I have been asked a question by a friend and I thought that others of you might be interested in the answer also, so here is my response.
QUESTION: IS THERE AN EBOLA VACCINE? DOES THIS GIVE US INFORMATON ABOUT A COVID-19 VACCINE?
Answer: So, as I understand it, there was an Ebola vaccine approved in December of 2019, just a few months ago.
Development of that vaccine began in 1967 (when Ebola was stilled called the Marburg virus). This is a good demonstration of how difficult it is sometimes to produce a vaccine.
Interestingly the newly approved vaccine uses an “attenuated virus”. As you may recall, the two ways to produce a vaccine are to use killed virus particles, or to use modified live virus that does not cause disease. Apparently with Ebola, killed virus vaccine was ineffective in generating an immune response, or at least one that could prevent infection.
Developing an attenuated virus is much more difficult and takes significantly more time.
Regarding COVID-19, there is some good news today. Recently a number of new techniques have been developed for generating a vaccine and several of them are being applied to COVID-19. These techniques promise vaccine development in much shorter periods of time. These new techniques are a direct result of the advances in molecular biology (funded not by commercial firms, but by government money for basic R&D).
(I am going to describe in as simple terms as possible what these new techniques are, but I want everyone to understand that the “shorter development time”, refers ONLY to the time necessary to get a vaccine ready for trials, it does not shorten the trial time and I will describe why below.)
The idea here is that once the genetic sequence of the RNA of the virus is known (and that took only a matter of weeks after the initial infections were seen in China), you can theoretically “read” the parts of the RNA that code for the proteins that could potentially generate an immune response. You can then synthesize those pieces of RNA, put them in “vectors” (pieces of other viruses that can be used to infect the human cells and inject those pieces of RNA inside of those cells), and attempt to get the human cells to then manufacture those specific proteins and export them either to their cell surfaces or secrete them into the blood. The hope is that the immune system will respond to these foreign proteins and generate a response that will be protective against a virus challenge.
WHAT TAKES SO MUCH TIME IN BRINGING A VACCINE TO MARKET?
The first step once the RNA pieces are made is to try the new vector in animal models to see if they generate an immune response. If they do, then you can move on to human trials. BUT, in order to do this, you need to have an animal model that you can use to test the vaccine. The first issue here is that you need an animal host that can be infected by the virus in order to test whether the vaccine can generate an immune response that can protect the animal from the virus. Sometimes this is mice or rats, sometimes it may be necessary to use primates like monkeys.
If you want to challenge the animal model with the virus, you need to have virus to challenge the animal. This is the second problem you need to solve; you need to develop a way to grow the virus in the lab, recover it, store it and deliver it to the animal.
In some cases you may not be able to infect the animal with the disease, but you may be able to generate an immune response, and the antibodies produced by the animal may be tested in tissue culture to see if they can prevent infection of human cells in the laboratory model.
If you have succeeded in the lab, demonstrating that the vaccine is capable of generating a protective immune response in the animal model, you can move to human trials.
All of these laboratory steps prior to initiating human trials take time.
HUMAN TRIALS
The first set of trials is to give the new “vaccine” to volunteer subjects in very small doses to make sure that the vaccine itself does not cause any type of adverse event.
Anytime you put something new into an individual you can’t be sure that the new vaccine, or the protein that is produced won’t cause some medical problem that you could not have predicted. For example, let’s say you have made a new plasmid (the new vaccine vehicle that is used to get the piece of RNA into a cell) for the spike protein of COVID-19. Maybe that protein, coded for in the new vaccine, is released into the blood with the hope that it will generate an immune response. Perhaps, and we won’t know until the test is done, that protein binds to lots of ACE2 proteins on cells, disrupting the normal metabolic pathways of the person, resulting in unforeseen problems like a sudden drop in blood pressure, or liver or kidney malfunction. Until you can be sure that administering the vaccine is safe, you can’t move to trials in larger numbers of people. Not only is it dangerous, but it is poor medicine and poor science.
Once safety is established, then you need to find out if the new vaccine can actually generate an immune response, and that the response generated is protective against the viral infection. This is a difficult thing to do. You need to be able to recruit volunteer subjects from a population that can provide results that you can analyze. For example, in this case you want to be able to vaccinate a group of people who WILL be exposed to the virus in the coming weeks. You then need to follow them very closely to determine if they are infected – if they show no virus, but generate an immune response; and, at the same time, you need to have a group receiving injections without vaccine, a “control” group, to allow you to see if the vaccine results are significantly different than the results of the population without vaccine.
In the case of COVID-19 this is particularly problematic since we believe that as much as 80% of infected individuals show no signs of disease. Think for a moment about your study with a vaccine. You inject a group of people and then a few weeks later, you see an immune response and no infection. Sounds great, no? Well what if a similar group of people, who were not vaccinated contracted the virus, were asymptomatic and generated an immune response. How can you tell whether the group of vaccinated people were truly protected from infection, or were just identical to the group who were not vaccinated? This is the reason that continual testing for BOTH the presence of virus, the vital signs and the presence of antibodies is so important.
At the same time, you need to find out how much vaccine is necessary to give to a person so that they develop a strong immune response. Do you need to give them 2 ml. of vaccine? 5 ml.? 10 ml.? Can you generate a good strong protective response? Sometimes you need to give 2 separate vaccinations, a couple of weeks apart or even a couple of months apart. Those of you who have gotten the new Shingles vaccine know that there are 2 injections needed, 2 months apart.
Finally, after you have significant demonstrable results from these trials, THEN you can move to trials on large groups of people. These are the trials that will show any potential side effects, health problems and “co-morbidities”. Only when you have a large enough population to study will you be able to detect these side effects in a fraction of that population. They will also allow you to determine how long the antibody lasts, how effective it is over time and whether reinfections are possible.
Unfortunately, there are no shortcuts here. If you move too quickly, you risk endangering the health and safety of large numbers of people. If you move too slowly you miss the window of opportunity to treat the disease.
This is the reason that self-isolation at this point is so critically important. If we can reduce the number of infections, the number of trips to hospitals, the number of ICU beds needed, etc., we can generate the time necessary to complete the vaccine trials. As I have said before, there is no guarantee that a vaccine will work. I am very hopeful that there will be one. It may not be 100% effective, or even 50% effective; it may not be totally protective but may reduce the severity of the disease. In either case it will give us enough breathing room (pun intended), to control this disease.
In the meantime, I remain hopeful that some of the therapeutic trials underway will yield useful results. I am particularly optimistic about the trials using the plasma from recovered patients to treat those who are ill, although these types of treatments may result in other potential health issues because of potential things brought along other than the antibodies (more on that some other time). Many other potential treatments are being tried including Remdesivir and some of the ACE2 inhibitors and ARBs. I am distressed about the push to use hydroxy-chloroquine, and I have laid out my reasoning before.
The issues of therapeutic treatments, in my opinion, will primarily center around the timing of the use. Some of these potential agents will only work at early stages of infection. Once the mucosal cells and the bronchia are damaged, inhibiting the virus will have much less effect. The cells will need to be regenerated and replaced before the patient can recover. I have said before, and restate again here, we need to be testing the patients with the earliest signs of disease in order to begin treatments; currently we are prohibiting those patients from getting tests unless they are the spouse or housemate of the seriously ill patient.
I pray in this season of reflection, that you and your family remain safe, healthy and supportive of each other.