COVID-19 Vaccines: What is Being Developed?

COVID-19 Vaccines: What is Being Developed?

by Jed Bassein

With cases on the rise, I want to discuss some of the biggest questions on everyone’s mind when it comes to the COVID-19 vaccine. When will a COVID-19 vaccine be available? What is the science behind the vaccine technology? And how safe will it be once its ready? 

Biorender has built an online resource that is currently tracking all the COVID-19 vaccines and therapies under investigation with regular updates. As of June 30th, 2020 Biorender has reported 150 vaccines are under development, with at least 122 currently in preclinical trials, and 26 in human trials [1]. In this blog I will discuss which vaccines are closest to completion, what is the science that supports their efficacy, and how have they been tested for safety. 

Safety Precautions for Vaccine Development

Let’s start by discussing the CDC guidelines and logistics associated with vaccine development and safety testing [2]. We all want the “silver bullet” that cures COVID-19, but rushing this process has cost human lives in the past with other diseases and we do not want to repeat that mistake. Vaccine development is not a trivial process and above all else vaccines must prove to be safe and effective before being used on a large scale. Drugs and vaccines start in the preclinical phase where theories and strategies are thoroughly tested. Before being considered for any type of human clinical trials a vaccine must prove safe and effective in numerous in vitro and in vivo models. Vaccines can then apply to the FDA to become an investigatory new drug (IND). These applications layout the foundation of how the vaccine is made, what its mechanism of action is, efficacy data, any potential side effects or toxicities that need to be considered, and the proposed protocol for beginning clinical trials. 

If the FDA approves an IND, it can then enter initial Phase I clinical trials. These are relatively small trials that are conducted in defined cohorts and are mostly geared to test safety and provide proof of principle. It should be noted that many drugs and vaccines fail at this stage and do not proceed further. Only after passing Phase I can an IND or vaccine enter the later phases of clinical trials in which cohorts are gradually expanded and broader applications are tested. Phase III and IV are where large double-blinded placebo trails can be conducted in human subjects. Each phase takes more monetary investment and demands greater rigor for success. Although the demand for a COVID-19 cure is high at the moment, I do not believe that our regulatory bodies have any intention to shortcut these phases.

Trained Innate Immunity

Currently, the vaccine that is furthest along in clinical trials is the Bacille Calmette-Guerin (BCG) vaccine. The BCG is a live, attenuated tuberculosis vaccine that was originally developed in the 1920s. The BCG vaccine has since been used on millions of people and has proven to be very safe in numerous clinical trials [3]. There has been previous evidence to suggest that the BCG vaccine was able to provide cross-protection against unrelated respiratory pathogens [4]. Based on these data, epidemiologists theorized that countries that mandated the BCG vaccine would fair better against the SARS-COV-2 virus than those that did not. Indeed in May 2020, Grusel et al. reported significantly fewer cases and deaths could be detected in BCG mandated countries [5]. These data supported the idea of using the BCG vaccine as a non-specific tool to help offset COVID-19 fatalities, which is currently under investigation [6]. 

While the routine use of the BCG vaccine could provide some potential to alleviate COVID-19 infection rates and mortality, it is not specific to SARS-COV-2. The BCG vaccine is thought to work by inducing trained immunity. Trained immunity is a novel concept in which previous immune experiences can train innate immune cells that are not antigen specific to be more effective at certain responses. It is thought that these changes are mediated through epigenetic mechanisms, but currently little is known and much remains to be discovered [7]. 

Along these same lines, researchers have begun to investigate if the oral Polio vaccine; the measles, mumps, and rubella (MMR) vaccine, or even the intranasal influenza vaccine could provide similar non-specific protection against SARS-COV-2. However, I want to clearly state that currently the BCG, Polio, MMR, and influenza vaccines are not approved for use to treat COVID-19 and I am not recommending for anyone who reads this post take those vaccines for that purpose. If you are experiencing symptoms of COVID-19, please seek appropriate medical advice. 

Mechanisms for Vaccine Protection

In order to acquire specific protection to SARS-COV-2, we must train the adaptive branch of our immune system. Adaptive immunity is conferred though two major mechanisms. The humoral B cell response, which generates antigen specific antibodies, and the cellular T cell response, which directly recognizes infected cells and guides other immune responses [8]. In general, effective pathogenic clearance involves the activation of both branches of the adaptive responses. However, some pathogens may be more susceptible to humoral or cellular mediated immunity. It is currently unclear if SARS-COV-2 requires a more B cell, T cells, or combination response for effective immunity.

SARS-COV-2 Specific Vaccination Strategies

Immunologists have developed numerous ways to activate the immune system and train it to respond to specific pathogens. One way would be to passage the SARS-COV-2 virus in a cell line until it has mutated to a non-virulent version that could provide protection, but did not induce disease. This strategy was used to create the Polio vaccine in the 1960s [9]. Another method could be to fuse an epitope of the SARS-COV-2 virus to a non-replicating vector that could initiate an inflammatory response, but not cause disease [10]. The draw back of these vaccination strategies is that they require the use of a live or attenuated virus, which can sometimes exhibit complications in immunocompromised individuals. 

More novel approaches to vaccine design include immunotherapy strategies, which use ex vivo programed adaptive cells, such as cytotoxic lymphocytes (CTL) or adaptive branch activator cells known as dendritic cells (DC) [11]. Similarly, the use of convalescent antibodies synthetic antibodies that target SARS-COV-2 may help to provide passive immunity for those that are infected [12]. Convalescent plasma is currently being tested as a possible therapy in non-human primates at the California National Primate Research Center here at UC Davis [13]. 

Another potentially powerful vaccination method is through the use of DNA or RNA vaccine technologies. This technology uses short electric pulses to electroporate cells on the skin’s surface and allows for the infusion of a synthetic viral gene constructs. The skin is one of the largest immune mucosal sites in the body and houses high numbers DCs and other immune activating cells. This makes the skin a more attractive delivery site compared to the common intramuscular injection [14]. 

In summary, current vaccination technology has come a long way and with the new SARS-COV-2 virus is moving rapidly forward. However, vaccines take a long time to develop and require thorough testing before they can be used safely and on a large scale. It should also be noted that there is no guarantee that an effective SARS-COV-2 vaccine will be developed. Nevertheless, we should not loose hope, but we must also be cognizant that a COVID-19 vaccine might still be far away.

References

1.          https://biorender.com/covid-vaccine-tracker.
2.          https://www.cdc.gov/vaccines/basics/test-approve.html.
3.          Colditz, G.A., et al., Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-analysis of the Published Literature. JAMA, 1994. 271(9): p. 698-702.
4.          Kristensen, I., P. Aaby, and H. Jensen, Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. Bmj, 2000. 321(7274): p. 1435-8.
5.          Gursel, M. and I. Gursel, Is Global BCG Vaccination Coverage Relevant To The Progression Of SARS-CoV-2 Pandemic? Medical Hypotheses, 2020: p. 109707.
6.          O'Neill, M.S., et al., Air pollution and health: emerging information on susceptible populations. Air quality, atmosphere, & health, 2012. 5(2): p. 189-201.
7.          Netea, M.G., et al., Trained immunity: A program of innate immune memory in health and disease. Science, 2016. 352(6284): p. aaf1098.
8.          Clem, A.S., Fundamentals of vaccine immunology. Journal of global infectious diseases, 2011. 3(1): p. 73-78.
9.          Blume, S. and I. Geesink, A Brief History of Polio Vaccines. Science, 2000. 288(5471): p. 1593-1594.
10.        Taylor, J., et al., Nonreplicating viral vectors as potential vaccines: Recombinant canarypox virus expressing measles virus fusion (F) and hemagglutinin (HA) glycoproteins. Virology, 1992. 187(1): p. 321-328.
11.        Dalgleish, A.G., Vaccines versus immunotherapy: overview of approaches in deciding between options. Human vaccines & immunotherapeutics, 2014. 10(11): p. 3369-3374.
12.        Bloch, E.M., et al., Deployment of convalescent plasma for the prevention and treatment of COVID-19. The Journal of Clinical Investigation, 2020. 130(6): p. 2757-2765.
13.        https://cnprc.ucdavis.edu/covid-19/.
14.        Leitner, W.W., H. Ying, and N.P. Restifo, DNA and RNA-based vaccines: principles, progress and prospects. Vaccine, 1999. 18(9-10): p. 765-777.