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A guide to COVID-19 vaccine modalities in the clinic

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Of the more than 90 vaccines in development for COVID-19, at least nine -- spanning nucleic acid, viral vector-based and inactivated vaccines -- are in clinical testing.

During infection with SARS-CoV-2, the host proteins ACE2 and TMPRSS2 mediate entry of the virus into the cell by binding the virus’ spike protein, which has emerged as the principal target for vaccination strategies. The host proteins are also targets of at least five therapeutic programs.

Figure: nucleic acid, viral vector and inactivated vaccines for COVID-19

Among the vaccine modalities in development, the newest format is nucleic acid vaccines, composed of either DNA or RNA. When not delivered in a vector, DNA is usually injected in a plasmid and introduced into cells via electroporation to facilitate uptake. In contrast, mRNA vaccines are usually delivered in a carrier such as a in lipid nanoparticles, which host cells internalize. Both vaccine types induce strong B cell and T cell immune responses.

Vectors used to deliver SARS-CoV-2 DNA into host cells include viruses, bacteria, yeast and exosomes. The vectors then direct the expression and presentation of SARS-CoV-2 proteins, triggering both B cell and T cell immune responses. This modality has the benefit of efficient delivery, but hosts could have pre-existing immunity to the vector being used, which would dampen the immune response.

Inactivated vaccines involve delivery of inactivated SARS-CoV-2, which can no longer replicate. This modality trades off strength of immune response for safety, and mainly triggers B cell responses. Antibodies against inactivated antigens diminish with time, meaning inactivated vaccines often require supplemental doses to boost antibody titers.

Protein-based vaccines make up at least 40% of COVID-19 vaccines in development, though none have reached the clinic. Other preclinical vaccine programs include engineered live-attenuated virus and cellular vaccines. An updated list of clinical and preclinical COVID-19 vaccines and treatments can be found in BioCentury’s COVID-19 Resource Center.

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ACE2 - Angiotensin-converting enzyme 2

SARS-CoV-2 S - SARS-CoV-2 spike protein

TMPRSS2 - Transmembrane protease serine 2

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