Ofer Levy
Subject: The Future of Vaccines
Bio: Professor of Pediatrics at Harvard Medical School and the Director of Precision Vaccines at Boston Children’s Hospital
Transcript:
Larry Bernstein:
Welcome to What Happens Next.
My name is Larry Bernstein. What Happens Next is a podcast which covers economics, politics, and culture.
Today’s topic is the Future of Vaccines. Our speaker is my good friend Ofer Levy who is a Professor of Pediatrics at Harvard Medical School and the Director of Precision Vaccines at Boston Children’s Hospital.
We will discuss the current controversy over vaccines that has escalated since COVID.
I am also including excerpts from a previous podcast with Paul Mango who ran Operation Warp Speed for Trump in his first administration that successfully got a working vaccine for COVID in record time.
Ofer, can you please begin with six minutes of opening remarks.
Ofer Levy:
I've prepared some comments today and wanted to give a shout out to my colleague, Dr. Christine Ben of Southern Denmark University, with whom I've been discussing this crucial topic of late in the words of the prominent vaccinologist, Dr. Stanley Plotkin. It is hard to overstate the beneficial impact of vaccines. Other than clean drinking water, vaccines are the most effective approach to improve public health. The smallpox vaccine eradicated a disease that caused significant mortality and left survivors scarred for life. Common severe childhood diseases such as measles and bacterial meningitis have all but disappeared since the introduction of vaccines. However, vaccines have become increasingly controversial. During the pandemic, the public was exposed to conflicting information. Predictably, vaccine confidence is declining. Public discourse has become more politicized. This was notable from contentious discussions at recent CDC vaccine advisory meetings where people were arguing equally fervently that children would be severely harmed from receiving or from not receiving vaccines.
The recent decision to eliminate vaccine mandates in Florida and in the heated debate in the recent Senate hearing with a Health and Human Service Secretary RFK Jr., the debate has become oversimplified. Are vaccines good or bad? While vaccines have overall provided enormous public health benefits, the answer is context specific, which vaccine, for what purpose, and for whom. To paraphrase the new CDC vaccine committee chair Dr. Martin Kulldorff, believing that all vaccines should be given to everyone is as extreme as believing that no vaccines should be given to anyone. Although they might not express it openly, most people intuitively know this to be the case.
Some vaccines provide greater benefit than others. For example, smallpox and measles vaccines are nearly 100% effective and can protect from diseases causing great morbidity and mortality, whereas other vaccines are helpful but have much less on overall mortality due to the limited mortality rate of the corresponding infection.
Furthermore, subpopulations have different benefit/risk balance from vaccines. Elder individuals are at a much higher risk of severe COVID than younger individuals and have much more to gain from vaccination. In young males, the risk of severe COVID has been low and COVID vaccination has been associated with an increased risk of heart inflammation called myocarditis, resulting in a much lower benefit/risk ratio.
Women generally mount greater immune responses to vaccines than men and suffer more adverse reactions. Immunocompromised people with weak immune systems who have a high risk of severe infection may especially benefit from some vaccines, but may be harmed by certain live vaccines that can cause vaccine derived infection. Controversy persists with regards to COVID-19 vaccination of pregnant women and healthy individuals younger than 65.
Much remains to be learned regarding optimal immunization practices. Countries have made different decisions with respect to which vaccines to include as well as their timing and sequence. For example, the U.S. recommends Hepatitis B vaccine at birth, while most European countries reserve this for high-risk populations.
Unfortunately, the public controversy surrounding vaccines has harmed scientific discourse. The new U.S. Federal Drugs Administration has emphasized vaccine safety and has appointed experts perceived to be vaccine critical to study controversial questions such as links of vaccine components such as ethylmercury with allergy and autism. This has prompted outrage from established vaccinologists.
There appears to be little discussion between these camps with a field becoming increasingly polarized. Each side has its blind spots, one downplaying safety concerns and the other minimizing the vast public health benefits vaccines provide. Consensus is breaking down and vaccine science risks losing the fertile middle ground for open data-based scientific discussion.
Fortunately, there is a path forward that is evidence-based increasing the nuanced understanding of vaccines, and eventually informed vaccination programs optimized to subpopulations that vary in vaccine responses.
To move forward, we need to have an open, honest, and challenging discussion about where current gaps in knowledge exist. While a given vaccine may be promising from the standpoint of protection against a target disease, it is also important to assess its overall effects on overall health.
Any given vaccine may work well in isolation, but we must consider interactions with other vaccines and potential differential effects across subpopulations. We should study vaccine safety and overall health effects of vaccines, welcome questions, and be open to changes in how we discover, develop, and evaluate vaccines. However, we should not tarnish confidence in well-established vaccines that save countless lives. It will be challenging to build consensus, but for our collective public health, this is the only path forward.
Larry Bernstein:
How did we get to this polarized place on vaccines? It started before COVID. I remember in the 2016 Republican presidential primary debate that Trump highlighted the benefits of vaccines and the crowd and some of his Republican opponents took him on. Trump said, I'm open to hearing both sides on this issue. Why was vaccine hesitancy already a hot topic in 2016?
Ofer Levy:
We have a very good process in the United States to evaluate vaccine safety and efficacy through the FDA. We don't have a perfect process. There are rare individuals who do get harmed from a vaccine. For example, if somebody is immunocompromised receives a live vaccine, that live vaccine can replicate in their body and cause severe disease. I've taken care of patients like that in the hospital. It's rare, but it happens.
Vaccines often get blamed for things when they're not causing harm because everybody gets a vaccine, and then bad things happen in life. And then you can have a post hoc fallacy of logic. Diseases that maybe had nothing to do with a vaccine might get blamed on the vaccine.
Larry Bernstein:
Tell us about the scientific evidence of the relationship between autism and vaccines.
Ofer Levy:
Years ago there was an article in Lancet published by a scientist called Dr. Wakefield that claimed that there was a link between vaccines and development of autism in children. This made a huge splash. Subsequently the findings were found to be flawed, and the paper was retracted. And many subsequent studies have shown that there is no link between vaccines and autism. I reserve the right to change my mind if reliable data shows something different. But everything I've seen has debunked any connection between vaccines and autism.
Larry Bernstein:
In the RFK testimony, one of the topics was the number of vaccines that children receive. 76 was mentioned. I did not receive 76 vaccinations when I was a child. Why has there been a surge?
Ofer Levy:
We have a large and diverse country also socioeconomically also with respect to the infections that threaten our children. Bacterial meningitis infections that we used to worry about when I was a resident training in Bellevue Hospital that we would see that now I don't see anymore because there's a vaccine against pneumococcal meningitis against Hemophilus Meningitis. We rarely see these conditions anymore because the vaccines are so effective. The number of jabs it's not 76 different vaccines. You require multiple doses until you're protected. Diphtheria, tetanus, doesn't protect with a single dose.
Larry Bernstein:
Why is it important to break up a vaccine into multiple boosters?
Ofer Levy:
Because you have an anamnestic response. Your first response to the first shot of a vaccine is often on the weak side, but then you boost it when you get another dose, you now amplify the immune response, the T-cells and the antibodies.
Larry Bernstein:
Florida recently said that we're going to give parents choice instead of mandates. How do you feel about delegating authority away from the state to the parent?
Ofer Levy:
In a perfect world, that would be great. Who wants mandates, right? Everybody would like to choose what's going in their body. It's certainly an American notion of autonomy and libertarianism. And at the same time, each person’s decision impacts everybody else around them. Having large measles outbreaks, that's a threat not only to that child, but to that child's family.
There are examples of countries in the world, a few that don't mandate vaccines that includes Iceland. They have a very high coverage rate.
In the U.S., we're so polarized. Communication has broken down. If you delegate, the downside of that approach is big drops in coverage and outbreaks.
Larry Bernstein:
There was this concept about herd immunity originally for the COVID vaccines, but then there was a realization that you would still get COVID with the vaccine. You wouldn't get as sick, but you could still transmit it just the same with the vaccine. And people thought it was irresponsible not to take the vaccine.
Ofer Levy:
We can all agree the pandemic had a very profound effect on vaccine attitudes. The public messaging was often unclear.
If you're getting the vaccine, why are you still getting infected? The point is that for high-risk individuals, that vaccine was lifesaving because it prevented upper respiratory infection with COVID, runny nose, sore throat, cough from becoming lower respiratory tract pneumonia, putting you in the ICU or death. That's the main deliverable with that vaccine. Impact on transmission is modest, probably some benefit, but by no means does it guarantee you don't spread it to somebody else. If you have a vaccine that's not doing much in preventing spread. The bioethical argument of mandating becomes questionable. In my view, it was a mistake at the time to mandate that vaccine to any population. US military and some other federal agencies mandated, I think in retrospect that was a mistake.
Larry Bernstein:
Your personal scientific research relates to improving the efficacy of vaccines for the elderly. Tell us about that.
Ofer Levy:
It's important to start with a Greek philosopher Heraclitus of Ephesus who said, the only constant thing in life is change. From the moment we are born to the moment we die, the only constant thing in life is change. And the immune system is no different. The immune system of a newborn is very distinct from that of a healthy middle-aged individual. And then the immune system of an elder 80 years old is very different from that of a middle-age individual. In fact, of any demographic feature, including sex, where you live, what you eat, age is the overriding factor that has the largest impact on your immune system, your defense against infection, your response to vaccines.
Now, if we look across all infectious diseases, COVID, bacterial, viral, fungal, parasitic, these do not hit randomly in a population. Infections hit hardest in the very young and in elders. The immune system is weaker early and late in life.
The philosophy for our precision vaccines program is the better we understand the cellular molecular basis for the distinct immune system in babies and elders, we can use that information to build vaccines tailored to those groups to be optimally safe and effective in those groups.
Larry Bernstein:
Take the flu vaccine. There's different vaccines for people who are elderly, but there's a discontinuity in the age. For example, if you're over 65, then you get vaccine one. If you're under 65, you get vaccine two. As someone who's 58, how should I think about these decisions?
Ofer Levy:
It's not one vaccine for all. Age is an important factor in how your body will respond to a vaccine and a vaccine that might be optimal for an infant might not be optimal for an elder and vice versa. ‘
There's an infant vaccine schedule. The CDC website has a nice table for that. And then there's a table for what vaccines elders should receive. In the future, we're going to get even more sophisticated around this as we apply precision medicine principles to vaccinology. We're moving towards modeling human responses, not just to vaccines, to all drugs outside the body and use of big data approaches and artificial intelligence.
Larry Bernstein:
How can we regain public confidence in vaccine?
Ofer Levy:
CDC estimates that in the past 20 years for U.S. children alone, vaccines will have prevented about three quarters of a million deaths and millions of hospitalizations.
There was a study done by a group of economists together with vaccinologists published in a prominent Journal of Science Translational Medicine during the pandemic. The Warp Speed initiative cost about 12.5 billion dollars. Sounds like a lot of money, but if you consider, had a safe and effective COVID vaccine been released 12 hours sooner, the benefit in reopening the global economy financially would've covered the entire cost of the Warp Speed initiative.
It was a tremendous success, very impressive and unprecedented. The only feedback I would have is it seems like not much thought was given how to scale availability of the vaccine globally.
Larry Bernstein:
We met when you started dating Sharon. Your wife was a college friend of mine and we became friends.
Ofer Levy:
I married Sharon Levy who studied medicine with me at New York University School of Medicine in Manhattan. Sharon and I lived on East 13th Street between Second and Third Avenue. Man, did it look different back then? I remember what a pleasure it was to meet all of Sharon's friends from UPenn, including Larry. At some point you lived on 14th Street.
Larry Bernstein:
Exactly. Let's talk about your journey.
Ofer Levy:
My father never graduated from high school. He was a truant in Israel. He was half Yemeni, half Sephardi, a Jewish boy in Tel Aviv in British Mandated Palestine, the 10th of 11 brothers and sisters.
Larry Bernstein:
Did he come over on Operation Magic Carpet when the Israelis airlifted the entire Jewish population living in Yemen to Israel around 1950?
Ofer Levy:
No. My grandfather, who was Yemeni had very dark skin, spoke Arabic as his first language became an orphan at age 15 because both of his parents had died of tuberculosis. Back then in Yemen, if you were an orphan, you needed to convert to Islam, and he didn't want to do that.
He was told if you go to Palestine, the Ottomans, if you pay your taxes, you can have whatever religion you want. So, his 8-year-old sister on his back, they walked through the desert two years by foot up through North Africa, up the Gaza coast. Jaffa port was there. Tel Aviv was just sand dunes. My grandfather built one of the first homes in the Yemeni quarter in Tel Aviv. And my father and his siblings were born and raised there.
Most Israelis know the Yemeni quarter is where you go to have good spicy food in the Carmel market. My father got in trouble in grade school because he liked to draw, His parents sent him to a boarding school when he was nine years old, a very beautiful location, an hour from Tel Aviv. The headmaster of that school, Moro said, Benjamin, keep drawing one day, you will be a great artist.
My dad became a highly successful artist, self-taught, oil paintings, lithographs, etchings. Spent a year in Paris and then back to Israel to marry my mom, who's a musician and composer. They moved to New York City in 1965 because the center of the art world was shifting from Paris to New York. 1966 I was born in the US so they could overstay their student visa and the rest is history.
Larry Bernstein:
Tell us why you went into vaccines.
Ofer Levy:
I always was interested in science. My mother's side of the family is Dutch. My maternal grandfather was a geologist. When he escaped the Netherlands during the Holocaust, my grandfather was immediately welcomed by the British to do the first detailed mapping of the State of Israel. The first topographic maps with the mountain ranges, concentric circles, proportional to the altitude. He won the National Science Award in Israel for that work. I brought together those interests, became a physician scientist.
And then when I did my rotations and I was in the neonatal intensive care unit, they'd say, the preterm babies got to be careful. They’re susceptible to infection. And I'd asked why? We're not sure, but they get lot of infections. That seems like something important to study. I was fascinated with infectious diseases and the difference of immune system with age. And then some of my experiments indicated that certain molecules boost immunity adjuvants in early life and then that has a potential application to build better pediatric vaccines. We moved to Boston Children's Hospital from Manhattan, Sharon, to pursue her career in substance use research in children and myself in infectious diseases and vaccines.
Larry Bernstein:
I end each podcast on a note of optimism. What are you optimistic about as it relates to your field of vaccines?
Ofer Levy:
I'm optimistic that 50 years from now, we will benefit from technological improvements to make vaccines that are safer, even more effective. It just makes sense to prevent disease rather than to react to it. I don't minimize the challenges we face. But in the long run we will all benefit from this.
Larry Bernstein:
Thanks to Ofer for joining us. I would now like provide some excerpts from a previous podcast with Paul Mango who ran Operation Warp Speed. Paul, can you please begin with six minutes of opening remarks.
Paul Mango:
I wrote Warp Speed for two reasons. One is the whole vaccine effort occurred during a presidential election year. And the success of Operation Warp Speed got buried because the media was focused on the campaign. Anything that was going well wasn't going to be talked about in the media, particularly if it was the incumbent president.
The second reason was because there's a lot of lessons to be learned from what we did well and what we would do differently. It's important for government policy makers, for the American people, for private industry, to understand how this happened.
The previous best time for bringing a vaccine to market was four and a half years. And the Operation Warp Speed did it in 10 months.
Why was it successful? Five reasons I talk about in the book. One is private industry invested in technology called messenger RNA. It was a technology platform that had never been used to develop vaccines, but it was available to us, and we took a shot at it. We invested a couple billion dollars in it and it worked.
The second reason was that we had a principle that said, do not permit the federal government to do anything that the private sector can do better.
The third reason was we had Secretary Alex Azar who was 10 years in the pharmaceutical industry, and he understood what the pharmaceutical industry would do and not do. And he understood that they wouldn't start manufacturing vaccines in a normal course if they didn't get FDA approval. So, we did in parallel things that were typically done in series, and we started manufacturing vaccines long before the FDA approved anything.
The fourth reason was Moncef Slaoui, who was our chief scientific advisor, had a venture capital mindset. He said, we're going to invest in six different vaccines across three different technology platforms. We only need one to win.
The very last reason was just a management philosophy that permitted experts rather than people with lofty titles to do what was necessary to get the job done.
What would we have done differently if we could do it over again? I think we failed miserably at communicating with the American people about how safe and effective these vaccines were. What we could have talked about was the standards we raised for these clinical trials — 50% more participants and a longer interval between the time people got their injections and the time we evaluated them for any type of adverse reaction. So, these were higher standards than was ever used before.
Larry Bernstein:
Let’s go over the venture capital mindset.
Paul Mango:
Steve Mnuchin said, every day the economy's running at half speed, I lose $6-7 billion of tax revenue. Whatever it takes to get these vaccines out as quickly as possible, my guess is it'll be worth it. We're also saving lives.
We brought in private sector leaders Moncef Slaoui was the most successful vaccine developer of our generation. He understood our mission, which was to have at least one safe and effective vaccine manufactured at scale before the end of 2020. He set it up in a way where we had three different technology platforms with two vaccine candidates in each one. It worked. We had three successful vaccines across two platforms.
After he chose the six vaccines, we asked experts independently what they thought the probabilities were that we had a 75% chance of having at least one of those six safe and effective manufactured at scale, and a 32% chance of having two or more and less than 10% chance of having three or more.
Larry Bernstein:
Why limit yourself to six vaccines?
Paul Mango:
it was about the logistics getting a minimum of 30,000 persons through each clinical trial acquiring syringes and needles every clinical trial site could only handle one vaccine type. we contemplated a seventh one. the probability we'd have at least one good vaccine before year end was 75%, adding a seventh one took it up only to about 77.5%. Each additional vaccine candidate, if it only adds a couple hundred basis points, but it adds tremendous complexity, we thought that was not a good trade off. The money wasn't the rate limiting factor at all. It was the logistical complexity.
Larry Bernstein:
At the outset when there was limited vaccine supply, why not try to get as much single dose out to the public?
Paul Mango:
You're exactly right. But we didn't know. Unfortunately, the 95% effectiveness that came out of the phase three clinical trials were all based on taking two doses. Maybe optimally, you give the first dose and then three months later, you give the second dose. We wanted to get through the clinical trials quickly.
Larry Bernstein:
Why did you decide that you had to live by the clinical trial results?
Paul Mango:
Because the FDA had laid out those standards Peter Marksis the head of the what's called the center for biomedical evaluation and research, which is the center within the FDA was absolutely committed to making sure not a single quality standard was compromised. The minimum effectiveness was 50%. The vaccines wound up significantly higher than that. The standards of evaluation weren't diminished.
Larry Bernstein:
Hypothetically, Pfizer said I can give you a million vaccines doses on October 15, 2020. What do you do?
Paul Mango:
I would not use them. The case fatality rate is about 0.3%. If you're going to be vaccinating 280 million Americans, you better be sure that vaccine doesn't have anything wrong with it. if there was something wrong and you had gone ahead and given it to millions of healthy individuals, you would've done more harm than good.
Larry Bernstein:
The Moderna vaccine was 95% efficacious. We had Ofer Levy on a previous episode of this podcast. Ofer told us that the typical flu vaccine is like 75% efficacious for kids and only 35% for 65 and older. You shoot that vaccine into a kid; the immune system response is incredible. And you stick it to an old guy, and nothing happens.
Now, when you say the flu vaccine is 55% efficacious for the flu, we normally say that means that there’s a 55% chance that you do not get sick from the flu. We don't say it's a 55% chance of not being hospitalized from the flu.
You talk about 95% efficacious for, let's say the Pfizer vaccine, you didn't say there's not a 95% that you don't get COVID, but merely that it's 95% chance that you don't get hospitalized from COVID. There was a lot of confusion when all of a sudden you take the vaccine and then you get COVID.
Paul Mango:
The formal scientific term is the primary endpoint of the clinical trial. For COVID vaccines, the primary endpoint was not infection. It was serious illness, hospitalization or death. from a public health perspective, it makes a big difference because people thought that, if I'm vaccinated, I can't transmit this virus.
Well, that was never true. we knew that you could be infected and have zero symptoms. it would've been almost a constant daily monitoring, that’s why it's much easier to monitor serious illness, hospitalization, and death.
Larry Bernstein:
The Federal Government funded the manufacturing of vaccines before they knew it worked. What happened?
Paul Mango:
Secretary Alex Azar understood what risks the pharmaceutical industry would take independently and which ones the federal government needed to assume. It made a lot of economic sense for us to assume that risk. we must start manufacturing right away.
Larry Bernstein:
What do you make of the nurse’s vaccine hesitancy?
Paul Mango:
This was one of the more perplexing things that public health leaders encountered when 30% of frontline healthcare workers did not want the vaccine.
Larry Bernstein:
Why not do first come, first serve. It is a logistical nightmare to get the vaccines to specific populations. I'll see you at Veterans Stadium in Philadelphia parking lots. We're going 24-7. Let's go.
Paul Mango:
The impact of COVID on individuals was tremendously asymmetric. I'd want to at least offer the limited vaccine supply to those who are most vulnerable first.
Larry Bernstein:
Should public health consider life-years saved?
Paul Mango:
I don't think it's the ethos of the United States. The ethos of American medicine is heroic intervention. Do what you absolutely have to do to save a life.
Larry Bernstein:
What are you optimistic about?
Paul Mango:
I'm very optimistic that the federal government and America's private sector have the ability and the innovative spirit to respond. No one else in the world could do what we did in such a short period of time. And despite all the political divisions the result was spectacular. The America I saw was very patriotic, committed, capable, innovative, entrepreneurial, and caring. This is an uplifting story about American exceptionalism.
Larry Bernstein:
Thanks to Ofer and Paul for joining us.
If you missed the last podcast, the topic was Persuading Younger Women to have More Children. Our speaker was Wolfgang Lutz who is a Professor of Demographics at the University of Vienna.
We discussed the role of education and increasing human capital and its relation to the delay in childbirth and decline in total fertility.
I would now like to make a plug for next week’s podcast. The topic is Don’t Damn the Dams.
Our speaker will be Patrick Allitt who is a Professor of History at Emory. Patrick has a new course coming out with the Teaching Company on the great rivers of the world. I hope to learn about the history of dams and why they were critical for the growth and financial success of the Western United States.
Patrick will be followed by Darren Schwartz who is the What Happens Next Culture Critic and we will discuss two classic films on rivers and dams: Deliverance and Chinatown.
You can find our previous episodes and transcripts on our website
whathappensnextin6minutes.com. Please follow us on Apple Podcasts or Spotify. Thank you for joining us today, goodbye.
Check out our previous episode, Persuading Younger Women to Have More Children, here.
