Science Diction Podcast | Live Attenuated Vaccines (Part 2 of 2)

Transcript—Live Attenuated Vaccines: Prepared to Strengthen a Future Pandemic Response

Dr. Amy Manning-Boğ
Last episode we spoke with virologist and immunologist and my colleague Dr. Christopher Weiss about live attenuated vaccines. And our conversation just kept going. We enjoyed it and learned so much that we wanted to share more of it with you and this second episode. Today on the show, part two of our conversation about live attenuated vaccines, good disease candidates for this type of vaccine, how researchers begin vaccine development before a virus is known, and their role in responding to a future pandemic. I’m Amy Manning-Boğ and this is Science Diction from MRIGlobal.

So, we talked about how the nasal spray flu vaccine is live attenuated. Are live attenuated viruses best suited for certain diseases?

Dr. Christopher Weiss
While long-lived protection is one of the greatest benefits of all live attenuated vaccines, this isn’t the only reason to consider a live attenuated vaccine approach for new vaccine targets. We previously discussed the benefits afforded by nasally administered vaccines for flu and oral polio vaccines. I wouldn’t go as far as to say a live attenuated vaccine is best suited for certain types of infections, but they offer benefits that should be considered as part of a holistic review of what approach to take. First generation COVID-19 vaccines were developed to focus on speed. mRNA vaccines are a surprisingly mature but adaptable technology that was waiting for the right target to go to market. In the case of a global pandemic, this rapidly deployable technology met the need of the moment. What we’re learning more and more, though, is that the protection from new infection wanes in under a year. There’s still long-lived protection from severe disease, but the virus can find new susceptible hosts, which will continue fueling a seasonal recurrent cycle.

Dr. Amy Manning-Boğ
I’m familiar with your work in vaccine development in response to COVID and chikungunya. Why are those diseases good candidates for a live attenuated vaccine?

Dr. Christopher Weiss
COVID-19 is a great candidate for a live attenuated vaccine because the specialized production of IGA and long-lived immunity in the nose will help shape the intensity and seasonal waves going forward.

It provides a durable and long-term protection right at the site of infection that can outlast some of these more traditional technologies, like a killed vaccine or even what we’re seeing now with mRNA vaccines.

Dr. Amy Manning-Boğ
What about chikungunya?

Dr. Christopher Weiss
Chikungunya virus is transmitted by mosquitoes, much like yellow fever and causes a really debilitating febrile disease called chikungunya fever. This occurs globally across the tropics and subtropics.

We’ve discussed how live attenuated vaccines offer an opportunity to guide the body’s immune system to respond in a way that is uniquely suited to protect against a particular disease. To understand why this is, though, we need to build a little bit more context around how the immune system responds to an infection and how other vaccination strategies seek to initiate this. When we get sick, a virus or bacterium or one factor colonize specific areas of the body, it’s important for the body’s immune response to not only recognize an invading pathogen, but also respond in a way that is appropriate to clear that microorganism from the site of infection and then ultimately prevent reinfection or disease. For example, viruses must infect cells to produce more copies of themselves. The immune response, in turn, must be able to recognize infected cells and drive a response to eliminate them before the virus can copy itself. Certain immune cells have a way of identifying the context in which an organism is encountered and require different signals to inform whether they help produce antibodies or program cells to seek and destroy infected cells.

Dr. Amy Manning-Boğ
Oh, we have to hear more about that.

Dr. Christopher Weiss
We can provide artificial signals to tell the immune system to produce antibodies or kill infected cells. But these approaches often lack the appropriate balance to build long term protection from infection. Since live attenuated vaccines replicate similarly to the organism they’re targeting, the body is given the full context of an infection without the need to tune the response.

Dr. Amy Manning-Boğ
So meaning the appropriate immune cells other than B cells which make antibodies become involved in the process.

Dr. Christopher Weiss
It’s exactly in this case. I’m discussing T cells, which recognize whether a virus is being encountered extracellularly and mopped up from outside of an infected cell or recognizing when a cell itself is infected and producing different parts of that virus or bacterium.

Dr. Amy Manning-Boğ
What about phagocytosis with chikungunya?

Dr. Christopher Weiss
That’s part of it. So chikungunya virus is a virus that replicates obligately within a cell. So, you need to be able to recognize when a cell is infected in that specific context. But chikungunya virus is also going to be detected outside of cells while it’s circulating throughout the body. And in this case, phagocytes such as macrophages or dendritic cells will pick up that extracellular virus, chew it up, and present it to the immune system. That’s when we get the production of these long lived IGGs and T cell receptors so that we can start clearing virus in a future encounter.

Dr. Amy Manning-Boğ
Several approaches to COVID-19 vaccine development have been tested and utilized concurrently the past few years, including inactivated virus, live attenuated, mRNA, and others, much like carrying different tools in a tool belt and using the right one for the job. There can be benefit to having multiple types of vaccines at the ready to help strengthen a future pandemic response.

Dr. Christopher Weiss
History has shown us that the next pandemic can come from anywhere. Recent outbreaks point to more likely sources like influenza viruses and coronaviruses. But prior to the SARS epidemic in the early 2000s, no one would have pinpointed coronaviruses as an emerging pandemic threat. By continuing to develop vaccines based on multiple technologies and against many known viruses, we lay the groundwork as a scientific community for that next iterative edition to face emerging challenges like COVID-19.

It’s important to remind here that mRNA vaccines weren’t developed in response to the recent pandemic. The technology has existed for over 30 years, and scientists refined and improved it. Similarly, live attenuated vaccines have existed for over a hundred years. But there’s still room to improve our methods for rational vaccine design to respond quickly to an emerging threat should the need arise.

Dr. Amy Manning-Boğ
So I spoke with our mutual colleague, Dr. Luca Popescu on a previous podcast about the mRNA vaccine platform, and he described it as being quick, nimble and adaptable to the disease need. How would you describe live attenuated vaccines?

Dr. Christopher Weiss
Since you mentioned quick and nimble, I think perhaps here the metaphor of the tortoise and the hare is in order. While mRNA vaccines are nimble and adaptable in a time of great need, live attenuated vaccines are more the slow and steady approach. You’re never going to see a live attenuated vaccine reach the market in a timeline that we saw with the mRNA vaccines for COVID-19. However, that doesn’t mean that they don’t have a role to play even where other vaccines already exist. Keep in mind that inactivated flu vaccines existed for years before we saw a live attenuated nasal flu vaccine. And yet here it is on the market. We may very well see the same thing happen where a live attenuated COVID-19 vaccine helps fill a niche role for protecting our communities alongside next generation mRNA vaccines.

Dr. Amy Manning-Boğ
What do you foresee in coming years for development and use of live attenuated vaccines?

Dr. Christopher Weiss
I really think we’re going to see a focus on live attenuated vaccines for respiratory and gastrointestinal bugs due to the simplicity of administration and the localized benefit for mucosal immunity. I also see a rational vaccine design being more informed by the genetics of a given pathogen than historic approaches like serial passage. I’d be willing to make one more prediction here for neglected tropical diseases, where administration of boosters every few years won’t be practical and the durability of protection from live attenuated vaccines will be the most feasible approach to protecting vulnerable communities.

Dr. Amy Manning-Boğ
So here’s the $64 billion question How do research scientists develop vaccines for a virus that might not even be known to them?

Dr. Christopher Weiss
This is a good example of where there exists a need for the development of a proof of concept that can serve as a platform for future vaccines. In the case of live attenuated vaccine design, chimeras come to mind so much like the mythical creatures consisting of body parts from different animals, chimeric live attenuated vaccines can be modified later to display key components from a yet unknown pathogen and serve as an all-in-one delivery vehicle to prime the immune system.

Dr. Amy Manning-Boğ
I like that idea. For years I’ve always gotten my flu vaccine year after year with the thought that there might be one small antigen present that would be in that next great bug. And I would have some stray antibody from some stray B cell that would recognize it. So I really like this idea of using a chimeric vaccine.

Chris, you have such a passion for this work. What initially sparked your interest in this area of research?

Dr. Christopher Weiss
I’ll just start out by saying the movie Jurassic Park, which came out when I was in elementary school, had an outsize impact on my desire to become a scientist. Though I will say I was very disappointed to learn that de-extinction genetics wasn’t a viable career path when I was older. I’ll say besides that, a particularly bad relationship with respiratory bugs every year. And I mean every year. When I was growing up, I never understood how I could get so many different vaccines yet still get sick.

Dr. Amy Manning-Boğ
You saw an opportunity there, didn’t you?

Dr. Christopher Weiss
I did. I viewed a career in vaccinology as my chance to take the fight to my childhood foe and maybe knock out one more pesky infection off that list of things that make us sick.

Dr. Amy Manning-Boğ
As a parent, and I know you’re one to especially one of a small child, I relish the idea of having a vaccine against rotavirus that produces such longstanding protection. If there could be one that could last from preschool all through college, I would be 100 percent on board.

Dr. Christopher Weiss
I know exactly what you mean here. Now we just need to come up with a vaccine for all of the plagues that our children come home with from daycare.