A guide to COVID-19 preclinical vaccine modalities

BioCentury is providing this content for free given the urgent need for information about the coronavirus crisis. Further analysis can be found in our COVID-19 Resource Center. For more, sign up for our daily email.

As the number of vaccines in development for COVID-19 climbs past 110, more modalities are starting to be represented in the clinic.

As of last week, the COVID-19 vaccine modalities in the clinic were inactivated viruses, vector-based vaccines and nucleic acids (see “A Guide to COVID-19 Vaccine Modalities in the Clinic“).

This week sees a protein-based vaccine enter trials, while live attenuated viruses and cellular vaccines remain in preclinical development.

Figure: Vaccine modalities for SARS-CoV-2

Summary of COVID-19 vaccines in development, and depiction of natural SARS-CoV-2 infection.

Protein-based vaccines include full-length viral proteins, peptide antigens or virus-like particles (VLPs).

They have the advantage of being highly safe, with few side effects, but typically only induce short-term immunity, primarily via B cell responses. Often, they require an adjuvant and/or booster shot to induce long-term immunity.

Most of the protein and peptide COVID-19 vaccines in development that have disclosed targets are delivering the SARS-CoV-2 spike protein. At least one combines the spike protein with SARS-CoV-2 envelope and membrane antigens.

Virus-like particles (VLPs) are protein assemblies that resemble a virus' outer shell, but lack genetic material and thus cannot replicate. VLPs are designed with a repetitive, high-density display of viral surface antigens, and can elicit both B cell and T cell immune responses. At least nine of the protein-based vaccines in development are VLPs -- one includes spike proteins from SARS-CoV-2, SARS-CoV-1 and MERS to create a “pan-coronavirus” vaccine.

Novavax Inc. (NASDAQ:NVAX) began a Phase I trial of NVX-CoV2373, a stable, prefusion version of the SARS-CoV-2 spike protein made with the company’s recombinant protein nanoparticle technology (see "Novavax to Scale Up Vaccine").

Figure: Protein-based vaccines for SARS-CoV-2

Protein-based vaccines include full-length proteins, peptides and virus-like particles (VLPs)

Live attenuated vaccines are weakened viruses evolved in the lab to mimic natural infections while causing few to no symptoms. These viruses can still replicate in the host and they trigger both B cell and T cell immune responses.

At least one company is developing a vaccine comprised of live attenuated SARS-CoV-2. Six others have engineered more established live attenuated viruses, such as measles, to express SARS-CoV-2 antigens.

The risks of live attenuated vaccines are their potential to cause harm in immunocompromised people, and their potential to mutate into more virulent forms.

Figure: Live attenuated vaccines for SARS-CoV-2

Live attenuated vaccines in development for COVID-19 include at least one vaccine based on weakened SARS-CoV-2, and at least six others in which a different live attenuated virus is engineered to express SARS-CoV-2 antigens.

Cellular vaccines either use whole cells as a source of antigens, or as a platform to deliver antigens. A common method involves delivering APCs engineered to express viral proteins and immune modulatory genes.

At least two companies have developed cellular vaccine platforms that promote antigen uptake and presentation by endogenous APCs.

A "decoy cell" vaccine from Sorrento Therapeutics Inc. (NASDAQ:SRNE) uses non-replicating, HLA-negative cells expressing membrane-bound SARS-CoV-2 spike proteins. These cells are targeted by NK cells and recruit APCs to present viral peptides to induce B and T cell immunity.

Another method from Heat Biologics Inc. (NASDAQ:HTBX) delivers cells expressing SARS-CoV-2 antigens fused to secreted heat shock proteins that enhance antigen uptake and presentation by APCs.

The degree to which cellular vaccines promote B cell and T cell responses depends on the preparation method, and further research is needed to establish the potency and duration of immunity they induce. The challenge of providing a consistent cell-based product and the cost of manufacturing limit their application.

Figure: Cellular vaccines for SARS-CoV-2

Cellular vaccines include engineered antigen presenting cells (APCs), cell decoys and antigen secreting cells.

An updated list of clinical and preclinical COVID-19 vaccines and therapies and further analysis of the coronavirus crisis can be found in BioCentury’s COVID-19 Resource Center.


HLA - Human leukocyte antigen

SARS-CoV-2 E - SARS-CoV-2 envelope protein

SARS-CoV-2 M - SARS-CoV-2 membrane protein

SARS-CoV-2 N - SARS-CoV-2 nucleocapsid protein

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

How to gain access

Continue reading with a
two-week free trial.