5.13 — Vaccines: an injection of hope

Host Walter Isaacson and guests look at how the field of immunology came to be, and the story behind the vaccines that beat some of the world's deadliest diseases.
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In this episode:

  • Protecting Catherine the Great (0:00)
  • A safer path to immunization (3:52)
  • Polio prevention (7:30)
  • The Godfather of Vaccines (11:41)
  • The world's first cancer vaccine (16:08)
  • Finding a cure in the developing world (19:38)
  • Battling COVID-19 and cancer (24:56)

Vaccines have been in the news lately, for obvious reasons. mRNA vaccines might be a modern invention but using weaker versions of a disease in order to fight it has been around for quite some time. Trace the history of this medical practice on a new Trailblazers.

More about the technology and uses for vaccines:

  • Scientists have set malaria in their sights for a vaccine.
  • How, EXACTLY, does the mRNA COVID-19 vaccine work? The CDC has the details.
  • mRNA technology isn’t just for vaccines. Find out what else it could do.
  • Hear more about the science behind vaccines with Trailblazers episodes on genomics and CRISPR.

“It would be very much an information technology, a major transformation in how we think about making medicines.”

— Dr. Stephen Hoge, president of Moderna

Guest List

  • Michael Kinch founded and directs the Centers for Research Innovation in Biotechnology and Drug Development at Washington University in St Louis, which analyzes the development of new medicines. Dr. Kinch is also the author of the book “Between Hope and Fear: A History of Vaccines and Human Immunity.”
  • David Oshinsky is a professor of history at NYU and a professor of medicine at the NYU Grossman School of Medicine, is the author of numerous books, including “Polio: An American Story,” which won the Pulitzer Prize for History; and, most recently, “Bellevue: Three Centuries of Medicine and Mayhem at America’s Most Storied Hospital.”
  • Stanlkey Plotkin developed the rubella vaccine now in standard use throughout the world, is codeveloper of the pentavalent rotavirus vaccine, and has worked extensively on the development and application of other vaccines including anthrax, oral polio, rabies, varicella, and cytomegalovirus.
  • Ian Frazer is a clinician scientist, trained as a clinical immunologist in Scotland. He is recognised as co-inventor of the technology enabling the HPV vaccines, currently used worldwide to help prevent cervical cancer.
  • Heinz Feldmann is the Chief of the Laboratory of Neurology at the National Institute of Allergies and Infectious Disease and one of the researchers responsible for developing what is today the most widely recognized Ebola virus vaccine.
  • Stephen Hoge serves as the President of the America pharmaceutical and biotech company Moderna. Moderna is an industry leader in the production of messenger RNA vaccines and was the second company in America to get approval for a mRNA COVID vaccine.

Walter Isaacson:

It’s October 12th, 1768. And Russia’s Catherine the Great is that the Imperial Palace in St. Petersburg. The Empress is nervous. And so is an English doctor named Thomas Dimsdale. He’s been brought to Russia to perform a risky and unusual procedure. A smallpox epidemic has infiltrated the Russian kingdom and killed 20,000 of her Siberian subjects. So Catherine, a great advocate of science and technology, has beckoned Dimsdale and volunteered to undergo a new treatment. She hopes it will not only prevent her from contracting the deadly disease, but also inspire trust in modern medicine. Dimsdale cut small slices in Catherine’s arm, and then grinds some pustules containing the smallpox virus into her wound. What could possibly go wrong?

Walter Isaacson:

Well, for one thing, the Empress could wind up getting smallpox, a disease that at the time killed about a third of everyone who contracted it. And even if Catherine survives, she might end up like most smallpox survivors, pockmarked and disfigured for life.

Walter Isaacson:

The procedure is called variolation. The idea is as simple as it is bizarre. Intentionally infect a healthy person with a weakened version of a pathogen so that person can develop an immunity to the pathogen. He’s performed the procedure thousands of times, but it’s always risky. Inject too much of the virus and a healthy person could become very ill. Inject too little, and the body would fail to develop the desired immunity. Dimsdale is so nervous about performing this procedure on the Empress that he secretly arranged a stagecoach to rush him out of St. Petersburg in case things don’t go as planned.

Walter Isaacson:

Luckily, the treatment is a success. Catherine develops a mild case of smallpox and has a full recovery in two weeks.

Walter Isaacson:

Since that evening in Russia, smallpox has been eradicated, and vaccines have saved millions of lives. And today vaccines against the COVID-19 virus are quickly turning the tide against a pandemic that threatened to bring the world to its knees. The idea behind what Thomas Dimsdale did 250 years ago, infect the body in order to save it, might sound counterintuitive, but it’s the foundation upon which vaccines have been built ever since. But recent advancements in vaccine technology might just change the way we fight disease forever.

Walter Isaacson:

I’m Walter Isaacson, and you’re listening to Trailblazers, an original podcast from Dell Technologies.

Speaker 2:

You’re now inoculated. Isn’t that great?

Speaker 3:

In vaccination, a substance called a vaccine is introduced into the body.

Speaker 4:

Medical science has almost wiped out the serious diseases.

Speaker 3:

Tiny particles called antibodies are being produced and poured into his bloodstream.

Speaker 5:

The enemy of man is now ready to become his servant.

Walter Isaacson:

Fortunately, at around the same time as Dimsdale was treating Catherine the Great, a safer path to immunization was being popularized by an English doctor named Edward Jenner. It involved a disease called cowpox, which was similar to smallpox but much less dangerous.

Michael Kinch:

And this cowpox disease was uniquely found at a high level in milkmaids.

Walter Isaacson:

This is Michael Kent. He’s the author of the book Between Hope and Fear, A History of Vaccines and Human Immunity.

Michael Kinch:

Now milkmaids in Europe were known for their beautiful skin. And the reason why they had beautiful skin is that it tended to not be pockmarked, scarred, by smallpox scars. So many people independently, about three or four of them at least, came to the realization that perhaps this cowpox disease, which the milkmaids got from the udders of the cows they were milking, and it was a minor disease on their hands and lower arms, perhaps this cowpox might protect against smallpox.

Walter Isaacson:

So instead of immunizing with the deadly smallpox virus, they began to use the cowpox virus.

Michael Kinch:

It turns out it was incredibly safe. Very few people, if any, died from cowpox, whereas many died from smallpox. And so that was the first vaccine. And actually vaccine is from the Latin word vaca for cow, and it reflects and really honors the fact that the first vaccine came from cows.

Walter Isaacson:

Word of a new procedure that was both safe and effective in preventing smallpox spread quickly throughout Europe and North America. By 1840 deaths from smallpox began a long decline that eventually led to its eradication in 1980.

Walter Isaacson:

But our understanding of how vaccines affected the body’s immune system was still very rudimentary. It wasn’t clear how people actually contracted diseases like smallpox. The prevailing wisdom was that it was caused by exposure to a bad gas known as miasma. That theory was challenged in the latter part of the 19th century by a group of scientists led by the great French researcher, Louis Pasteur.

Walter Isaacson:

He hypothesized that disease was actually caused by germs.

Michael Kinch:

What Pasteur realized was that there were these tiny little microscopic things that couldn’t be seen with the naked eye that were responsible for disease. He further realized that you could manipulate these organisms. You could either isolate them and kill them, or you could weaken them, what’s known as attenuation. And if you did that intentionally, and either killed the pathogen, or weakened it, something in the body would be triggered that would then prevent that organism from causing disease in the future.

Walter Isaacson:

This idea of attenuating, or weakening a virus, was a critical step on the road to creating vaccines that would eradicate a whole host of deadly diseases. It was the beginning of what is known as the age of immunology. But in the early years of the 20th century, a deadly new virus emerged that disproportionately attacked children.

David Oshinsky:

It was extraordinarily frightening for parents because there was no prevention. There was no cure.

Walter Isaacson:

This is David Oshinsky. He’s a Professor of Medicine at NYU and the author of the book Polio, An American Story.

David Oshinsky:

It simply was a matter of luck as to whether you came down with this virus.

Walter Isaacson:

The first recorded polio epidemic in the United States occurred in Vermont in 1894. 18 people died and 50 were left permanently paralyzed. By the summer of 1916, an outbreak in several Northeastern states claimed 27,000 lives, the vast majority of whom are children under five. Doctors scrambled to unlock the mystery of the polio virus in the hope of finding ways to treat it and ultimately a vaccine that would prevent it.

Walter Isaacson:

The battle eventually came down to two remarkable combatants and two very different approaches to the vaccine. The first approach was developed in the 1950s by Dr. Jonas Salk.

David Oshinsky:

Jonas Salk worked on a killed virus vaccine. What Salk did was to take the polio virus and kill it with formaldehyde. And then what he would do would be use things called adjuvants, which kind of alert the body to the fact that an invader has now entered the system. And those adjuvants along with the killed virus were enough to stimulate immune resistance against the polio virus.

David Oshinsky:

What made Salk’s vaccine so absolutely important was that if done correctly, it could not cause polio in the kid who was getting the injection because it was dead virus vaccine. It could also be made more quickly.

Speaker 8:

Then in 1954, a vaccine to prevent paralytic polio, developed by Dr. Jonas Salk, was tested in the largest field trials in medical history.

Walter Isaacson:

In 1955, after an extensive trial that involved more than a million children, Salk’s killed virus vaccine was declared safe and effective and a massive nationwide inoculation campaign began.

Walter Isaacson:

Meanwhile, Salk’s great rival, Albert Sabin, was developing a second approach to the polio vaccine.

David Oshinsky:

Albert Sabin, on the other hand, used what most virologists thought was the better way of going, and that was an attenuated live virus vaccine, meaning they would take live polio virus and weaken it to the point where it would still create a natural infection in your body. In other words, give you a teeny case of polio, but not strong enough in any way to give you a real case of polio. And what made the attenuated vaccine, the live virus vaccine, better is that it lasted longer, the immunity lasted longer and the belief was that it was stronger.

Walter Isaacson:

Sabin’s attenuated live virus vaccine, delivered orally, was approved for use in 1961, and quickly replaced Salk’s as the go-to polio vaccine. The Salk and Sabin vaccine were so successful that by the 1970s polio had all but disappeared from the American landscape. It was an extraordinary success story, but there were still more childhood diseases to come, and more vaccines to be developed.

Walter Isaacson:

In 1964, an unprecedented epidemic of rubella, also known as German measles, swept the United States. It infected more than 12 million people, or roughly one in 15 Americans. In most people, rubella resulted in only a mild fever or a rash, but the disease could be devastating for women in the early stages of pregnancy. During the epidemic of the mid 1960s, 20,000 babies in the US were born with serious birth defects, including blindness, deafness, and heart and cognitive defects that could be traced back to rubella.

Stanley Plotkin:

It was terrible to see the anguish in the women, and then subsequently to see them come with damaged babies, their realization that in some sense it was their fault that the baby had been infected and damaged. It was an emotional as well as a scientific experience, left no doubt that it was a disease that had to be prevented.

Walter Isaacson:

Stanley Plotkin was a 32 year old pediatrician who already had considerable experience in vaccine research when the rubella epidemic began. He had worked in Africa on an attenuated live virus polio vaccine that was never developed, but the lessons he learned while researching polio proved useful when he turned his attention to rubella,

Stanley Plotkin:

I cultivated numerous samples of the virus and selected one that I decided I would try to attenuate, although it could not be done in the same way as the polio viruses, because they were very different viruses. But nevertheless, the idea, the overall idea of weakening the virus so that it could give you permanent immunity, but not cause any illness is the underlying theme, both for the polio viruses and for rubella virus.

Walter Isaacson:

But Plotkin was not alone in his research for the rubella vaccine. And one of the people Plotkin had to win over was none other than Albert Sabin himself.

Stanley Plotkin:

There was a meeting, a very large meeting, hundreds of people, at which all of the candidates vaccines were presented. And I had to go up against Albert Sabin who had not developed a vaccine himself, but was critical of the vaccine that I had developed, which caused me to, as a young man, fearless young man, get up and criticize Albert Sabin, tell him that he was full of crap, of course not in those terms, but that was a dramatic moment. Fortunately, most people agreed with me.

Walter Isaacson:

Plotkin went on to work on vaccines for anthrax, rabies, and rota virus. Today he is widely known as the godfather of vaccines.

Walter Isaacson:

But it was his work to permanently end the scourge of rubella that still gives him the most pride.

Stanley Plotkin:

At age 88, one, I imagine I’m not the only one who asks himself has my life made any difference or not? That’s a question I’ve asked myself many times, and it is certainly rewarding to think that I’ve prevented a lot of children from dying or being malformed, and prevented a lot of anguish in women. That is a very good feeling to have that you haven’t wasted your life. I mean, what else can I say?

Walter Isaacson:

Stanley Plotkin and his predecessors have saved countless lives, but there are still viruses out there that, despite our best efforts, avoid the healing touch of vaccinologists. Luckily, sometimes trying to solve one problem can lead to a solution for a different problem altogether.

Walter Isaacson:

June 5th, 1981, a day that will live on in infamy. This is the day that the first person was diagnosed with HIV. As of 2019, it’s estimated that 42 million people have died of the HIV/AIDS virus. And while we’ve developed effective treatments to manage the spread of HIV and treat those who have it, we still don’t have a vaccine. But oddly enough, the AIDS epidemic might have inadvertently helped save the lives of millions of women who otherwise would have succumbed to another potentially lethal virus.

Ian Frazer:

I am Ian Frazer, and I am Professor of Medicine at the University of Queensland.

Walter Isaacson:

In the 1980s, Ian Frazer observed that many HIV patients were developing lesions that look like cancer. A colleague suggested Frazer look into the possibility that those cancerous lesions were caused by the human papilloma virus, or HPV. HPV is a sexually transmitted virus that has been identified as the cause of cervical cancer, the fourth most common form of cancer in women worldwide. Frazer took up the challenge and along with his colleague Jian Zhou set out to develop a therapeutic vaccine for HPV. But to do that, they needed to actually grow HPV in a lab, a feat that nobody had achieved up until then.

Ian Frazer:

We thought, right, we can’t grow up the virus by conventional means, so we can’t make a vaccine by conventional means. We decided that we would actually set up to work out if we could make the virus in cells in the laboratory. So we started to try and make shell of the virus, and that was a slow and technically difficult process. It took us about a year to work out how to do it. But in doing that, we created something which looked like the virus and it was at that point that we started thinking about vaccine.

Walter Isaacson:

But Frazer and Zhou still needed to demonstrate that the shell of the virus, that virus-like particle that they had built, could be used as a vaccine.

Ian Frazer:

The eureka moment was when we actually saw it on the electron microscope, the shell of the virus, and realized that not only had we put the building blocks into the system, in other words we’d managed to meet all the building blocks that made up the shell, but they had self-assembled into this virus-like particle, the shell of the virus. And the reason that that was important was that if the bits had been there, but they hadn’t self-assembled, it would have been very difficult to make them assemble in the lab and it wouldn’t have been feasible to make a vaccine that way and it wouldn’t have been feasible to make an infectious papillomavirus that way either.

Walter Isaacson:

It was only after seeing that self-assembled viral shell at the bottom of a test tube, that Frazer was confident that he had reason to celebrate.

Ian Frazer:

Oh, well, I went home and had a drink with my wife and said, “I think we might have done something significant today.”

Walter Isaacson:

In fact, they had. In 2006 Frazer and Zhou’s HPV vaccine was approved in the US and Australia. In doing so, it became the world’s first cancer vaccine.

Walter Isaacson:

Hundreds of millions of young women around the world stood to benefit from an HPV vaccine, and Frazer’s discovery quickly attracted interest from several drug companies, but vaccines for diseases without that kind of market potential can sometimes struggle to get licensed, with potentially tragic consequences.

Walter Isaacson:

Take the Ebola virus, for example.

Heinz Feldmann:

My name is Heinz Feldmann and I’m the Chief of the Laboratory of Virology at the National Institute for Allergies and Infectious Diseases.

Walter Isaacson:

Heinz Feldmann is one of the researchers responsible for developing what is today the most widely recognized Ebola virus vaccine. Although Ebola outbreaks are relatively rare, the Ebola virus is extremely lethal, and spreads quickly through a human to human contact. To Feldmann the need to develop an Ebola vaccine was obvious, but not many people agreed with him.

Heinz Feldmann:

So in the years from ’88, when I kind of entered the field of Ebola, there was no interest in vaccines. Actually most of my mentors told me, “Forget about vaccines. There’s not enough cases. There’s no interest. There’s no market for a vaccine. And we don’t even know how to get to the people because it usually happens in very remote areas. And there’s certainly no money. People can’t pay for vaccines. And we don’t even know if these vaccines would work.”

Walter Isaacson:

But Feldmann says all that changed in the early 2000s after the attack on 911 and the growing threat of international bio-terrorism. The threat of Ebola showing up in our own backyard was very real, and a very promising approach to a vaccine was already being developed. In the 1990s, a Yale University researcher had turned a virus that infects livestock, vesicular stomatitis virus, or VSV, into a vaccine delivery system. VSV could infect humans, but not make them sick. So in the 2000s, a team of researchers led by Feldmann set out to determine if VSV would work for Ebola. They swapped the glycoprotein on the surface of the VSV virus and replaced it with the Ebola glycoprotein and injected it into mice. They were hoping that this modified VSV would be a safe way to teach the immune system to defend itself against an Ebola virus infection.

Heinz Feldmann:

And so we sat down and we decided that we would just challenge the mouse with Ebola. And what we found out that normally Ebola kills this mice within about six days, that these mice didn’t even get sick and were completely protected. And so we could state at that point that if we give these mice these recombinant VSVs that express the Ebola glycoprotein, then they are protected from an Ebola virus infection.

Walter Isaacson:

The first paper demonstrating VSV as an effective vaccine against Ebola was published in 2004, but there was still a long road ahead. It was hard to get drug companies to fund human trials for a vaccine for which there was no real demand. That changed in 2013, when a serious Ebola outbreak began in West Africa. By the time it ended in 2016, more than 28,000 people were infected and over 11,000 had died. In the middle of the outbreak the World Health Organization approved the use of the VSV vaccine, now called ERVEBO.

Walter Isaacson:

The vaccine proved to be safe and highly effective. And when another Ebola outbreak hit the Democratic Republic of the Congo in 2018, more than 250,000 people received the ERVEBO vaccine. In December 2019, ERVEBO became the first Ebola vaccine to be approved by the FDA, to the great relief of Heinz Feldmann and others who had spent more than two decades on the project.

Heinz Feldmann:

It does get frustrated at times, but if you put your public health hat on, still Ebola is a small problem compared to COVID right now, compared to HIV. And there is just not enough money available and I think I have understanding for the view of the industry and also for public health.

Walter Isaacson:

It takes a big problem to align the competing interests of health officials, drug companies, scientists, and the public, and nothing aligns them quite as quickly as a global pandemic.

Walter Isaacson:

In the race to develop a vaccine for COVID-19, scientists around the world have relied on some tried and true techniques. Heinz Feldmann’s viral vector approach to the Ebola vaccine is the basis of the COVID vaccine developed by Johnson and Johnson. Two Chinese companies are promoting a vaccine using the killed virus approach pioneered by Jonas Salk. And a vaccine developed by Novavax works by injecting a virus like fragment of the SARS-CoV-2 spike protein, which is the same approach used by Ian Frazer in his work on the HPV vaccine.

Walter Isaacson:

But the great breakthrough in COVID-19 vaccines has come using a revolutionary new approach that may be the most important development in vaccine research since the smallpox vaccine, more than 200 years ago. It’s called messenger RNA or MRNA. Rather than injecting infected pathogens into our body MRNA vaccines send a message to ourselves on how to make a protein, or even just a piece of a protein, that then triggers an immune response. Two groups rapidly develop MRNA vaccines against COVID. The first was led by a German firm named BioNTech, which partnered with the drug giant Pfizer. The other was a small company in Cambridge, Massachusetts named Moderna.

Stephen Hoge:

The thing that jumped out to me was this idea that if messenger RNA could be harnessed to make medicines and vaccines, that it would be very much an information technology, a major transformation in how we think about making medicines.

Walter Isaacson:

This is Dr. Stephen Hoge. He’s the president of Moderna. Hoge and the folks at Moderna believe the technology has the potential to revolutionize not just the development of vaccines, but therapeutic drugs as well.

Stephen Hoge:

Because what messenger RNA is, is it’s just a way to send instructions to a cell in the body to make a protein. And that meant that if you could crack the code, if you will, if you could find a way to produce messenger RNA and get it into cells and cause them to make proteins, that you would be able to do a nearly limitless number of things, because you would just need to change the instructions, as opposed to change everything about the vaccine or about the medicine, which is the traditional way that they’ve been developed. And that idea just was captivating.

Walter Isaacson:

When Moderna was founded in 2010, the company was primarily interested in using MRNA to develop therapeutics, but it quickly shifted its focus to vaccines. In fact, by the time news began to filter out of China about a new Corona virus, Moderna had already used MRNA in nine successful trials for different vaccines. That’s why Hoge says the company was confident that their COVID-19 vaccine would work, but it still needed to go through clinical trials and approval by regulators.

Stephen Hoge:

And I will never forget the moment that the Independent Data Safety Monitoring Board allowed myself and it was actually Dr. Fauci was there as well, we were allowed into their virtual meeting room, and they read out the results and that the vaccine was 94% effective and that was far, far beyond I think our assumptions going into that read out, just this incredible sense of elation and little bit of pride, but just joy that all of this work, the last eight years, and particularly everything that happened in 2020 was going to pay off and that we were going to be able to stop this pandemic.

Walter Isaacson:

Developing a safe and effective vaccine in less than a year is an extraordinary accomplishment. The previous record was four years, and we’ve only begun to tap the potential of MRNA. Moderna has now turned its attention back to the vaccines it was developing before COVID-19 came along, including Avian flu and the Zika virus, but it’s a vaccine that can treat cancer after it’s already developed that has long been the holy grail for researchers. Most infectious diseases have a limited number of variations, but every cancer tumor is different. So how can you develop a vaccine for a disease with such a high degree of personalization?

Walter Isaacson:

Hoge is convinced that it’s now possible using MRNA.

Stephen Hoge:

It’s a really unique approach. It is a personalized cancer vaccine. So we actually make our vaccine for each individual, individually, based on their cancer. And so what you do is you take a biopsy of their cancer and you figure out what does that cancer look like? What are the mutations that that cancer has? And then we turn those mutations into a vaccine that specifically drives an immune response to those mutations and give that back to the individual. Think of it as really just strengthening the immune response or helping to teach the immune system what the cancer looks like. And one of the great things about a software like technology like messenger RNA, is that we really are able to create an individualized vaccine using the same technology just by copying and pasting your information into it. And it’s the same technology really that we used to create a billion doses of a coronavirus vaccine.

Walter Isaacson:

There’s no question that MRNA has radically changed the future of vaccine science. There’s now hope for diseases like cancer that once seemed impervious to vaccines. Researchers are also working on a universal vaccine for influenza and for rare genetic diseases such as cystic fibrosis that are caused by dysfunctional or deficient proteins. But if 200 years of vaccine research has taught us anything, is that there’s no place for overconfidence. The next pathogen that comes along may be even more deadly, more elusive, than we’ve encountered before. The good news is that we will now go into the next battle better armed than ever before.

Walter Isaacson:

I’m Walter Isaacson, and you’ve been listening to Trailblazers, an original podcast from Dell Technologies. If you’d like to learn more about the guests in today’s episode, please visit delltechnologies.com/trailblazers. Thanks for listening.