The University of Michigan is encouraging all of its students to receive the COVID-19 vaccine before returning to campus, but many young people are hesitant to take it. The Michigan Review’s editors believe that vaccination is the safest, most effective way to protect our campus community.
The Michigan Review sat down with Dr. Louis Saravolatz, an infectious disease specialist and Principal Investigator of the trials for Inovio Pharmaceuticals’ COVID-19 vaccine at Ascension St. John Hospital in Detroit, where he serves as Chief of Medicine. Dr. Saravolatz is also a Michigan alumnus, having completed both his undergraduate work and medical school in Ann Arbor.
Suffice it to say, he knows what he’s talking about. Here are Dr. Saravolatz’s answers to your questions about the COVID-19 vaccine:
Michigan Review: Can you speak to how much the vaccines have been tested and what processes they need to go through to get approved? What brought the COVID-19 vaccine to widespread use so quickly?
Dr. Saravolatz: There are 3 phases of clinical research that must be performed prior to FDA approval. Phase 1 which involves dose finding and generally involves less than 100 patients. Phase 2 trial is a study looking at safety and efficacy frequently between 100-600 patients. Phase 3 is also looking at safety but establishes efficacy. The phase 2 trial is too small to establish efficacy. I would emphasize that all 3 phases emphasized the importance of safety. In the area of coronavirus research this has been done in what is called telescoping of trials. They have combined phases 1 and 2 and sometimes 2 and 3 to answer questions. There is careful monitoring that occurs in all of these phases with early phases having more frequent monitoring. As you might expect if events occur at a very low frequency like one in 100,000 they may not be picked up in the 3 phases. This leads to the FDA conducting post-marketing surveillance. This is the case in the case with the FDA and CDC continuing to monitor adverse events associated with the vaccines. Remember the vaccines have been given to over 160 million people who are fully vaccinated at this time with Michigan having 4.8 million or 48.1% fully vaccinated.
Remember efficacy is determined by confirmed coronavirus infections, hospitalizations and deaths. Thus, if the disease is prevalent in the community the question of efficacy can be answered quicker as was the case with the Pfizer and Moderna vaccines.
MR: How do the vaccines work? Do they create immunity to the coronavirus, or do they bolster the body’s ability to fight the infection without serious side effects? Or is it something else?
DS: There are 3 platforms for vaccine development. In terms of the Moderna, Pfizer and Inovio vaccines these are all nucleic acid-based platforms. Moderna and Pfizer being RNA vaccines and Inovio being a DNA vaccine. The advantage of this is that you are giving a noninfectious vaccine to the recipient. The RNA or DNA are formulated to be taken up by cells and they are at a map that encodes for the spike protein (the target for antibody production) This mechanism permits the individual cells to start producing spike protein and the recipient will produce their own antibody against it. Thus, creating immunity or bolstering the body’s ability to fight the infection. Although these are the first vaccines to actually use the platform there have been multiple human clinical trials that have been initiated and preclinical data over the past several years. The second platform is a traditional viral transport vector for the spike protein. This includes vaccines such as the Johnson & Johnson vaccine, AstraZeneca (Oxford) vaccines. This has been a very good vaccine with about an 85% efficacy which is very good but not as good at the 95% for the Moderna or Pfizer vaccines. The third platform for the vaccine is administering the spike protein. This platform has not had as good result based upon the Australian experience. Nonetheless, it is the same platform that we use for the Hepatitis B vaccine which is a very effective vaccine.
MR: What are the risks of getting side effects (e.g. blood clots, inflammation, etc.) from the vaccines, and how do they compare to the risks of getting lingering symptoms from COVID-19? How do the fatality rates of the side effects compare to the fatality rates of COVID-19?
DS: The risk of blood clots from COVID-19 is at least 10 fold greater than the risk of getting it from the vaccine. In early experience in New York City the risk of blood clots with COVID-19 was up to 30%. The risk of blood clots from the vaccine Is much lower. The early experience at the CDC which is probably incomplete was only 35 cases reported out of the 12.5 million who first receive the vaccine. The risk is about 10 per million which is considered extremely rare.
The lingering symptoms of COVID after 6 months after infection are estimated to be about 8 to 10%. This is much higher than for other viral respiratory illnesses and certainly much higher than any of the vaccine-associated events. These lingering symptoms can be severe and associated with respiratory systems, nervous system, and cardiovascular disorders, musculoskeletal pain, and mental health problems.
MR: Why should college students get the vaccine given their much lower fatality rates from COVID-19 infections?
DS: While it is true that college-age students have a much lower fatality rate than older individuals, we have seen a dramatic shift in the age of COVID-19 patients from the first surge which was predominantly over the age of 6o. The most recent experience wh is predominantly under the age of 60. And then the question is what about the college-age students. We are seeing increasing numbers of people in their 20s and 30s. We also have university staff and faculty at university settings who will need to be protected and are at higher risk. Thus, one might conclude that just have the faculty vaccinated. This would be a consideration. However institutions, such as hospitals around the country where at least 14 systems to date are mandating COVID-19, have the added responsibility to make sure that they protect people who come in contact with their staff. Universities already require proof of vaccination for a number of infectious agents. Schools have done this for decades. We are fortunate to enjoy the benefit of the success of vaccine development in this country that is essentially preventing measles, chickenpox, diphtheria, pertussis, tetanus, hepatitis and polio from becoming serious and life-threatening illnesses for the young population. Thus, we enter into a question of public health versus individual freedoms. Certainly public health looks at the aggregate experience in terms of the greatest benefit for the health of the entire population. Individual freedom looks at your freedom of choice. I don’t need to remind you that our constitution does not provide us for having freedom of choice that would permit us to harm another person from an infectious agent that we might contract and spread This is well illustrated by tuberculosis for which courts and public health measures permit us to detain the person who has active tuberculosis who is not complying with treatment in order to make sure that they are not infecting others in the community. This is a cumbersome process to go through but it is a legal process. Similarly, requiring vaccinations for certain institutions is already well-established in the healthcare industry. It is also established at universities where vaccinations can be mandated for certain conditions. this is an area where people have strong opinions but I emphasize we live in a country that still has great public health that keeps us well.
MR: Very few people will dispute the morality of quarantining someone with an active infection of COVID-19 or another contagious disease like tuberculosis, but is there a distinction you make between someone who has an active infection and someone who is not vaccinated but without an active infection?
DS: There’s always a risk-benefit, and the relative risk for transmission. Let’s say, you’re working as a computer analyst, in front of a computer all day, and you have meetings by Zoom. Your ability to transmit it to other people based upon minimal social contact, in your work environment is minimal. But let’s say you were in the hospital here. Legally, we can inquire and obtain information about whether you’ve been vaccinated, and we can require vaccines for people who are not infected. Why? Because we know that they pose a greater risk to people who are susceptible and at great risk in the hospital environment. So 14 Health Systems United States have already mandated, we (Ascension) have not yet, but they’ve already mandated that you must take the COVID vaccine to work, including Henry Ford. We’re in the process of discussing that. But you’re right, there are relative degrees of risk. And so if the relative degrees of risk: Why should be mandated for everybody? Well, we’re a social people. You like to go to the grocery store, you like to go to Michigan football games, you like to go to a movie, like to interact with people at CVS. So in most environments, what is our obligation to protect people? We have a vaccine for Pasteurella pestis, which is the Bubonic plague. Well, we don’t mandate that for anyone in the United States, the risk is extremely low for transmission What we do mandate is for you to go to school, in Michigan, you have to have had measles, mumps, rubella, diphtheria, tetanus, pertussis, polio, you have to have all of those vaccines before you can go to school. Why? Because we know those are serious infectious agents that in fact, continue to pose a risk if we have a population that’s susceptible. The issue of who do we mandate it for and when do we cross the line of individual freedom? Well, I think that’s a political discussion. But I always look at it as a risk-benefit. We’ve eliminated smallpox vaccinations in this country. Why? Because people have that longer as smallpox. So there is no benefit. And there is some risk of having any medication injected into you. So we’ve eliminated that. We have not eliminated polio, in this country. When Jonas Salk worked on the polio vaccine, at the University of Michigan School of Public Health, they couldn’t get people to take the vaccine, because they were afraid. And there are people who hear something and that they want to offer protection to a friend or someone else and they go share that information Unfortunately, that information is not always accurate. So what did Jonas Salk do when he could not get people to participate in the vaccine trials? He went on national TV and vaccinated his two sons with the Salk vaccine. And Dr. Salk was an amazing, effective promoter of vaccines. After vaccinating his two sons on national TV, people started taking the vaccine so he could complete the trial showing the effectiveness of the Salk vaccine.
MR: What do you think the best marketing strategy is to get vaccine-hesitant young people to take the vaccine?
DS: I think you might have some better ideas than I do. But, certainly, the youth today is very knowledgeable and effectively utilizing electronic social media. So if we identified celebrities, athletic stars, people who have greater influence in young people’s minds. The more educated people, I would hope that they would rely on the science and appreciate the benefit of this safe vaccine. I actually agree with the Surgeon General. I saw a man in my office a week ago, the 77-year-old man said he didn’t want to take the vaccine. They said, why he said, he had a friend whose daughter had a miscarriage. I said, ‘you don’t have to worry about that yourself.’ Then he had another friend who had a history of seizures. And several months after getting the vaccine, he had a seizure, I said, ‘Well, he already had a history of seizures, that was unrelated to the vaccine.’ Now, any medication has some initial side effects. The most common side effects after you get the vaccine, you probably have a 20 to 30% chance that having a sore arm and feeling fatigued during the next day, which will go away after a day. Now, nobody wants to feel tired. No one wants a sore arm. But that’s the most common side effect. These other side effects are very, very infrequent, as I pointed out when you ask the question about thrombosis. Complications of thrombosis are much worse with getting COVID illness than getting the COVID vaccine.
MR: Why should people who have already had a case of COVID-19 still get the vaccine given their likely immunity to the virus?
DS: 50% lose their protection within 3 months. I have seen repeat cases of COVID 19 in patients.
MR: I think it’s pretty well-established that your antibody count certainly drops off after three months. But there were some studies that came out, suggesting that your T-cell immunity could last. Is that a possibility?
DS: Our immune system has both B-cell and T-cell responses. And for viruses, we rely on both of them for containment. So, yes, it is possible that that may happen. And we have a precedent with that with the Hepatitis B vaccine, in which your B-cell responses go down, but T-cell responses persist for longer. And we know that those are, in fact, different measurements and tests that are done. So that is a possibility. However, we can’t do widespread T-cell assessments to determine that. So as a consequence, we rely on B-cell responses determining what threshold to use, and, for the most part, that’s a pretty reasonable approach.
MR: How do the COVID-19 vaccines compare to those developed to fight SARS?
DS: Since 2004 there have been no known cases of SARS reported anywhere in the world. This containment occurred because of travel restrictions and careful infection prevention strategies. In addition the mortality rate for SARS when it first occurred was less than 10%. Only 8 people in the United States got SARS and none of them died. Thus the need for a vaccine was very short-lived. However, we should be able to use the same vaccine strategies as we have for COVID 19 for a SARS vaccine, should this epidemic emerge again.
MR: The University of Michigan, to name one example, requires students living in residence halls to be vaccinated, and many faculty are pushing for the requirement to be universal. In your opinion as a physician, is it medically ethical to mandate the vaccine given that it’s been authorized for emergency use and has not been fully approved yet?
DS: As this vaccine has been given to over 160 million people in our country, our knowledge of the safety of it far exceeds that of any other medication that is approved by the FDA. In general when medications are fully approved fewer than 5000 people have received the medication for chronic illnesses such as hypertension, diabetes and cardiovascular illnesses. The method of EUA emergency use authorization is a process whereby a more rapid turnaround time can be secured. The full approval requires that the FDA review reams of data regarding the effectiveness of the vaccine, its safety, and any issues related to manufacturing. This is an extremely labor-intensive process which I anticipate will be coming in the near future.
MR: Does the mRNA vaccine use or bear any similarity to HIV-1 envelope glycoprotein 160?
DS: The answer is no, it has no genetic or molecular or structural similarity to that. There have been reports of the spike protein in Australia, inducing an antibody that was similar to the antibodies against HIV. But then that vaccine has fallen, out of consideration. The mRNA codes for the spike protein, and the antibody induced by that does not have any relationship to the glycoprotein antibody. We have struggled with the HIV vaccine platform for now over 30 years, and we still cannot come up with an effective HIV vaccine, which is why it was miraculous utilizing the nucleic acid platforms which have been, in fact, under President Trump–and I will put this balance in for people to consider–under President Trump we had Project Warp Speed, which put in great resources, and developed relationships with industry. And the partnerships between industry and the government had been very effective and created a competitive yet successful environment. So you had Modern developed by the NIH, and you had the Pfizer vaccine developing on their own. They both came up with similar types of vaccines, and both very effective, and demonstrating a phenomenal efficacy of 95%, far beyond what we had hoped for. So the issue of vaccine development under President Trump had lots of resources to get industry to work in partnership with the government in vaccine development. So the success at that time was two great vaccines, which I would point out, both President and Mrs. Trump received, even after having been infected. But then the other issue is: distribution of the vaccine, which the Biden administration built upon the success of the development of the vaccine so people could get the vaccine. So we have two different parties, political parties engaged in this process, and each making a major contribution to the success of the vaccine program.
MR: What is your role in the development of Inovio’s vaccine? What is the procedure like for administering Inovio’s vaccine? When can people expect to be able to get it?
DS: I am the principal investigator for one of the sites for the phase 2 trial for the Inovio–4800 COVID-19 vaccine. There are approximately 500 patients enrolled in the phase 2 trial which has been going on now for approximately 7 months. The phase 3 trial which has just started has a sample size over 6000 subjects.
As the PI for the Ascension St. John site, it is my responsibility to monitor the participants to assure safety and there is strict adherence to the protocol. This phase is meticulously done looking at a variety of laboratory and clinical parameters to assure that the vaccine is not causing adverse events. But again if adverse events are occurring at a rate of less frequent than 1 out of 500 it is unlikely to be picked up during this phase.
The development of the Inovio vaccine will take longer than the first two because of fewer events occurring compared to the beginning of the epidemic. Also, participants will be harder to recruit because of the ability to receive the vaccine as opposed to participating in a placebo-controlled trial where you have a 50% chance of getting the vaccine.
The study is blinded so we do not know whether the patient is receiving the vaccine or a placebo. We will not receive results of this study until 12 months have occurred. However, there is a data safety monitoring committee (DSMC) that is looking at the results at defined intervals to see whether there are any adverse event signals or if there is any difference in terms of the efficacy in the 2 arms of the study. To avoid bias, this committee is composed of experts who are not doing the study and not working for the pharmaceutical industry.
The vaccine is given with a method called electroporation. The method enhances uptake of the vaccine into the muscle cells leading to a more robust antibody response. This approach has been used in animal models for a number of infectious agents including ZIKA, West Nile, and SARS coronavirus.
The obvious question is why do we need another vaccine when we already have the Pfizer, Moderna and J&J vaccines. At this point in time, only about 12% of the world population has received a coronavirus vaccine. In many countries, the rates are very low including South Africa 1.1% India 13.7%, Russia 12.2%, and Mexico 18.8% to name only a few. These countries which have limited resources will greatly benefit by an additional vaccine. The Inovio vaccine can stay at room temperature for a year and at regular refrigerator temperature for 5 years. The Pfizer vaccine must be stored at -70 degrees which is not available in most physician offices in the United States and must be utilized on the same day the vaccine vial is entered. Thus there is a need for a vaccine that is more portable and has better storage conditions to vaccinate large populations in underserved areas of the world.
MR: Can you give us one last “go get your vaccine” message, one final pitch before we sign off to wrap it up?
DS: I would just say three words. Don’t hesitate: vaccinate. That’s the mantra I’ve been advocating for. President Schlissel is a very knowledgeable scientist. I met him. I had him speak at a meeting–your dad was in attendance–a few years ago, shortly after his arrival. And I had him speak about translational medicine, and how the university is preparing for basic science to clinical medicine. And this was pre-COVID. So he is a thoughtful individual, in my opinion, and he listens, in my opinion. So that’s my interactions which, on a personal level have been, you know, having lunch and listening to him speak and talking to him shortly before his presentation. So the fact that the university is advocating for that, you’ve got so many balancing parts with faculty, graduate students, co-workers, residential students who live in crowded situations where they might be at risk. It is very, very complex. But this is an incredibly serious illness, which is afflicting young people, even children. Risk is lower compared to older people, but the risk is there and the risk for serious complications is there. So don’t hesitate: vaccinate.
Disclosure: This interview was conducted partially in written format and partially over the phone. Dr. Saravolatz is a colleague of both the mother and father of the author of this article, which accounts for references such as “your dad.”