Summary

Background

Additional proper and efficacious vaccines are indispensable to manipulate the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate.

Programs

HERALD is a randomised, observer-blinded, placebo-managed, segment 2b/3 clinical trial conducted in 47 centres in ten international locations in Europe and Latin America. By assert of an interactive web response machine and stratification by country and age community (18–60 years and ≥61 years), adults with out a ancient past of virologically confirmed COVID-19 were randomly assigned (1:1) to acquire 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 main efficacy endpoint became the incidence of a prime episode of virologically confirmed symptomatic COVID-19 of any severity and precipitated by any pressure from 15 days after the 2nd dose. For the main endpoint, the trial became regarded as a hit if the lower restrict of the CI became larger than 30%. Key secondary endpoints were the incidence of a prime episode of virologically confirmed moderate-to-excessive COVID-19, excessive COVID-19, and COVID-19 of any severity by age community. Major safety outcomes were solicited native and systemic adversarial occasions within 7 days after every dose and unsolicited adversarial occasions within 28 days after every dose in segment 2b contributors, and excessive adversarial occasions and adversarial occasions of particular hobby up to 1 yr after the 2nd dose in segment 2b and segment 3 contributors. Right here, we tale recordsdata up to June 18, 2021. The survey 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 contributors were enrolled and randomly assigned to acquire either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 got no now not up to one dose of CVnCoV and 19 746 got no now not up to one dose of placebo. After an realistic observation interval of 48·2 days (SE 0·2), 83 cases of COVID-19 came about in the CVnCoV community (n=12 851) in 1735·29 person-years and 145 cases came about in the placebo community (n=12 211) in 1569·87 person-years, ensuing in an total vaccine efficacy in opposition to symptomatic COVID-19 of 48·2% (95·826% CI 31·0–61·4; p=0·016). Vaccine efficacy in opposition to moderate-to-excessive COVID-19 became 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 contributors gentle 18–60 years, vaccine efficacy in opposition to symptomatic disease became 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 came about in contributors gentle 61 years or older (CVnCoV 12, placebo nine) to allow main evaluation of vaccine efficacy. Solicited adversarial occasions, which were largely systemic, were extra long-established 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 adversarial occasions. The most most continuously reported native response after any dose in the CVnCoV community became injection-voice wretchedness (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most most continuously 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 excessive adversarial occasions and 66 (0·3%) of 19 746 placebo recipients reported 76 excessive adversarial occasions. Eight excessive adversarial occasions in 5 CVnCoV recipients and two excessive adversarial occasions in two placebo recipients were regarded as vaccination-associated. Now now not regarded as one of many lethal excessive adversarial occasions reported (eight in the CVnCoV community and 6 in the placebo community) were regarded as to be associated to survey vaccination. Negative occasions of particular hobby were reported for 38 (0·2%) contributors in the CVnCoV community and 31 (0·2%) contributors in the placebo community. These occasions were regarded as to be associated to the trial vaccine for 14 (<0·1%) contributors in the CVnCoV community 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.

Introduction

SARS-CoV-2, which emerged in China’s Wuhan province in December, 2019, has led to more than 225 million cases of COVID-19 and more than 4·5 million deaths globally as of September, 2021.

WHO

WHO coronavirus (COVID-19) dashboard.

Through unprecedented effort from governments, national and international research funders, regulatory bodies, and research organisations, vaccine development has been, and continues to be, expedited. The first conditionally approved vaccine in Europe was administered in December, 2020, within 9 months of WHO characterising COVID-19 as a pandemic on March 11, 2020.

WHO

WHO Director-General’s opening remarks at the media briefing on COVID-19—11 March 2020.

More than 100 COVID-19 vaccines are currently in clinical development, and as of September, 2021, 21 are being offered to the general population.

Gavi, the Vaccine Alliance

The COVID-19 vaccine race—weekly update.

These vaccines have been developed by use of different platforms, all with specific advantages and disadvantages.

  • Huang Q
  • Yan J

SARS-CoV-2 virus: vaccines in development.

mRNA is a promising platform that allows the rapid development of immunogens and vaccine production.

  • Pardi N
  • Hogan MJ
  • Porter FW
  • Weissman D

mRNA vaccines—a new era in vaccinology.

  • Jackson NAC
  • Kester KE
  • Casimiro D
  • Gurunathan S
  • DeRosa F

The promise of mRNA vaccines: a biotech and industrial perspective.

The BNT162b2 (Pfizer-BioNtech) and mRNA-1273 (Moderna) SARS-CoV-2 vaccines were the first mRNA preventive vaccines to be approved for emergency use in humans in Europe and the USA on the basis of data from phase 3 efficacy trials.

  • Polack FP
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  • et al.

Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.

  • Baden LR
  • El Sahly HM
  • Essink B
  • et al.

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.

CVnCoV is a chemically unmodified mRNA vaccine candidate based on the RNActive mRNA vaccine platform encoding the stabilised, full-length, native SARS-CoV-2 spike protein of the SARS-CoV-2 wild-type strain. The mRNA is protected by lipid nanoparticles used for delivery. Preclinical studies have shown that CVnCoV induces a robust immune response and protects against SARS-CoV-2 in hamster and primate virus challenge models.

  • Rauch S
  • Roth N
  • Schwendt K
  • Fotin-Mleczek M
  • Mueller SO
  • Petsch B

mRNA-based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus-neutralising antibodies and mediates protection in rodents.

  • Rauch S
  • Gooch K
  • Hall Y
  • et al.

mRNA vaccine CVnCoV protects non-human primates from SARS-CoV-2 challenge infection.

In a phase 1 dose-escalation study, two doses of CVnCoV administered 28 days apart were safe and immunogenic, with dose-dependent increases in anti-spike protein IgG antibodies and SARS-CoV-2-neutralising antibodies.

  • Kremsner PG
  • Mann P
  • Kroidl A
  • et al.

Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2: a phase 1 randomized clinical trial.

Median antibody titres against spike protein and its receptor binding domain after two 12 μg doses of CVnCoV were similar to those observed in convalescent serum samples from patients with COVID-19, with seroconversion observed 2 weeks after the second dose in all participants receiving this dosage. On the basis of these findings, the 12 μg dose was selected for further phase 2/3 testing. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in a phase 2b/3 trial.

Research in context

Evidence before this study

We searched PubMed for clinical trials published between Jan 1, 2019, and Sept 19, 2021, without language restrictions, using the terms ‘SARS-CoV-2’ OR ‘COVID-19’ AND ‘Vaccine’ AND ‘Efficacy’. At the time of the search, we identified 12 peer-reviewed publications of phase 2/3 and phase 3 clinical trials reporting the efficacy of COVID-19 vaccines in different populations. We did not consider press releases or preprints as sources of information. Eight primary publications reported vaccine efficacies ranging from 62% to 95%. The mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNtech) mRNA vaccines have shown 94% and 95% efficacy, respectively, in preventing COVID-19, with cases accrued at a time when no circulating variants had been identified. Variant-dependent differences in vaccine efficacy have been reported, with reductions in efficacy of up to 60 percentage points against newly emerged SARS-CoV-2 variants of concern.

Added value of this study

We report the primary efficacy analysis of the CVnCoV mRNA vaccine candidate from the phase 2b/3 HERALD trial that comprised 39 680 participants from ten countries in Europe and Latin America. CVnCoV had an acceptable safety profile. Solicited adverse events were common, and more frequently reported in the CVnCoV group than in the placebo group, but the median duration of grade 3 solicited adverse events was 1 day. CVnCoV was 48·2% efficacious in the prevention of COVID-19 of any severity in a variant-dominated setting. Indeed, only seven (3%) of all 204 sequenced COVID-19 cases were of B.1 lineage, with the others caused by 14 different variants. In Europe, 45 (92%) of 49 cases were caused by the alpha variant of concern (B.1.1.7), compared with Latin America where 20 (13%) of 155 cases were caused by the alpha variant and 35 (23%) cases were caused by the gamma variant of concern (P.1).

Implications of all the available evidence

In view of the changing environment, including the emergence of SARS-CoV-2 variants, and taking into account timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the promising and rapidly progressing development of next-generation vaccine candidates. In addition, it might be necessary to consider alternative designs for future global efficacy trials given the number of rapidly emerging SARS-CoV-2 variants and the high uptake of COVID-19 vaccines under emergency use authorisation.

Methods

 Study design and participants

HERALD is an ongoing, randomised, observer-blinded, placebo-controlled, phase 2b/3, clinical trial in 47 public and private hospitals and clinics across four countries in Europe (ie, Belgium, Germany, the Netherlands, and Spain) and six countries in Latin America (ie, Argentina, Colombia, Dominican Republic, Mexico, Panama, and Peru). Participants were recruited by study sites through their databases and advertisements. Adults aged 18 years or older with no history of virologically confirmed COVID-19 were eligible for inclusion, unless they had received (within 28 days before first administration of CVnCoV), or planned to receive, any investigational or non-registered vaccine or drug; had received any live (within 28 days) or inactivated (within 14 days) vaccine; or had received, or planned to receive, any investigational SARS-CoV-2 vaccine or other coronavirus vaccine before trial initiation or during the trial. A list of all inclusion and exclusion criteria is provided in the appendix (p 4). Eligibility could be assessed and recording of baseline data could be done up to 21 days before administration of the trial vaccine, but had to be reviewed before administration on day 1.

The initial phase 2b part of the trial was designed to characterise the safety, reactogenicity, and immunogenicity of the CVnCoV vaccine candidate, and the phase 3 part of the trial was designed to evaluate its efficacy and safety. The two parts of the trial were designed to allow participants with COVID-19 accrued in the phase 2b part of the trial to be pooled with those in the phase 3 part of the trial for the primary analysis of vaccine efficacy. An independent data and safety monitoring board (DSMB) conducted interim safety reviews of the phase 2b part of the trial before enrolment for the phase 3 part of the trial was initiated and will continue to monitor safety until study end. An enrolment target was that 20–25% of the population would be aged 61 years or older. We planned to enrol the first 4000 participants in the phase 2b part of the trial and to include the first 600 participants in each age group in the assessment of immunogenicity endpoints. The DSMB reviewed the safety data when approximately 1800 participants (900 in both treatment groups) had been enrolled in the phase 2b part of the trial and had at least 1 week of safety follow-up after the first dose. Enrolment of participants into the phase 3 part of the trial would begin without interruption from the phase 2b part of the trial if the safety profile was considered acceptable. The DSMB also reviewed all safety data after all participants in each group in the phase 2b trial had received their second trial vaccination and had at least 1 week of safety follow-up.

The trial protocol and its amendments received ethics approval from the appropriate independent ethics committees or institutional review boards at each study centre. The trial is being conducted in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent before initiation of any trial procedures.

 Randomisation and masking

Trial participants were randomly assigned (1:1) to receive either CVnCoV or placebo. Randomisation, stratified by country and age group (18–60 years and ≥61 years), was done centrally by use of an interactive web response system. The randomisation scheme was generated and managed by an independent statistics group at the contract research organisation, PRA. Due to the difference in appearance and presentation between the CVnCoV vaccine candidate and placebo, site personnel involved in preparing the vaccine masked the content of the syringe with a label and were not involved in further conduct of the trial. Investigators, site personnel, and others directly involved in the conduct of the trial were masked to participant allocation for the duration of the trial. The statisticians analysing the data were masked to group assignment until the final analyses. Unmasking of participants was allowed in emergency situations for reasons of participant safety or for participants who became eligible to receive an authorised SARS-CoV-2 vaccine and requested unmasking.

 Procedures

Participants in both the phase 2b and the phase 3 parts of the trial received either two 0·6 mL doses of CVnCoV containing 12 μg of mRNA, formulated with the RNActive mRNA vaccine platform, or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. Each 0·6 mL dose was administered by intramuscular injection in the deltoid area. Blood samples (6 mL) were taken from all participants on day 1 and day 43 (14 days after the second dose) and will be taken on day 211 and day 393 (study end) to measure SARS-CoV-2 nucleocapsid protein serostatus. The samples were sent to one of two central laboratories in the USA or the Netherlands and tested with the Elecsys assay on the COBAS system (Roche Diagnostics; Mannheim, Germany). The results on day 1 and day 43 identified whether participants were naive to SARS-CoV-2 infection at trial entry and 15 days after the second vaccination, and were therefore eligible for inclusion in the efficacy analysis subset.

Participants were requested to contact site investigators if they had symptoms potentially indicating COVID-19 (eg, fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhoea),

US Department of Health and Human Services

US Food and Drug Administration. Development and licensure of vaccines to prevent COVID-19. Guidance for industry.

and participants were contacted twice per week by site staff via a mobile application to respond yes or no to having potential COVID-19 symptoms. Site personnel then contacted participants who replied yes to ascertain whether their symptoms were indicative of COVID-19 by following a scripted interview. Upon suspicion of COVID-19, participants underwent a rapid antigen test (Abbott Panbio COVID-19 Ag Rapid Test; Jena, Germany) to allow them to comply with local quarantine rules if the results were positive. In addition, samples were sent to central laboratories for SARS-CoV-2-specific RT-PCR testing (In-house test, with probes and primers from Eurofins [Louisville KY, USA]; Latin America testing done in Lancaster [PA, USA]; European testing done in Breda [Netherlands]) for virological confirmation of COVID-19. In case of discrepancies between tests, the RT-PCR test result was considered definitive. All primary efficacy cases were confirmed by an independent adjudication committee. Sequencing of the complete viral single stranded RNA genome was carried out using Illumina Next Generation Sequencing (Viracor-Eurofins, Lee’s Summit, MO, USA).

Mild COVID-19 was defined as disease without shortness of breath or difficulty breathing, and an altitude-adjusted oxygen saturation (SpO2) of at least 95%. Moderate disease was defined by the presence of symptoms and shortness of breath, difficulty breathing, a respiratory rate of 20–29 breaths per min, abnormal SpO2 (but still >93% when adjusted for altitude), clinical or radiographic evidence of lower respiratory tract disease, or radiological evidence of deep vein thrombosis. Extreme COVID-19 became outlined by clinical indicators at relaxation which will seemingly be indicative of excessive systemic sickness (respiratory price ≥30 breaths per min, heart price ≥125 beats per min, altitude-adjusted SpO2 ≤93%, or PaO2/FiO2 ratio <300 mmHg), respiratory failure, evidence of outrage, with out a doubt intensive renal, hepatic, or neurological dysfunction, admission to an intensive care unit, or demise.

US Department of Health and Human Products and services

US Food and Drug Administration. COVID-19: constructing remedy and organic products for treatment or prevention. Steering for industry.

The segment 2b contributors feeble a diary to tale solicited native adversarial occasions (ie, injection-voice wretchedness, redness, swelling, and itching) and solicited systemic adversarial occasions (ie, fever, headache, fatigue, chills, myalgia, arthralgia, nausea or vomiting, and diarrhoea) for 7 days after every dose. Solicited adversarial occasions were graded by intensity from 0 (absent) to a few (excessive) based entirely mostly on predefined requirements equipped in the appendix (p 5). Unsolicited adversarial occasions were recorded in the diaries for 28 days after every dose, and investigators assessed their severity.

Medically attended adversarial occasions will seemingly be composed for all contributors from day 1 unless 6 months after the 2nd dose. Negative occasions of particular hobby and excessive adversarial occasions will seemingly be composed unless 1 yr after the 2nd dose. An inventory of adversarial occasions of particular hobby is equipped in the appendix (pp 6–7). The intensity of unsolicited adversarial occasions, adversarial occasions of particular hobby, and excessive adversarial occasions, and their relationship to survey vaccination, were assessed by the survey investigators.

 Outcomes

The main efficacy end result became the incidence of a prime episode of virologically confirmed symptomatic COVID-19 of any severity and precipitated by any pressure from 15 days after the 2nd dose up to 1 yr. The main end result became assessed by a blinded, central adjudication committee. Key secondary efficacy outcomes integrated the incidence of a prime episode of virologically confirmed moderate-to-excessive COVID-19, and the incidence of a prime episode of virologically confirmed excessive COVID-19, total and by age community (18–60 years vs ≥61 years). An exploratory efficacy endpoint, which became added in the protocol amendment on March 29, 2021, became the incidence of a prime episode of virologically confirmed COVID-19 precipitated by a person variant of assert or hobby.

Major safety outcomes were the monitoring of solicited native and systemic adversarial occasions for 7 days after every dose and unsolicited adversarial occasions for 28 days after every dose in segment 2b contributors, medically attended adversarial occasions (which is ready to be reported in the relaxation analysis at survey stop) up to 6 months after the 2nd dose, excessive adversarial occasions and adversarial occasions of particular hobby up to 1 yr after the 2nd dose, lethal excessive adversarial occasions up to 1 yr after the 2nd dose, and adversarial occasions leading to vaccine withdrawal or trial discontinuation for 1 yr after the 2nd dose (which is ready to be reported in the relaxation analysis at survey stop). A fat checklist of survey endpoints, including endpoints now not reported on in this survey, with causes for omission, is integrated in the appendix (p 8).

 Statistical analysis

HERALD is an tournament-pushed trial, and sample size and vitality issues were based entirely mostly on the main purpose of exhibiting the efficacy of CVnCoV in fighting virologically confirmed cases of COVID-19 of any severity meeting the main case definition. Assuming a vaccine efficacy of 60%, with an total two-sided α of 5%, we estimated that 160 contributors with COVID-19 of any severity, with a third of cases being moderate to excessive, were indispensable for the relaxation analysis to private a vitality of 90% to present an rationalization for a vaccine efficacy of larger than 30% based entirely mostly on the lower certain of the CI for efficacy. Assuming a COVID-19 incidence of 0·15% per month in contributors in the placebo community, an total non-evaluable percentage of 20% (honest like contributors excluded from the efficacy analysis voice and of us who dropped out), and a vaccine efficacy of 60%, we estimated that 36 500 contributors (18 250 per community) enrolled over roughly 3 months would accrue 160 COVID-19 cases of any severity at roughly 9 months after the first vaccination.

All by strategy of case accrual, sooner than the 2nd interval in-between analysis became carried out, we seen that the correct percentage of contributors with moderate-to-excessive COVID-19 became roughly 20%, which became lower than the anticipated 30%. The protocol became amended to allow accrual of extra cases to develop the planned sample size (about 53 contributors with moderate-to-excessive COVID-19) indispensable for the major secondary endpoint of measuring vaccine efficacy in opposition to moderate-to-excessive COVID-19.

Vaccine efficacy in opposition to symptomatic disease became analysed in the main efficacy analysis voice, which comprised all contributors in the segment 2b and segment 3 aspects of the trial who got both doses of either CVnCoV or placebo based entirely mostly on their treatment allocation, had now not developed virologically confirmed COVID-19 sooner than day 43 (15 days after the 2nd dose), and were SARS-CoV-2-naive at baseline and day 43. Vaccine efficacy became outlined as 1 minus the ratio of the attack price in contributors receiving CVnCoV to contributors receiving placebo, multiplied by 100. In every community, the attack price became outlined as the collection of contributors presenting with virologically confirmed COVID-19 divided by the whole notice-up time. For the main analysis, the speculation became examined with the correct take a look at for binomial proportions. The trial became regarded as a hit if the lower restrict of the correct two-sided Clopper-Pearson 95% CI (discipline to adjustment for multiple checking out based entirely mostly on the cumulative O’Brien-Fleming sort error spending characteristic, giving an proper CI of 95·826%) of the main efficacy endpoint (COVID-19 cases of any severity) became larger than 30%. Success for key secondary endpoints became outlined as the lower restrict of the correct two-sided 95% CI being larger than 20% for moderate-to-excessive disease, and bigger than 10% for excessive disease. Kaplan-Meier curves and associated log-foul assessments were carried out in a key prespecified sensitivity analysis to private in mind time to first incidence of virologically confirmed COVID-19. Post-hoc, we evaluated vaccine efficacy by build.

Solicited adversarial occasions were evaluated in the segment 2b reactogenicity analysis voice, which comprised all contributors in the segment 2b segment of the trial who got no now not up to one dose of CVnCoV or placebo based entirely mostly on treatment got and for whom no now not up to one diary entry reporting the presence or absence of a solicited adversarial tournament became in the market. Unsolicited adversarial occasions were evaluated in the segment 2b safety analysis voice, which comprised all contributors in the segment 2b segment of the trial who got no now not up to one dose of CVnCoV or placebo based entirely mostly on treatment got. Serious adversarial occasions and adversarial occasions of particular hobby were assessed in the segment 2b/3 safety analysis voice, which comprised all contributors in the segment 2b and segment 3 aspects of the trial who got no now not up to one dose of CVnCoV or placebo, based entirely mostly on the correct dose got. All analyses were carried out by assert of SAS, version 9.4. For the main end result, a p payment of now not up to 0·02087 became regarded as main. This trial is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020–003998–22.

 Aim of the funding source

CureVac became liable for trial construct and conduct, recordsdata analysis, recordsdata interpretation, and writing of the story. The German Federal Ministry of Training and Study had no position in survey construct, recordsdata collection, recordsdata analysis, recordsdata interpretation, or writing of the story.

Results

HERALD is an ongoing clinical trial and the cutoff date for this analysis became June 18, 2021. Between Dec 11, 2020, and April 12, 2021, 3999 contributors were enrolled and randomly assigned in the segment 2b trial (appendix p 11), of whom 3994 were vaccinated with out a now not up to one dose (2007 got CVnCoV; 1987 got placebo). Altogether, 39 680 contributors were enrolled and randomly assigned in the segment 2b and segment 3 aspects of the trial, of whom 39 529 (99·6%) got no now not up to one dose of CVnCoV (n=19 783) or placebo (n=19 746; figure 1). 25 contributors who were randomly assigned to placebo got no now not up to one dose of CVnCoV, and 6 contributors who were randomly assigned to CVnCoV got two doses of placebo. Any participant who got no now not up to one dose of CVnCoV became regarded as as being in the CVnCoV community for the safety analyses. Both groups had identical demographic traits (desk 1). Sooner than the relaxation efficacy analysis, 14 410 (36·5%) of 39 529 vaccinated contributors requested to be unmasked (6715 [33·9%] of 19 783 in the CVnCoV community; 7695 [39·0%] of 19 746 in the placebo community), as allowed per protocol when a SARS-CoV-2 vaccine modified into in the market. 3494 (69·8%) of 5004 contributors gentle 61 years or older were unmasked, when put next with 10 913 (31·6%) of 34 525 contributors gentle 18–60 years. These unmasked contributors were censored in the efficacy analysis at the time of unmasking. Causes for exclusion from the main efficacy analysis voice have not but been analysed per treatment community, nonetheless the most frequent causes were certain or missing serostatus result at baseline or day 43, unmasked within 15 days after the 2nd dose, failed to acquire two doses of randomised treatment, or developed COVID-19 disease, discontinued the trial, or got a licenced COVID-19 vaccine within 15 days after the 2nd dose.

Table 1Baseline and day 43 traits in the segment 2b–3 safety analysis voice

Records are n (%), median (IQR), or n/N (%). The segment 2b–3 safety analysis voice contains all contributors who got no now not up to one dose of CVnCoV or placebo, who are analysed in the community of the treatment dose got. BMI=body-mass index.

The main efficacy analysis integrated 12 851 contributors in the CVnCoV community and 12 211 in the placebo community. The mean observation interval, starting 15 days after administration of the 2nd dose, became 48·2 days (SE 0·2). Of the 228 adjudicated COVID-19 cases of any severity precipitated by any pressure, 83 came about in the CVnCoV community after a whole notice-up of 1735·29 person-years and 145 came about in the placebo community after a whole notice-up of 1569·87 person-years, ensuing in a vaccine efficacy in opposition to symptomatic disease of 48·2% (95·826% CI 31·0–61·4; p=0·016) in the total survey population (desk 2). 179 (79%) of the 228 COVID-19 cases were soft. In contributors gentle 18–60 years, 71 adjudicated cases of COVID-19 came about in the CVnCoV community after 1591·47 person-years of notice-up and 136 came about in the placebo community after 1449·23 person-years of notice-up (vaccine efficacy 52·5%, 95% CI 36·2–64·8). There private been too few contributors gentle 61 years or older with virologically confirmed COVID-19 to private in mind vaccine efficacy in this age community (desk 2). We elaborate the cumulative incidence of symptomatic COVID-19 starting on day 43 in the main efficacy analysis voice for all contributors (figure 2A) and these gentle 18–60 years (figure 2B).

Table 2Efficacy of CVnCoV in opposition to virologically confirmed COVID-19 going down 15 days or extra after the 2nd dose in the main efficacy analysis voice

Figure thumbnail gr2

Determine 2Kaplan-Meier cumulative incidence of virologically confirmed COVID-19 of any severity in the main efficacy analysis voice

(A) Total survey population. (B) Participants gentle 18–60 years. On the graphs, day 0 corresponds to day 43 of the survey, which is 15 days after administration of the 2nd dose. Records are seemingly to be now not shown for contributors gentle 61 years or older as there were too few occasions to be statistically main. Participants were censored in the event that they were unmasked, got an licensed COVID-19 vaccine, or discontinued participation in the trial for some other aim; censoring started on the day the tournament came about. Log-foul assessments evaluating community differences were main (p<0·0001) in the total survey population and the 18–60 years age community.

Total, 49 contributors (12 in the CVnCoV community and 37 in the placebo community) developed moderate-to-excessive COVID-19, in opposition to which vaccine efficacy became 70·7% (desk 2). Of these, 45 contributors were gentle 18–60 years (nine in the CVnCoV community and 36 in the placebo community), for whom vaccine efficacy became 77·2% (desk 2). The collection of cases of moderate-to-excessive COVID-19 in contributors gentle 61 years or older and the collection of contributors with excessive COVID-19 total were inadequate to meaningfully private in mind vaccine efficacy (desk 2).

Vaccine efficacy became identical between Europe and Latin America in submit-hoc analyses (desk 2). Sequence recordsdata were in the market for 184 of 207 adjudicated cases in of us gentle 18–60 years. Seven (3%; two in the CVnCoV community and 5 in the placebo community) of these cases in the total population were wild-sort, outlined as WT/D614G lineages A.1/B.1 with out the B.1.1.7 (alpha), B.1.351 (beta), and B. 1.429 (epsilon) variants of assert. A fat checklist of sequenced variants is offered in the appendix (p 9). 102 (50%) of 204 cases of COVID-19 were precipitated by variants of assert, and 23 (35%) were precipitated by variants of hobby. The relaxation cases were precipitated by wild sort (seven [3%]) and diverse variants listed in the appendix, p 8 (23 [11%]).

WHO

Monitoring SARS-CoV-2 variants.

In Europe, 45 (92%) of 49 cases were precipitated by the alpha variant (the relaxation four cases were precipitated by the gamma variant [P.1; two], by the delta variant [B.1.617.2; one], and by an unidentified variant at the time [one]). In Latin America, 20 (13%) of 155 cases were precipitated by the alpha variant, 34 (22%) were precipitated by the gamma variant, 43 (28%) were precipitated by the lambda variant of hobby (C.37), and 29 (19%) were precipitated by the Mu variant of hobby (B.1.621). The relaxation cases were precipitated by alpha (20 [13%]), B.1.526 (iota; one [1%]), wild-sort (seven [5%]), P.2 (zeta; one [1%]), and other (20 [13%]). Vaccine efficacies in opposition to the alpha, gamma, and lambda variants in of us gentle 18–60 years were honest just like the total efficacy (desk 2).

Now now not now not up to one solicited native or systemic adversarial tournament became reported by 1933 (96·5%) of 2003 contributors in the CVnCoV community, with 542 (27·1%) reporting grade 3 occasions, and by 1344 (67·9%) of 1978 contributors in the placebo community, with 61 (3·1%) reporting grade 3 occasions (desk 3). Native reactions were extra long-established in contributors receiving CVnCoV than in these receiving placebo (desk 3; figure 3A, B). The most most continuously reported native response after any dose in the CVnCoV community became injection-voice wretchedness (83·6%, 1678 of 2007), with 22 grade 3 reactions. Native reactions were transient, with a median duration of two days for wretchedness and 1 day for redness, swelling, and itching in contributors receiving CVnCoV (appendix p 10). The median duration of all grade 3 native reactions became 1 day for all reactions (appendix p 8). Solicited systemic reactions, and grade 3 solicited systemic reactions, were also extra long-established in contributors in the CVnCoV community than in these in the placebo community (desk 3; figure 3C, D). The most most continuously reported solicited systemic reactions after any dose in contributors receiving CVnCoV were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%]). The median duration of systemic reactions became 2 days for headache, fatigue, and myalgia, and 1 day for fever, chills, arthralgia, nausea or vomiting, and diarrhoea in CVnCoV recipients (appendix p 10). The median duration of grade 3 systemic reactions became 1 day for all reactions (appendix p 10). No elevate in solicited reactions became viewed between the first and 2nd CVnCoV doses (figure 3).

Table 3Negative occasions

Records are n/N (%) or n/N (%); collection of occasions. Serious adversarial occasions are reported from without delay after the 2nd dose to the date of recordsdata cutoff (June 18, 2021).

The proportions of contributors reporting unsolicited adversarial occasions and grade 3 unsolicited adversarial occasions going down all around the 28 days following any vaccination were quite elevated in the CVnCoV community than in the placebo community (desk 3). The most most continuously reported unsolicited adversarial occasions in the CVnCoV community were headache (210 [10·4%] of 2007; 42 [2·1%] regarded as vaccine-associated) and nasal congestion (127 [6·3%]; 28 [1·4%] regarded as vaccine-associated).

176 excessive adversarial occasions were reported by 148 (0·4%) of 39 529 contributors in the segment 2b–3 safety analysis voice (desk 3). 100 excessive adversarial occasions came about in 82 (0·4%) of 19 783 contributors in the CVnCoV community and 76 excessive adversarial occasions came about in 66 (0·3%) of 19 746 contributors in the placebo community. Eight excessive adversarial occasions in 5 CVnCoV recipients (acute myocardial infarction, atrial fibrillation, and cardiac arrest [n=1]; supraventricular extrasystoles and ventricular tachycardia [n=1], appendicitis [n=1], cellulitis [n=1], and seizure [n=1]) and two excessive adversarial occasions in two placebo recipients (hypersensitivity [n=1] and deep vein thrombosis [n=1]) were regarded as vaccination-associated by survey investigators. Lethal adversarial occasions were reported for eight contributors in the CVnCoV community and for six contributors in the placebo community, none of which were regarded as associated to vaccination (desk 3). Negative occasions of particular hobby were reported for 38 contributors (0·2%) in the CVnCoV community and 31 contributors (0·2%) in the placebo community. Negative occasions of particular hobby regarded as to be associated to the trial vaccine were reported for 14 contributors (<0·1%) in the CVnCoV community and for five contributors (<0·1%) in the placebo group. The primary safety outcomes for 1 year after the second dose are not provided to preserve study blinding. Data for these outcomes up to 1 year will be reported in a future publication.

Discussion

The phase 2b/3 HERALD trial evaluating the CVnCoV vaccine candidate met the prespecified success criteria for efficacy against symptomatic COVID-19 of any severity (lower limit of the 95% CI >30%) and for efficacy in opposition to moderate-to-excessive COVID-19 (lower restrict of the 95% CI >20%), as outlined in the protocol. WHO guidelines imply a lower certain of no now not up to 30% and a vaccine efficacy of no now not up to 50%.

WHO

Considerations for evaluation of COVID19 vaccines.

Vaccine efficacy in opposition to COVID-19 of any severity became 48·2% (95·826% CI 31·0–61·4) in the total main efficacy analysis voice of SARS-CoV-2-naive contributors, and 52·5% (95% CI 36·2–64·8) in these gentle 18–60 years. Vaccine efficacy in opposition to moderate-to-excessive COVID-19 became 70·7% (42·5–86·1) total and 77·2% (51·8–90·4) in contributors gentle 18–60 years. There private been too few contributors gentle 61 years or older who developed COVID-19 to allow a prime estimate of efficacy in this age community.

Though the prevalence of solicited and unsolicited adversarial occasions became elevated in CVnCoV recipients than in placebo recipients, these occasions were transient and largely soft-to-moderate (grade 1–2). The percentage of CVnCoV recipients reporting solicited native and systemic adversarial occasions in the 7 days following any dose became honest like that viewed in other mRNA vaccine segment 3 trials.

  • Polack FP
  • Thomas SJ
  • Kitchin N
  • et al.

Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.

  • Baden LR
  • El Sahly HM
  • Essink B
  • et al.

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.

No elevate in solicited reactions became viewed between the first and 2nd CVnCoV doses. Serious adversarial occasions and adversarial occasions of particular hobby were uncommon and identical in frequency between the CVnCoV and placebo groups, even though the rapid notice-up duration ought to be regarded as when interpreting these findings. The safety of the CVnCoV vaccine candidate will continue to be monitored all around the trial, and findings will seemingly be offered in a future e-newsletter. Taken along with the safety recordsdata from segment 1 trials with CVnCoV and with the CV7202 rabies mRNA vaccine,

  • Kremsner PG
  • Mann P
  • Kroidl A
  • et al.

Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate in opposition to SARS-CoV-2: a segment 1 randomized clinical trial.

  • Aldrich C
  • Leroux-Roels I
  • Huang KB
  • et al.

Proof-of-opinion of a low-dose unmodified mRNA-based entirely mostly rabies vaccine formulated with lipid nanoparticles in human volunteers: a segment 1 trial.

the findings seen in this trial present extra increase for the safety of the RNActive mRNA vaccine platform.

  • Rauch S
  • Lutz J
  • Kowalczyk A
  • Schlake T
  • Heidenreich R

RNActive® technology: technology and checking out of proper and immunogenic mRNA vaccines.

HERALD became conducted in an extra special evolving panorama that shows the altering actuality of the world COVID-19 pandemic, with an increasing collection of SARS-CoV-2 variants including extra challenges to the evaluation of COVID-19 vaccine candidates. The mRNA assert of the CVnCoV vaccine candidate encodes the SARS-CoV-2 spike protein, take care of the 2 mRNA vaccines (BNT162b2 and mRNA-1273) which were licensed as of August, 2021. Nonetheless, handiest 3% of adjudicated and sequenced cases of COVID-19 in HERALD were identified as which ability that of B.1 lineage SARS-CoV-2. About 50% of cases of COVID-19 in our trial were precipitated by variants of assert, 35% were precipitated by variants of hobby, as categorized by WHO in September, 2021, and about 3% were precipitated by wild-sort, with the relaxation 11% precipitated by other variants.

WHO

Monitoring SARS-CoV-2 variants.

Though we were handiest in a situation to private in mind vaccine efficacy in opposition to those variants in contributors gentle 18–60 years, the outcomes demonstrate that the vaccine had identical efficacies in opposition to alpha, gamma, and lambda variants. Many newly emerged strains private shown elevated transmissibility,

  • Hossain MK
  • Hassanzadeganroudsari M
  • Apostolopoulos V

The emergence of most traditional strains of SARS-CoV-2. What does it mean for COVID-19 vaccines?.

and differences in neutralising antibody assert in opposition to those strains may well alter vaccine efficacy.

  • Garcia-Beltran WF
  • Lam EC
  • St Denis Good enough
  • et al.

More than one SARS-CoV-2 variants spoil out neutralization by vaccine-brought about humoral immunity.

These concerns are supported by outcomes from other segment 3 efficacy trials, with SARS-CoV-2 variant-dependent differences in efficacy reported for the ChAdOx1 nCoV-19 (Oxford-AstraZeneca),

  • Voysey M
  • Clemens SAC
  • Madhi SA
  • et al.

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in opposition to SARS-CoV-2: an interval in-between analysis of 4 randomised managed trials in Brazil, South Africa, and the UK.

  • Emary KRW
  • Golubchik T
  • Aley PK
  • et al.

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine in opposition to SARS-CoV-2 variant of assert 202012/01 (B.1.1.7): an exploratory analysis of a randomised managed trial.

  • Madhi SA
  • Baillie V
  • Cutland CL
  • et al.

Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine in opposition to the B.1.351 variant.

NVX-CoV2373 (Novavax),

  • Heath PT
  • Galiza EP
  • Baxter DN
  • et al.

Safety and efficacy of NVX-CoV2373 Covid-19 vaccine.

  • Shinde V
  • Bhikha S
  • Hoosain Z
  • et al.

Efficacy of NVX-CoV2373 Covid-19 vaccine in opposition to the B.1.351 variant.

and Advert26.COV2.S (Janssen) SARS-CoV-2 vaccines.

  • Sadoff J
  • Grey G
  • Vandebosch A
  • et al.

Safety and efficacy of single-dose Advert26.COV2.S vaccine in opposition to Covid-19.

The point estimates for proper-world mRNA vaccine effectiveness, in settings with increasing range of variants, are lower than the point estimates for efficacy as reported in clinical trials.

  • Kustin T
  • Harel N
  • Finkel U
  • et al.

Evidence for elevated breakthrough rates of SARS-CoV-2 variants of assert in BNT162b2-mRNA-vaccinated people.

  • Puranik A
  • Lenehan PJ
  • Silvert E
  • et al.

Comparison of two highly-effective mRNA vaccines for COVID-19 all over classes of alpha and delta variant prevalence.

  • Nasreen S
  • He S
  • Chung H
  • et al.

Effectiveness of COVID-19 vaccines in opposition to variants of assert, Canada.

In this context, the comparability of vaccine efficacy in opposition to varied SARS-CoV-2 variants and between Europe and Latin America, even though now not prespecified in the protocol, is excessive from a public health point of view. Gargantuan geographical illustration ought to mild which ability that of this fact be regarded as when designing future studies evaluating the efficacy of SARS-CoV-2 vaccines and vaccine efficacy in opposition to emerging variants.

HERALD became initiated when the first SARS-CoV-2 vaccines were licensed for emergency assert. As national COVID-19 vaccination programmes prioritised the vaccination of older adults, recruiting non-vaccinated contributors gentle 61 years or older became subtle, and this limitation may well need contributed to the percentage of the survey population gentle 61 years or older being now not up to the non-binding purpose enrolment of 20–25%. As well to, per protocol, contributors eligible for an licensed vaccine may well build apart a question to unmasking and subsequent vaccination with an in the market vaccine, and this allowance resulted in extra censoring of contributors in the efficacy analyses. Finest 12·7% (5004 of 39 529) of the contributors in the segment 2b–3 safety analysis voice and 10·0% (2499 of 25 062) of contributors in the main efficacy analysis voice were gentle 61 years or older. As well to, 69·8% of contributors gentle 61 years or older in the main efficacy analysis voice were unmasked when put next with 31·6% of these gentle 18–60 years. This unblinding resulted in markedly fewer analysable contributors gentle 61 years or older in our survey than in most other segment 3 efficacy trials assessing COVID-19 vaccines.

  • Polack FP
  • Thomas SJ
  • Kitchin N
  • et al.

Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.

  • Baden LR
  • El Sahly HM
  • Essink B
  • et al.

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.

  • Voysey M
  • Clemens SAC
  • Madhi SA
  • et al.

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in opposition to SARS-CoV-2: an interval in-between analysis of 4 randomised managed trials in Brazil, South Africa, and the UK.

  • Heath PT
  • Galiza EP
  • Baxter DN
  • et al.

Safety and efficacy of NVX-CoV2373 Covid-19 vaccine.

  • Sadoff J
  • Grey G
  • Vandebosch A
  • et al.

Safety and efficacy of single-dose Advert26.COV2.S vaccine in opposition to Covid-19.

The low recruitment, mixed with the mammoth collection of older contributors who were unmasked and which ability that of this fact contributed much less notice-up time to the efficacy analyses, restricted the interpretability of our findings in this age community and affected the total survey outcomes.

The enormous case definition and the twice weekly reminders to contributors to tale any capacity COVID-19 indicators in HERALD intended that indicators that doubtlessly effect now not private precipitated RT-PCR confirmation in other trials of SARS-CoV-2 vaccines may well need resulted in confirmation of soft COVID-19 in HERALD, as evidenced by the truth that practically 80% of cases were soft. Most vaccines, including CVnCoV, private shown elevated efficacy in opposition to COVID-19 with increasing disease severity.

  • Polack FP
  • Thomas SJ
  • Kitchin N
  • et al.

Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine.

  • Baden LR
  • El Sahly HM
  • Essink B
  • et al.

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.

  • Heath PT
  • Galiza EP
  • Baxter DN
  • et al.

Safety and efficacy of NVX-CoV2373 Covid-19 vaccine.

  • Sadoff J
  • Grey G
  • Vandebosch A
  • et al.

Safety and efficacy of single-dose Advert26.COV2.S vaccine in opposition to Covid-19.

The clinical implications of CVnCoV’s 70·7% efficacy in opposition to moderate-to-excessive COVID-19, when it comes to all cases of which were precipitated by variants of assert or variants of hobby, imply a excessive capacity for a certain affect on public health. To find entry to to vaccines keeping in opposition to moderate-to-excessive disease, and thus fighting disruption to the trendy functioning of hospitals and intensive care models, is indispensable to prevent non-COVID-19-associated morbidity and mortality.

  • Berg GM
  • Wyse RJ
  • Morse JL
  • et al.

Reduced adult trauma admission volumes and altering harm patterns all around the COVID-19 pandemic at 85 trauma amenities in a multistate healthcare machine.

  • Woolf SH
  • Chapman DA
  • Sabo RT
  • Weinberger DM
  • Hill L
  • Taylor DDH

Extra deaths from COVID-19 and other causes, March-July 2020.

  • Dopfer C
  • Wetzke M
  • Zychlinsky Scharff A
  • et al.

COVID-19 associated bargain in pediatric emergency healthcare utilization—a relating fashion.

CVnCoV contains 12 μg of mRNA, considerably now not up to BNT162b2 (30 μg) and mRNA-1273 (100 μg) possess. We can’t brush apart the likelihood that this dose became inadequate to elicit a protective immune response. Nonetheless, in a segment 1 dose-escalation survey of contributors gentle 18–60 years, two 12 μg doses of CVnCoV brought about antibodies in opposition to the SARS-CoV-2 spike protein and its receptor binding domain and anti-SARS-CoV-2 neutralising titres that were honest like these viewed in convalescent serum samples from patients who had had COVID-19.

  • Kremsner PG
  • Mann P
  • Kroidl A
  • et al.

Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate in opposition to SARS-CoV-2: a segment 1 randomized clinical trial.

Nonetheless, in gape of the altering atmosphere, including the emergence of SARS-CoV-2 variants, and taking into tale timelines for extra construction, the choice had been made to cease actions on the CVnCoV candidate, and to focal point efforts on the promising and posthaste progressing construction of the subsequent technology vaccine candidates. One among these, the CV2CoV candidate, has already been shown to induce excessive humoral and cell immune responses in non-human primate studies.

  • Gebre MS
  • Rauch S
  • Roth N
  • et al.

Optimization of non-coding areas for a non-modified mRNA COVID-19 vaccine.

In conclusion, the 2-dose regimen of CVnCoV had a suitable safety profile and became efficacious in the prevention of symptomatic COVID-19 in adults. As well to, we seen vaccine efficacy in opposition to newly emerged variants, including variants of assert.

Contributors

PGK, AK, IL-R, PM, OS-Good enough, TV, and LO conceived the HERALD trial; PGK is the coordinating investigator and LO is survey lead. HJ is the certified physician and co-chair of the DSMB. PGK, RC, EJLDB, MAGG, AK, IL-R, PM, MFM-R, OS-Good enough, TV, and LO contributed to the trial construct and protocol. PGK, HJ, PM, and TV participated in the knowledge curation and had fat collect correct of entry to to and verified all survey recordsdata. PGK, AK, PM, OS-Good enough, TV, and LO did the statistical analyses. PGK, RAAG, EA-A, GJAM, MB, RC, RC GC, EJLDB, LE, JJG, CAGL, LG, MAGG, NG, MPG, ADH, CFL, CL, IL-R, MFM-R, TJO, CAP, MJRF, LMRM, VVRH, XS-L, MS, ASG, IV, and MV are survey voice main investigators. PGK, PM, OS-Good enough, and LO were in the core writing community liable for preparation of the manuscript and got increase from a clinical creator. Manuscript drafts were reviewed by all authors, and the command of the submitted version became licensed by all authors sooner than submission. All authors had remaining accountability for the choice to submit for e-newsletter. This ability that of the survey is ongoing, authors is maybe now not given collect correct of entry to to the total dataset analysed in this Article, nonetheless they are going to seemingly be given fat collect correct of entry to when the survey is terminated.

Records sharing

Anonymised participant recordsdata will seemingly be made in the market when the trial is whole, on requests directed to the corresponding creator. Proposals will seemingly be reviewed and licensed by the sponsor, investigator, and collaborators on the premise of scientific advantage. After approval of a proposal, recordsdata can handiest be shared by strategy of a proper online platform after an recordsdata collect correct of entry to agreement is signed. All recordsdata will seemingly be made in the market for no now not up to 5 years from the stop of the trial.

Declaration of interests

MB announces institutional funding from CureVac all around the conduct of this survey, institutional funding from Janssen Vaccines, Molecular Companions, and Merck originate air the submitted work, and consulting prices from Janssen Vaccines originate air the submitted work. EJLDB, MFM-R, TJO, and XS-L recount institutional funding from CureVac all around the conduct of this survey. LE and LG recount institutional funding from CureVac all around the conduct of this survey and outdoor the submitted work. CFL announces institutional funding from CureVac all around the conduct of this survey and outdoor the submitted work and is a member of the WHO Covid-19 Vaccine Effectiveness Working Team and the WHO Product Pattern for Vaccines Advisory Committee. CL announces institutional funding from CureVac all around the conduct of this survey and is a member of the German Society of Infection board. IL-R announces institutional funding from CureVac all around the conduct of this survey and institutional funding from Johnson & Johnson and OSE Immunotherapeutics originate air the submitted work. PGK announces institutional funding from CureVac all around the conduct of this survey and is a member of the scientific advisory board for the HERALD clinical trial. VVRH announces institutional funding from CureVac all around the conduct of this survey and audio system prices from Gilead originate air the submitted work. HJ announces handbook prices from CureVac, is the certified physician for the HERALD clinical trial, and is co-chair of the DSMB for the HERALD clinical trial. AK and PM are employed by CureVac and shield stock alternatives. OS-Good enough announces handbook prices from CureVac all around the conduct of this survey and is a member of the DSMB for a CVnCoV segment 1 trial. TV announces handbook prices from CureVac all around the conduct of this survey, and handbook prices from CureVac, AstraZeneca, Pfizer, Johnson & Johnson, and Moderna originate air the submitted work. LO is employed by CureVac and holds stock alternatives and is the holder of a pending patent. All other authors recount no competing interests.

Acknowledgments

This survey became funded by the German Federal Ministry of Training and Study ( grant 01KI20703 ) and CureVac. Draft variations of this manuscript were reviewed by Giulia Povellato and Robert Tensen (Medical Affairs Department, CureVac, Frankfurt, Germany). Medical writing services and products were equipped by Jarno Jansen and Margaret Haugh, who also equipped editorial increase, both funded by CureVac. We thank all survey contributors for their contribution to HERALD. We also thank all workers at the clinical survey centres, the contract review organisations, the laboratories, and in CureVac, who are too reasonably a few to be named nonetheless are on the opposite hand recognised for their tireless work, which is mild ongoing. Particular thanks creep to the participants of the DMSB, chaired by Fred Zepp.

Supplementary Cloth

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Article Records

Newsletter History

Published: November 23, 2021

Identification

DOI: https://doi.org/10.1016/S1473-3099(21)00677-0

Copyright

© 2021 Elsevier Ltd. All rights reserved.

ScienceDirect

To find entry to this text on ScienceDirect

Linked Articles

  • World emergence of SARS-CoV-2 variants: fresh foresight indispensable for improved vaccine efficacy
    • As adverse to COVID-19-appropriate behaviour, effective vaccine coverage is the single most indispensable intervention indispensable to manipulate the ongoing SARS-CoV-2 pandemic. Though a few vaccines are being feeble below emergency assert authorisation, worldwide vaccination coverage will handiest be finished when vaccine availability exceeds vaccine inquire of. Globally, a few prominent institutions, universities, and leading pharmaceutical companies private efficiently developed COVID-19 vaccine candidates which private advanced to clinical trials.


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