By Felicia Ho | Published May 29, 2020
As of May 27, we are reaching nearly 5.5 million confirmed cases worldwide and over 350,000 deaths due to the novel SARS-CoV-2 virus. (2) On January 11, 2020, the first full sequence of the SARS-CoV-2 genome was published by Chinese scientists for public use. (3) Almost immediately, biotechnology companies, educational institutions, and labs began screening the genome sequence for potential vaccine candidates. Techniques have differed from one study to the next, but as more and more companies join the race to develop a COVID-19 vaccine, a few frontrunners have emerged with the promise of delivering a vaccine to the public on an accelerated timeline.
In a normal timeframe, vaccine development can take up to 15 years, as Supriya Munshaw, PhD, explains life science technologies commercialization in a recent interview at Johns Hopkins. (4) Basic research to pinpoint the exact aspects of the virus most susceptible to a vaccine typically takes 2-4 years; pre-clinical research to test the vaccine in animals takes another 2 years. Only then can phase trials in humans commence, with phase I enrolling a small cohort of 20-30 patients to ensure safety standards are met with minimal side effects. Phase II enrolls hundreds to thousands of patients to determine the appropriate dosage for the vaccine and safe administration practices. Phase III enrolls thousands of patients to engage in a longer study to observe disease rates in a larger population that has now been vaccinated for the pathogen. These phase trials typically span over 5 years, and even after a vaccine successfully passes phase III, commercialization plans must be developed for scaling mass production to the greater public. After a vaccine is approved and administered to the general public, the FDA and CDC continue to carefully monitor vaccine safety for additional potential side effects and already have an extensive system in place for doing so.
(see graphics below)
During the COVID-19 pandemic, vaccine development has accelerated at breakneck speed. Munshaw believes that the foundational research from MERS and SARS-CoV-1 (two viruses that resemble the current SARS-CoV-2 and each without vaccines at the moment) and urgency to develop a vaccine in this time of crisis have greatly propelled this process.
There are currently eight different types of vaccines in development for SARS-CoV-2 that have been grouped into the following larger general categories by the Mayo Clinic. (5) Live vaccines consist of a pathogen that has been weakened when injected into the patient (examples include measles/mumps/rubella, smallpox, and chickenpox); inactivated vaccines consist of fully killed pathogens, but may require more doses (examples include the flu, hepatitis A, and rabies); and genetically engineered vaccines like DNA or RNA vaccines lead the body to encode for harmless viral proteins. The immune system can then recognize these foreign proteins and clear them appropriately, even keeping these foreign proteins’ identities saved in a unique immune memory.
In these cases, the purpose of the vaccine is to expose the patient’s immune system to some aspect of the SARS-CoV-2 virus so as to encourage the body to create neutralizing antibodies (molecules that can latch onto a virus and prevent the virus from infecting the patient) that will be ready to attack in the case that the patient is exposed to SARS-CoV-2 in the future. (5)
Due to the nature of these vaccines and the novel character of SARS-CoV-2 (in that humans currently do not have any immunity to SARS-CoV-2), it is likely that patients will need two rounds of vaccinations to ensure a sufficient immune response according to the Mayo Clinic. (5)
Frontrunner vaccines that are currently in development for SARS-CoV-2 (6):
BCG live-attenuated vaccine in phase III trials
Investigators include: University of Melbourne and Murdoch Children’s Research Institute, Radboud University Medical Center, Faustman Lab at Massachusetts General Hospital
The Bacillus Calmette-Guérin (BCG) vaccine is over 100 years old and comprises the attenuated-live bacillus bacteria closely related to tuberculosis. It has primarily been used in countries with higher rates of tuberculosis (TB) as a TB vaccine, but its role in potentially inducing the innate immune response (our body’s first line of defense) to respiratory viruses has prompted researchers to investigate whether the BCG vaccine could be used to counter COVID-19. (7) The Netherlands and Australia are now offering phase III trials to healthcare workers who are at the highest risk of being exposed to SARS-CoV-2 in hopes that the cells of the innate immune system can be “trained” prior to COVID-19 infection and, upon exposure, greatly enhance the immune response, as efforts to develop a definitive vaccine against COVID-19 continue. (8) One concern with this vaccine is that because BCG is a live bacteria, it would not be suitable to use among immunocompromised individuals (as greater BCG infection can occur). (7)
mRNA-1273 in phase I trials
Investigators include: Moderna and Kaiser Permanente Washington Health Research Institute
The mRNA-1273 vaccine being developed by Moderna and in trials in partnership with the Kaiser Permanente Washington Health Research Institute is a genetically engineered vaccine that has largely been developed based on previously established research on SARS and MERS. Moderna recently published interim phase I clinical data and has been cleared for phase II trials, with a goal of initiating phase III in July. (9) Although the available data seems promising as low doses of the vaccine have presented neutralizing antibody levels similar to those who had recovered from COVID-19 infection, much work remains in order to establish appropriate dosage - especially for seniors who are at highest risk of infection and do not respond to vaccines as readily as others. (10)
See graphic below if you are interested in learning more about the details of how this mRNA vaccine works:
Ad5-nCoV in phase II trials
Investigators include: CanSino Biologics and Tongji Hospital (Wuhan, China)
The Ad5-nCoV vaccine, a vector vaccine (a weakened virus carrying material for one part of the SARS-CoV-2 virus) being developed by CanSino Biologics and in trials with Tongji Hospital in Wuhan, China, is the first of the COVID-19 vaccines with Phase I study data that has been peer-reviewed and published in medical journal The Lancet. (11) Results indicated that most participants developed neutralizing antibodies and more robust and rapid T-cell activity. (12) The vaccine is now being developed in Phase II trials.
AZD1222 in phase II trials
Investigators include: The University of Oxford and the Jenner Institute
The AZD1222 vaccine, another vector vaccine, has arguably been receiving the most media attention. Developer AstraZeneca partnered with The University of Oxford and has begun expanding enrollment of both older and younger patients into phase II/III of clinical trials, despite Phase I data not being shared publicly yet. They will soon be enrolling thousands of UK residents in order to generate results that would support immunization of the general public first in the UK by September. Although researchers expect a delay of two to six months to be able to observe whether the vaccine is working, AstraZeneca and The University of Oxford have already committed to shipping 1 billion doses of the vaccine to the general public at the conclusion of the program. (13)
There are many other vaccines that are currently in various stages, but as we look towards reopening and moving forward, the aforementioned vaccines may be most promising in one of the most urgent and accelerated research processes in the modern era.
For a great visual guide on how each of these different vaccines interact with the cellular components, see this fantastic Nature article: https://www.nature.com/articles/d41586-020-01221-y.
For more information on other vaccines and a great review article on how these vaccines are being developed so quickly: https://www.nejm.org/doi/pdf/10.1056/NEJMp2005630.
For an interactive tool to adjust different measures that can be taken to accelerate the development of the COVID-19 vaccine: https://www.nytimes.com/interactive/2020/04/30/opinion/coronavirus-covid-vaccine.html.
Results from ongoing research and the current understanding of COVID-19 are constantly changing and growing. This post contains information that was last updated on May 27, 2020.