Novel approaches for vaccine development

Gebre, Makda S.; Brito, Luis A.; Tostanoski, Lisa H.; Edwards, Darin K.; Carfı́, Andrea; Barouch, Dan H.

doi:10.1016/j.cell.2021.02.030

Cited by 191 publications

(174 citation statements)

References 150 publications

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“…The features of lipid nanoparticle–mRNA formulations have been thoroughly preclinically and clinically investigated, which has allowed the rapid development and clinical use of the COVID-19 lipid nanoparticle–mRNA vaccines. For example, the clinical-grade COVID-19 vaccine, mRNA-1273, was produced within a month after the SARS-CoV-2 genome sequence was available 15 , 17 . About 2, 5 and 6 months from sequence availability, clinical trial phases I, II and III were initiated, respectively 15 , 17 .…”

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

“…For example, the clinical-grade COVID-19 vaccine, mRNA-1273, was produced within a month after the SARS-CoV-2 genome sequence was available 15 , 17 . About 2, 5 and 6 months from sequence availability, clinical trial phases I, II and III were initiated, respectively 15 , 17 . Finally, mRNA-1273 obtained Emergency Use Authorization from the FDA and conditional marketing authorization from the EMA within a year 15 , 17 .…”

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

“…About 2, 5 and 6 months from sequence availability, clinical trial phases I, II and III were initiated, respectively 15 , 17 . Finally, mRNA-1273 obtained Emergency Use Authorization from the FDA and conditional marketing authorization from the EMA within a year 15 , 17 . Many other lipid nanoparticle–mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders 2 , 4 , 8 , 12 – 14 (Tables 1 , 2 ).…”

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

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Lipid nanoparticles for mRNA delivery

et al. 2021

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Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle–mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers and possible administration routes for lipid nanoparticle–mRNA systems. We then consider key points for the clinical translation of lipid nanoparticle–mRNA formulations, including good manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies of lipid nanoparticle–mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technology.

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Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

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Lipid nanoparticles for mRNA delivery

et al. 2021

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“…Moreover, improved resistance to denaturation and shelf-life stability at various temperatures could be particularly impactful for reliable distribution in developing countries that lack cold chain infrastructure. Finally, as knowledge of the prefusion-stabilizing “2P” mutations prior to the emergence of SARS-CoV-2 proved critical to pandemic response efforts ( 1 , 2 , 84 ), the ability to reliably improve vaccine manufacturability using stabilizing mutations to the RBD may be an important tool for optimizing vaccine designs against other coronaviruses circulating in zoonotic reservoirs that threaten to cross over to humans.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design

et al. 2021

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The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40°C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.

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“…Additional vaccine candidates are under development and a continually updated list is available at https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. Most COVID-19 vaccines and vaccine candidates target the SARS-CoV-2 full-length (FL) spike (S) glycoprotein, which mediates attachment and entry of the virus into host cells ( 2 ), and employ both traditional and novel vaccine platforms such as inactivated virus, protein-based preparations and virus-vectored and nucleic acid-based formulations ( 2, 3 ).…”

Section: Introductionmentioning

confidence: 99%

COVID-eVax, an electroporated plasmid DNA vaccine candidate encoding the SARS-CoV-2 Receptor Binding Domain, elicits protective immune responses in animal models of COVID-19

Conforti¹,

Marra²,

Palombo³

et al. 2021

Preprint

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The COVID-19 pandemic caused by the β-coronavirus SARS-CoV-2 has made the development of safe and effective vaccines a critical global priority. To date, four vaccines have already been approved by European and American authorities for preventing COVID-19 but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle, a technology previously utilized for cancer vaccines. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 Spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax – a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein RBD – induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function and significantly lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started in Italy.

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Novel approaches for vaccine development

Cited by 191 publications

References 150 publications

Lipid nanoparticles for mRNA delivery

Lipid nanoparticles for mRNA delivery

Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design

COVID-eVax, an electroporated plasmid DNA vaccine candidate encoding the SARS-CoV-2 Receptor Binding Domain, elicits protective immune responses in animal models of COVID-19

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