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Transcript—Live Attenuated Vaccines: Eliciting a Specialized, Robust, and Long-Lasting Immune Response
Dr. Amy Manning-Boğ
Smallpox with its mortality rate, approximately 30%, was the leading cause of death globally in the 18th century. But then eradicated by 1979. Measles, mumps, and rubella were terrible childhood diseases that we don’t hear much about anymore. And while 95 percent of American adults have had chickenpox, there are now fewer than 150,000 pediatric cases annually. Dr. Christopher Weiss is a virologist and immunologist who has worked with mosquito borne viruses like chikungunya and respiratory viruses like COVID-19.
His experience includes designing and developing live attenuated vaccines in response to these and other infectious disease threats. Today on the show Live Attenuated Vaccines. Their history, how these vaccines work and differ from other types of vaccines, and their interesting connection to eggs. I’m Amy Manning-Bog and this is Science Diction.
Dr. Christopher Weiss
Vaccine technologies have evolved over the years, but they share a common purpose: to prime an immune response and either prevent or lessen disease severity when a microorganism is encountered in the future. These come in many forms today, including live attenuated vaccines, which are whole microorganisms that replicate and stimulate an immune response but don’t cause disease.
Dr. Amy Manning-Boğ
So when were live attenuated, vaccines first developed, Chris?
Dr. Christopher Weiss
For more than a thousand years, scholars have recognized that survivors of smallpox became immune to the disease, but didn’t necessarily understand why. As early as a thousand years ago, early Chinese doctors began inoculating patients by scratching matter from a smallpox sore and blowing the powdered material up the nose of a healthy patient or scarifying it into the skin in a process called variolation. The patient would develop pustules identical to those caused by smallpox, but usually resulting in a less severe disease. Take note of the word usually here.
Dr. Amy Manning-Boğ
Okay.
Dr. Christopher Weiss
This procedure is not without risks, however, as an inoculated person could suffer from smallpox itself or become infected by another disease unintentionally transferred by the procedure.
Dr. Amy Manning-Boğ
And they could potentially spread the disease?
Dr. Christopher Weiss
That’s correct. And it wasn’t until the end of the 18th century when Edward Jenner intentionally infected a child with a milder pox virus called cowpox, that we really get our first attempt at a live attenuated vaccine. Jenner had observed that dairy maids didn’t develop smallpox like the population at large, and he hypothesized that the reason for this is previous exposure to cowpox was acting similarly to this process of variolation. In this case, cowpox causes a very mild disease in humans, but offers the same protection as variolation against smallpox disease.
Years later, Louis Pasteur, the namesake of pasteurization which is used today to kill microbes in foods like milk, was the first to intentionally develop a live attenuated vaccine in 1885. While studying rabies, he attenuated the virus in rabbits and harvested it from them by passing the virus through rabbits. Pasteur made the virus less dangerous to human hosts while still giving the body enough information to recognize the antigen and develop immunity against the quote unquote “wild type” version of the disease.
As scientists gained a better understanding of germ theory and what causes disease, their understanding of how to manipulate these diseases has also increased. Up until the 19th century, the dominant belief was that the common diseases were caused by bad air or some other celestial influences. That’s where we get names like malaria and influenza.
Dr. Amy Manning-Boğ
Wait a second. Wait a second. Malaria.
Dr. Christopher Weiss
Exactly. It translates from Latin to “bad air.” So with a greater understanding of the causative agents now, scientists formed hypotheses about how the viruses and bacteria work to cause disease. We no longer rely solely on those early methods of passing a germ repeatedly outside its target host to force it to change.
The next hundred years saw development of live vaccines for diseases like diphtheria, plague, tuberculosis, yellow fever, measles, mumps, rubella, varicella and rotavirus. You’re probably noticing a trend here that some of the worst diseases in our shared history are addressed with live attenuated vaccines.
Dr. Amy Manning-Boğ
Well, what about polio? You know, this was a major worry in my grandparents heyday. Was Salk’s polio virus live attenuated?
Dr. Christopher Weiss
The polio virus represents another monumental success story for live attenuated vaccines. But it also serves as a cautionary tale for the development of current generation live attenuated vaccines. In this case, to answer your question, Dr. Salk’s polio vaccine was not a live attenuated vaccine, but instead used a mixture of inactivated or killed polio virus strains of all three polio types.
However, around the same time that Salk’s vaccine was approved for childhood vaccination campaigns, a scientist named Dr. Albert Sabin and his team developed a live attenuated polio vaccine that became widely used to drive polio virus to the brink of eradication.
Dr. Amy Manning-Boğ
We hear so much about the Salk vaccine, like even in high school.
Dr. Christopher Weiss
The Sabin vaccine or oral polio virus vaccine – OPV – was highly successful at preventing polio virus infection in vaccinated children with an excellent safety record. But that success story doesn’t capture the full history of this vaccine. As a live attenuated vaccine, OPV grows in the gut of a vaccinated child and produces a very strong and durable protection in that child. However, the vaccine virus is also shed from the vaccinated child and over time can undergo what’s called genetic reversion to cause disease.
Dr. Amy Manning-Boğ
Do you mean reversion as in mutation back to infectious?
Dr. Christopher Weiss
That’s exactly what’s happening. However, by the time the virus is able to cause disease, the vaccinated child is protected. But unvaccinated children and adults can encounter that virus and get sick with polio. This isn’t a problem if everyone in the community is getting vaccinated. But you can probably see where I’m going with this. As we’ve neared eradication of polio, a goal that still hasn’t been met today mind you, vaccination hesitancy has fueled hotspots where vaccine derived polio outbreaks can thrive.
As a result, Salk’s original inactivated polio vaccine has been adopted as the standard bearer once again to get us closer to eradication of this debilitating and sometimes deadly childhood disease without risking vaccine associated disease outbreaks. It’s really important to note here that both IPV and OPV have a robust safety record for the vaccinated individual and produce strong antibody responses to all three types of polio virus, preventing nervous system infection and devastating paralysis that can result.
Dr. Amy Manning-Boğ
Okay, just thinking about development of the technology and assuming it’s no longer as easy as passing the virus through a rabbit, how is the virus rendered noninfectious?
Dr. Christopher Weiss
Modern approaches rely on a rational vaccine attenuation strategy. Gone are the days of repeatedly growing a virus in rabbits or mice and seeing if it still makes people sick. These techniques might be used as a starting point, but sequence-based techniques must also be used to identify why an organism is it attenuated? Then test these sets of mutations in isolation. With a thorough understanding of how a virus or a bacterium grows, we can also selectively modify individual parts to make them less efficient at reproducing or even deleting a tool that the organism uses to evade our immune system, which had been gained over millennia of infecting people. These complex approaches are often combined to create a failsafe to prevent the return to pathogenicity, that is to cause disease that we saw with Sabin’s live attenuated oral polio vaccine.
Dr. Amy Manning-Boğ
And then how are these vaccines produced?
Dr. Christopher Weiss
Once a live attenuated vaccine has been developed, it undergoes extensive testing in a laboratory setting before it makes it to people for clinical trial testing. These experiments include everything from predicting safety to the mechanisms of protection. This also includes the stage where scientists start thinking ahead about production because it’s no use having an incredible vaccine if you can’t make it in high enough quantity to be useful. Modern, live attenuated vaccines can be grown in everything from eggs to large bioreactors full of isolated cells. The most important consideration for production method is that it produces a clean and safe final product before it can go into people.
Dr. Amy Manning-Boğ
So eggs. Eggs are a great source for growing virus.
Dr. Christopher Weiss
Certain viruses. Yes.
Dr. Amy Manning-Boğ
Okay. So what are the benefits of a live attenuated vaccine versus those developed through other methods?
Dr. Christopher Weiss
Well, the most effective immune responses are generally produced in response to antigens present in a live organism. There are a myriad of reasons for this, but it largely comes down to the context in which the immune system encounters a foreign target. When your immune cells are first alerted to a new infection, replication is well underway and your infected cells are sending danger signals to put out the alert. This process occurs when a live attenuated vaccine replicates as well.
Live attenuated vaccines have a role to play in many scenarios. In some cases, there may be a benefit in the type of immune response that’s generated. In others, there may be a benefit to the longevity of the protection generated.
Dr. Amy Manning-Boğ
While this method of vaccine development has been around for more than 100 years, the technology continues to have application in response to today’s existing and emerging disease threats alongside newer technologies.
Dr. Christopher Weiss
There are absolutely benefits to having many vaccine technologies in use to combat today’s recurrent and emerging threats. One example is the persistent seasonal waves of respiratory viruses like influenza virus and now COVID-19. Inactivated vaccines like the annual flu shot or mRNA vaccines like those developed for COVID-19 are great at producing antibodies that help block and eliminate virus inside the body.
Dr. Christopher Weiss
These antibodies called immunoglobulin G – that’s a mouthful – so, let’s call them IgG. They’re able to circulate through the body in a non specialized way to encounter virus, wherever it’s at. There are more specialized types of antibodies, though, including one called IGA, that resides exclusively on mucous covered surfaces like in the nose. As a specialist, IGA is secreted in these areas and laid out like a trap to catch incoming viruses before they’re able to cause infection elsewhere.
Dr. Amy Manning-Boğ
Okay, I’m obsessing a little on this, but what are the possible benefits of the nasal vaccine versus an intramuscular one? I’m used to the jab in the arm.
Dr. Christopher Weiss
Live attenuated vaccines like the nasal flu vaccine are able to teach the body to make this powerful type of antibody. But the injected killed flu vaccines don’t. Both vaccines are effective, but the nasal vaccine is more robust and the protection is longer lived.
It’s important to note that not everyone is eligible to receive a live attenuated vaccine. For instance, severely immunocompromised individuals and very young children should not receive a live attenuated vaccine because there’s elevated risk the vaccine itself could cause disease.
Dr. Amy Manning-Boğ
So as people get the nasal spray flu vaccine this fall, that’s a live attenuated vaccine, correct?
Dr. Christopher Weiss
Yes. These are live attenuated vaccines designed to replicate only in the nose so that the immune system can build strong protection right at the site of infection. This is a great option for needle averse people that still want to protect themselves and those around them from the flu.
Dr. Amy Manning-Boğ
Chris, I’ve really enjoyed this conversation so much and there’s still so much to cover because we didn’t even get into your work with chikungunya. And I think that we’re going to have to bring you back for another episode.
Dr. Christopher Weiss
Thank you so much for having me on today. Let’s do it.
Dr. Amy Manning-Boğ
Great.