandra; Longhi, Andrea; Vecchio, Claudia Del; Mastruzzo, María; Fernandez, A. Ocana; Borchowiek, Silvina; Potito, Roberto; Guardiani, Fernando Martin; Castella, Sofia; Foccoli, Monica; Pedernera, Aldana; Braida, Ariel; Durigan, Virginia; Martella, C.; Bobat, A.; Boggia, Bruno Emilio; Nemi, Sergio Andrés; Tartaglione, Javier Gerardo; Piedimonte, Fabián; Bie, Jessie De; Londoño, Humberto Reynales; Ordóñez, Paula Andrea Rodríguez; Cruz, Johanna Marcela García; Toloza, Leonardo Bautista; González, Margot Cecilia Ladino; Ochoa, Adriana; Pradera, Iñigo Prieto; Hernández, Daniela Torres; D, Elorza; Lennis, Maria Fernanda Collazos; Dominguez, Beatriz Vanegas; Mosquera, Lina Marianur Solano; Fendel, Rolf; Fleischmann, Wim Alexander; Koehne, Erik; Kreidenweiss, Andrea; Köhler, Carsten; Esen, Meral; Horn, Carola; Eberts, Sandra M.; Kroidl, Arne; Huber, Kristina L.; Thiel, Verena; Rosario, S.; Reyes, Gilda; Rivera, Laura; Donastorg, Yeycy; Lantigua, Flavia; Almanzar, Dania Torres; Candelario, Rosalba; Mendez, Lourdes Peña; Gomez, Nadia Rosario; Portolés, Antonio; Ascaso, Ana; Velasco, Leonor Laredo; Odriozola, Maria Jesus Bustinduy; Arranz, Igor Larrea; Alcorta, Luis Ignacio Martínez; Laviña, María Isabel Durán; Imaz-Ayo, Natale; Meijide, Susana; García-de-Vicuña, Aitor; Santorcuato, Ana; Gallego, Mikel; Aguirre-García, Gloria Mayela; Vega, Jocelyn Olmos; Limón, Pablo González; Villar, Andrea Vázquez; Barón, Jaime Chávez; Saldaña, Felipe Arredondo; Palacios, Juan D.; Choza, Laura Julia Camacho; Saldaña, Eduardo Gabriel Vázquez; Domínguez, Sandra Janeth Ortega; Orozco, Karen Sofia Vega; Quiroz, Ivonne Aimee Torres; Avendaño, A; Sanchez, Javier Herrera; Guzmán, E Pastor; Castrezana, Laura Castro; Santos, Guillermo Miguel Ruiz Palacios y; Winter, Ronald Frank Jacobus de; Jonge, Hanna K de; Schnyder, Jenny L.; Boersma, Wim; Hessels, Lisa; Djamin, Remco S.; Sar, Simone van der; DeAntonio, Rodrigo; Peña, Moisés; Rebollon, Gabriel; Rojas, M Victoria De; Escobar, Johnny; Icaza, Bruno Hammerschlag; T, Digna Y Wong; Perigault, Paulo Barrera; Ruíz, Sergio; Chan, Milagros; Hoo, Dommie Janneth Arias; Gil, Ana I.; Celis, Carlos R.; Balmaceda, Maria Pia; Flores, Omar; Ochoa, Mayra; Peña, B. Chapi; Flor, Carolina de la; Webb, Camille M.; Cornejo, E; Sanes, Fatima; Mayorga, Valerie; Valdiviezo, Gladys; Lamas, Suzanne Pamela Ramírez; Castillo, Gustavo Alberto Grandez; Lama, Javier R.; Aguirre, Milagros Erika Matta; Luna, Lesly Angela Arancibia; Paulet, Óscar Carbajal; Ortiz, José Zambrano; Camara, Anais; Quintanilla, Fernanda Guzman; Diaz-Parra, Carmen; Morales-Oliva, Jose; Cornejo, Rubelio; Ricalde, Sheby A; Vidal, Jhonny; Nogales, Luis Rios; Cheatham-Seitz, Darline; Gregoraci, Giorgia; Brecx, Alain; Walz, Lisa; Vahrenhorst, Dominik; Seibel, Tobias; Quintini, Gianluca

doi:10.1016/s1473-3099(21)00677-0

Cited by 120 publications

(75 citation statements)

References 24 publications

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“…The Phase 2b/3 study, the Herald study in 39,680 volunteers, conducted in Latin America and Europe, followed the suggested dose from the Phase 1 study, which consisted of dosing with a prime/boost regimen of 12 µg. Unfortunately and surprisingly, the ultimate readouts showed a lower vaccine efficacy of 48% in preventing disease of any severity [149] when compared to >94% reported in the Moderna and BioNTech/Pfizer trials [3,150]. Many elements such as timing and location of study where newer, more transmissible SARS-CoV-2 variants were dominant, mRNA modality, or lower doses were all potential contributing factors to lower efficacy.…”

Section: Next Generation Covid-19 Mrna-vaccinesmentioning

confidence: 88%

Lipid Nanoparticle Delivery Systems to Enable mRNA-Based Therapeutics

et al. 2022

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The world raced to develop vaccines to protect against the rapid spread of SARS-CoV-2 infection upon the recognition of COVID-19 as a global pandemic. A broad spectrum of candidates was evaluated, with mRNA-based vaccines emerging as leaders due to how quickly they were available for emergency use while providing a high level of efficacy. As a modular technology, the mRNA-based vaccines benefitted from decades of advancements in both mRNA and delivery technology prior to the current global pandemic. The fundamental lessons of the utility of mRNA as a therapeutic were pioneered by Dr. Katalin Kariko and her colleagues, perhaps most notably in collaboration with Drew Weissman at University of Pennsylvania, and this foundational work paved the way for the development of the first ever mRNA-based therapeutic authorized for human use, COMIRNATY®. In this Special Issue of Pharmaceutics, we will be honoring Dr. Kariko for her great contributions to the mRNA technology to treat diseases with unmet needs. In this review article, we will focus on the delivery platform, the lipid nanoparticle (LNP) carrier, which allowed the potential of mRNA therapeutics to be realized. Similar to the mRNA technology, the development of LNP systems has been ongoing for decades before culminating in the success of the first clinically approved siRNA-LNP product, ONPATTRO®, a treatment for an otherwise fatal genetic disease called transthyretin amyloidosis. Lessons learned from the siRNA-LNP experience enabled the translation into the mRNA platform with the eventual authorization and approval of the mRNA-LNP vaccines against COVID-19. This marks the beginning of mRNA-LNP as a pharmaceutical option to treat genetic diseases.

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Section: Next Generation Covid-19 Mrna-vaccinesmentioning

confidence: 88%

Lipid Nanoparticle Delivery Systems to Enable mRNA-Based Therapeutics

et al. 2022

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“…Along with the two FDA-approved mRNA vaccines, there are two additional vaccine candidates. The first is CVnCoV, which is currently in Phase III clinical trials [ 52 ]. This vaccine candidate is produced by CureVac AG and is a chemically unmodified mRNA that encodes the full-length S protein of SARS-CoV-2 and utilizes the RNActive mRNA vaccine platform [ 52 ].…”

Section: Rna Therapeuticsmentioning

confidence: 99%

“…The first is CVnCoV, which is currently in Phase III clinical trials [ 52 ]. This vaccine candidate is produced by CureVac AG and is a chemically unmodified mRNA that encodes the full-length S protein of SARS-CoV-2 and utilizes the RNActive mRNA vaccine platform [ 52 ]. CVnCoV induces a robust immune response and provides immunity against SARS-CoV-2 infection.…”

Section: Rna Therapeuticsmentioning

confidence: 99%

Current Advances in RNA Therapeutics for Human Diseases

Zogg

Singh

2022

IJMS

101

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Following the discovery of nucleic acids by Friedrich Miescher in 1868, DNA and RNA were recognized as the genetic code containing the necessary information for proper cell functioning. In the years following these discoveries, vast knowledge of the seemingly endless roles of RNA have become better understood. Additionally, many new types of RNAs were discovered that seemed to have no coding properties (non-coding RNAs), such as microRNAs (miRNAs). The discovery of these new RNAs created a new avenue for treating various human diseases. However, RNA is relatively unstable and is degraded fairly rapidly once administered; this has led to the development of novel delivery mechanisms, such as nanoparticles to increase stability as well as to prevent off-target effects of these molecules. Current advances in RNA-based therapies have substantial promise in treating and preventing many human diseases and disorders through fixing the pathology instead of merely treating the symptomology similarly to traditional therapeutics. Although many RNA therapeutics have made it to clinical trials, only a few have been FDA approved thus far. Additionally, the results of clinical trials for RNA therapeutics have been ambivalent to date, with some studies demonstrating potent efficacy, whereas others have limited effectiveness and/or toxicity. Momentum is building in the clinic for RNA therapeutics; future clinical care of human diseases will likely comprise promising RNA therapeutics. This review focuses on the current advances of RNA therapeutics and addresses current challenges with their development.

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“…The second most significant domain that induced the 'some concern' was bias caused by deviations from the intended intervention (domain 2), in which 27 trials also appeared to have a probability of risk [24,33,37,44,[46][47][48]51,[53][54][55][58][59][60]62,64,[66][67][68][69][70][73][74][75][76][77]. Almost all of the bias on domain 2 is because of disclosure of the intervention, whether to patients and or the carer of the patients.…”

Section: Adherence To Consort Recommendationsmentioning

confidence: 99%

Adverse Events Reporting Quality of Randomized Controlled Trials of COVID-19 Vaccine Using the CONSORT Criteria for Reporting Harms: A Systematic Review

et al. 2022

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Background: Assessing the quality of evidence from vaccine clinical trials is essential to ensure the safety and efficacy of the vaccine and further enhance public acceptance. This study aims to summarize and critically evaluate the quality of harm reporting on randomized controlled trials for the COVID-19 vaccine and determine the factors associated with reporting quality. Methods: We systematically searched the literature using PRISMA guidelines for randomized controlled trials (RCT) on COVID-19 Vaccine until 30 December 2021. Published articles were searched from electronic databases such as PubMed, Science Direct, Google Scholar, and Bibliovid. Bias analysis was performed using RoB-2 tools. The quality of reporting was assessed by the Consolidated Standards of Reporting Trials (CONSORT) harm extension modified into 21 items. Results: A total of 61 RCT studies (402,014 patients) were analyzed. Over half the studies demonstrated adequate reporting (59.02%), and 21 studies (34.4%) reported a low risk of bias. All studies reported death and serious adverse events (AEs), but only six studies mentioned how to handle the recurrent AEs. Reporting of AEs in subgroup analysis was also poor (25%). Conclusion: The RCTs on the COVID-19 vaccine were less biased with good quality on reporting harm based on the modified CONSORT harm extension. However, study quality must be considered, especially for a balance of information between effectivity and safety.

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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

Cited by 120 publications

References 24 publications

Lipid Nanoparticle Delivery Systems to Enable mRNA-Based Therapeutics

Lipid Nanoparticle Delivery Systems to Enable mRNA-Based Therapeutics

Current Advances in RNA Therapeutics for Human Diseases

Adverse Events Reporting Quality of Randomized Controlled Trials of COVID-19 Vaccine Using the CONSORT Criteria for Reporting Harms: A Systematic Review

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