Issues in the Creation, Testing and Use of a COVID-19 Vaccine
By Stuart M. Caplen, M.D.
The entire world’s population is susceptible to the novel COVID-19 infection caused by the SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus 2). Herd immunity is unlikely to be achieved in the near future without unacceptably high hospitalization and mortality rates, so a vaccine seems to be the most likely way this pandemic will be resolved. There are a number of issues involved in the creation of a COVID-19 vaccine, and hurdles that have to be overcome to move it rapidly into production.
SARS-CoV-2 Virus and Antibody
The coronavirus is named after the corona or crown of protein spikes that surrounds each viral particle. These spikes can attach to a cell’s membrane via the ACE2 (Angiotensin-Converting Enzyme 2) receptor located on many cells in the human body. SARS-CoV-2 depends on the TMPRSS2 protease enzyme (Transmembrane protease, serine 2), already in human cells, to breach the cell membrane, allowing the virus to enter the cell and turn it into a living factory for making more viruses. Eventually the cell lyses(disintegrates), releasing the newly created viruses to infect other cells.[2,3]
SAR-CoV-2 antibodies are naturally produced in the body during an infection by T and B lymphocyte cells. T helper cells help the B cells produce antibodies, while cytotoxic T cells (killer T cells) attack infectious viruses directly. Neutralizing antibodies produced by the B and T cells can latch onto the SARS-CoV-2 spikes, and block the virus from attaching to the ACE2 receptors and infecting new cells. Most vaccines now in development are an attempt to create antibodies to the SARS-CoV-2 protein spike, however it may turn out that more than just this antibody blocking action might be needed to protect against infection. A successful vaccine might also need to stimulate the cytotoxic T cell immune responses against SARS-CoV-2. 
Vaccine Development and Testing
A new vaccine for a disease typically can take about ten years in research, testing, regulatory approval, manufacturing, and distribution. That is too long a time period to deal with the current COVID-19 pandemic, and scientists are hoping with new approaches and technology a vaccine can be produced in an unprecedented 12 to 18 months.
Vaccines are tested in phases. It starts with preclinical testing in animals to test for safety and possible efficacy. Phase I is testing in a small group of people. If there are no serious adverse events and some evidence of the vaccines ability to stimulate antibody response, Phase II or expanded trials can commence. In this phase hundreds of people are tested and divided into age groupings to again test for adverse events and efficacy. In Phase III, thousands of people are given the vaccine and compared to people who just received a placebo to see how many in each group become infected. If the vaccine is found to be successful in decreasing the numbers of infections and the side effect profile is acceptable, the next stage is approval by regulators. Finally, after approval the vaccine must be manufactured and distributed.
As of early June, there are more than 135 different COVID-19 vaccines in development. Most have not yet reached clinical testing, with only seven currently in Phase I, seven in Phase II, and one in Phase III testing.[7,8]
In order to decrease the time required to do testing, phases are being combined in the search for a COVID-19 vaccine. For example, Phase I and II are being merged by some manufacturers, so the first test of the vaccine immunizes hundreds of people rather than a few. Some authorities have suggested that actively infecting vaccinated people in phase III rather than waiting for some of them to be infected randomly would also speed up the process.[9,10] This presents ethical issues as well as the possibility that if a vaccine is found to cause adverse events, or not provide adequate antibody protection, more people will likely be harmed in the testing phase than in the standard vaccine approval pathway.
A whole virus vaccine is produced by growing the virus in eggs or cells and then inactivating it so it is not infectious, but can still induce the immune system to create antibodies. In some vaccines the virus is still alive but attenuated rather than fully inactivated.
Genetic and protein-based vaccines are based on generating all or part of the SARS-CoV-2 spike protein to induce antibody production.
Genetic vaccines use a small portion of a virus’s DNA or messenger RNA to deliver genetic instructions for synthesizing a viral protein to a cell. This causes an immune response without causing infection. The DNA vaccine causes the cell to produce messenger RNA which then forces the cell to produce inactive viral proteins. In messenger RNA vaccines, as DNA is not required, there is one less step involved. In viral vector vaccines, a DNA or RNA fragment is introduced into the body’s cells by attaching the fragment to the genome of a virus, such as a cold virus, that has been rendered noninfective. The vector virus enters cells and the spliced gene fragment causes the cell to produce viral proteins, eliciting an antibody immune response. DNA and RNA vaccines use only a viral DNA or RNA fragment without using a vector virus. The DNA or RNA is introduced into cells and induces production of viral proteins that stimulate the immune system to produce antibodies. DNA and RNA vaccines can be produced more quickly than other vaccines, but there are no DNA or RNA vaccines currently licensed for use.
Protein-based vaccines use a viral protein or a protein fragment to provoke an immune response.
Recombinant vaccines are a type of protein-based vaccine where viral genes are added to the genomes of yeast or other cells which then can produce all or part of a viral protein to be used in a vaccine.
All of the above vaccine development methods are being pursued by one or more laboratories around the world. It is likely that in the next year vaccines from multiple laboratories may become available.[7,8]
There is also a Phase III clinical trial going on in several countries of the Bacillus Calmette-Guerin (BCG) vaccine.[7,12] The BCG is a 100-year-old vaccine, used mainly in developing countries to prevent tuberculosis complications in children, such as meningitis and disseminated disease. It has been found to have immune bolstering effects in other diseases, and is being tested to see if it can do the same with COVID-19.
Many vaccines contain an adjuvant. An adjuvant is a substance that helps the immune system recognize the vaccine as a foreign material, requiring an immune response and antibody production. Different adjuvants can stimulate different pathways in the immune system, depending on the disease being vaccinated against. Whole virus vaccines are less likely than other types to need an adjuvant, as they have naturally occurring ones. Adjuvants can be made from lipids, proteins, nucleic acids, or most commonly, aluminum salts. It is likely that a COVID-19 vaccine will need an adjuvant to be effective. [13,14]
Speeding Up Vaccine Manufacture and Distribution
The US government has embarked on Operation Warp Speed, where they have given five companies with promising vaccines 2.2 billon dollars to help accelerate the testing process. Manufacturing facilities will be set up in advance of knowing if that company’s vaccine will be effective. The five companies are Johnson & Johnson, Merck, Moderna, the Oxford-AstraZeneca group, and Pfizer, which are all researching genetic vaccines. The Moderna and Pfizer vaccines are RNA vaccines, while the Johnson & Johnson, Merck and Oxford vaccines are viral vector vaccines. [15,16]
The Warp Speed initiative will also include having the selected companies use their increased manufacturing capacity for whichever vaccine is actually chosen, even if it is not their own. The government will also start plans for distribution of the vaccine by expanding supplies of needed resources such as syringes, refrigerated transport, and storage facilities. The military will be used to help distribute the vaccines, which is expected to be a more expeditious process than if the manufactures did it on their own.
Questions That Have to Be Answered Before a COVID-19 Vaccine Can Be Used in the General Population
First, does it work? Will it produce an antibody response adequate to protect an individual? How long does the antibody protection last for?
Will producing just viral antibodies be protective, or are additional immune system components needed to be activated to adequately protect a person from infection?
Will it work on all people, or is it effective only in a percentage of people? The influenza vaccine, depending on the year, has an average of 33% to 61% effectiveness.
Will the antibodies produced by the vaccine provide protection across all age groups, or will it be less effective in elderly and immunocompromised patients? Will these people need higher doses of vaccine to achieve an adequate immune response, as is the case with the influenza vaccine?
Some people have medical conditions that may not allow them to produce adequate antibodies when infected with the virus. Will they actually be able to produce effective antibodies when vaccinated? This group may benefit from herd immunity due to others being vaccinated. When an estimated minimum of 60% of the population have immunity from COVID-19, people who don’t have immunity start to get some protection, as fewer people are available for the virus to infect and further spread the disease. 
What is the risk-benefit ratio of the vaccine? Will the benefits of protection from infection outweigh the adverse effects of the vaccine some people may experience? For example, the 1976 swine flu vaccine caused a higher than average number of Guillain-Barre paralysis cases, and the expected swine flu epidemic never emerged.
Finally, will a viral mutation between now and when the vaccine is produced cause the vaccine to become ineffective?
The amount of research going on now around the world is unprecedented in its scope. The compressed time frames being discussed to produce the COVID-19 vaccine would have been unimaginable before this crisis. With essentially the entire world’s medical scientific community looking for a cure, it is hoped that this pandemic will end in 2021. It is also hoped that the nation or nations that develop a successful vaccine will share it with the world, and not use it as a tool to gain advantage over other countries that do not. Creating, manufacturing, distributing and administering over 7 billion doses of a COVID vaccine to the world’s population by next year would be an epic public health achievement.
“With infectious disease, without vaccines, there's no safety in numbers.”-Seth Berkley
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ABOUT THE AUTHOR
Stuart M. Caplen, MD, FACEP, MSM
Dr. Caplen is a former emergency physician and emergency department medical director, now retired from clinical practice. His current interests include how quality is produced and maintained in health care, and he recently achieved greenbelt certification in lean/six sigma.
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