COVID19 Vaccine Trials
As of April 8, 2020, 115 different SARS-CoV-2 vaccine candidates are under development worldwide. Conventional approaches include the production of live attenuated virus in which the genome has been altered, and inactivated virus particles.
Attenuated live vaccines used a weakened form of the virus to produce an immune response without causing serious illness. Since they use live virus, these vaccines need extensive safety testing. Some live viruses can be transmitted to other people, which is a concern for people who are immunocompromised. Examples of attenuated live vaccines include measles, mumps, rubella, chickenpox and smallpox.
Inactivated viruses use a killed virus to produce an immune response. Often, they do not produce as strong of an immune response as attenuated live vaccines and require multiple doses and booster doses to provide long-term immunity. Common examples include influenza, hepatitis A and rabies.
SARS-CoV-2 has a spike-like structure on their surface called an S protein, which attaches to the surface of human cells. A vaccine that targets this protein should theoretically prevent it from binding to human cells and stop the virus from reproducing. The advent of genetic engineering may allow scientists to produce novel vaccines that specifically target this antigen.
A gene for a single SARS-CoV-2 protein, such as the spike protein, can be introduced into cell cultures, which produce large quantities of relatively pure protein. This is the method currently used to produce the vaccine for hepatitis B virus.
Another approach is to insert a SARS-CoV2 gene into another innocuous virus, such as adenovirus. This virus is injected into humans so that it can infect human cells and begin to reproduce. The genetically engineered adenovirus expresses the spike protein of SARS-CoV-2 protein.
Lastly, some companies are attempting to produce nucleic-acid vaccines in which a gene for a SARS-CoV-2 antigen is introduced directly as a segment of either DNA or RNA. Theoretically, nucleic acid vaccines should have less risk of contamination because they do not require cultured cells or viruses. The problem is that no RNA or DNA vaccine has ever been licensed for use in humans anywhere in the world.
DNA-plasmid vaccines work by transferring the genetic blueprint for RNA into cells, which then begin synthesizing spike antigens. A DNA plasmid vaccine was developed for MERS but never manufactured.
RNA vaccines eliminate the need for DNA plasmids and embed RNA lipid globules that can merge with cell membranes. The body’s cells then synthesize the corresponding antigen. RNA vaccines may produce more potent immunity than DNA plasmids. However, RNA vaccines are less stable and must be stored frozen. Some RNA vaccines are in early-stage clinical trials for other viral illnesses, including rabies, HIV and Zika.
Besides vaccine type, other variables influence a vaccine’s effectiveness. Some vaccines depend on adjuvants to enhance the immune response. Some companies are committed to making licensed adjuvants for use with COVID-19 vaccines.
The development of safe and effective vaccines typically takes years. Usually a vaccine is first tested in animals. If it appears safe and effective, then the three phases of human clinical trials begin. Phase I evaluates the safety of the vaccine in humans. Some vaccines can make a viral infection more virulent by a mechanism called antibody dependent enhancement. This adverse effect occurred in some people who received CYD-TDV (Dengvaxia), a vaccine against Dengue fever. Phase 2 establishes the formulation and doses of the vaccine to optimize its effectiveness. Phase 3 then tests the safety and efficacy of the vaccine in a larger group of people. Only after a vaccine passes all three phases is it licensed, manufactured, distributed and administered to humans.
Because of the urgency of the COVID19 pandemic, some scientists propose replacing this slower method with challenge trials, which deliberately expose vaccinated volunteers to the virus. For example, young healthy volunteers could be inoculated with a candidate vaccine and then purposely exposed to SARS-CoV-2. The vaccine’s effectiveness could determine in a matter of weeks instead of years.
References
Thanh Le, T et al. The COVID-19 vaccine development landscape, Nature Reviews Drug discovery, April 9, 2020.
Schmidt C. Genetic engineering could make COVID-19 vaccine in months rather than years. Scientific American, June 2020
So many candidates, so little time: can the world find a good COVID-19 vaccine quickly enough? The Economist, April 16, 2020.
