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Malaria is a deadly, mosquito-vectored disease in areas of the Developing World. Intensive efforts have resulted in few effective prophylactic or therapeutic practices or products that are without serious limitations. A vaccine against the causative organism would be ideal, but even vaccine strategies have drawbacks. Dr. Stefan Kappe and his team have devised a new vaccine strategy based on attenuation of the plasmodium parasite, using genetic engineering. CRISPR/Cas9 has been used to alter genes associated with life cycle and development, conferring immunological response to a complex set of antigens. Trials suggest good protection and safety from this strategy.
Talking Biotech is a weekly podcast that uncovers the stories, ideas and research of people at the frontier of biology and engineering.
Each episode explores how science and technology will transform agriculture, protect the environment, and feed 10 billion people by 2050.
Interviews are led by Dr. Kevin Folta, a professor of molecular biology and genomics.
Talking Biotech 368 - A Gene Edited Vaccine Against Malaria - Dr. Stefan Kappe, University of Washington
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Kevin Folta: [00:00:00] Hi everybody, and welcome to this Week's Talking Biotech podcast by Colabra. Now, I know it's a little bit of a cliche that when we talk about malaria, we always start out by talking about sharks. . It's the visibility of shark attacks. It's the role of sharks and TV and movies, the violent nature of the damage they inflict.
We think of them as the ultimate animal that can harm humans. But we need this occasional tap on the shoulders. A little reminder that the most deadly animal on this planet is a much less conspicuous one. The mosquito mosquito vector disease is a tremendous global health threat, and we've covered this at length over the years on this podcast from the GE Mosquitoes to the Therapeutic Agents, You name it.
What if there was a vaccination against the plasmodium? The plasmodium being the infectious agent. This unicellular ucar, [00:01:00] well unicellular in this context causative agent of the symptom spectrum in humans. It's also the, in the infectious agent that's vectored by mosquitoes. This would be an incredible game.
and a recent paper indicates that maybe a little gene editing may make this breakthrough a reality. Today's guest is Dr. Stefan Kapa. He's a professor in the Department of Pediatrics at the University of Washington, and a principal investigator at Seattle's Children's Research Institute. So welcome to the podcast, Dr.
Kapa. Thank you. Yeah, this is a very exciting project and I really wanted to host more podcasts on malaria because I feel it's something that many of us in the industrialized world failed to realize the impact of. So could we really start by talking about how much of a problem it is in the developing world and how many people are affected worldwide?[00:02:00]
Stefan Kappe: Yes, you're absolutely right. It is a problem of mostly developing countries and. Remains a tremendous global health threat, particularly in Sub-Saharan Africa. So the majority of the malaria burden is in African countries, but it's also a problem in Southeast Asia and South America, and it remains a problem there as well.
Uh, So we are looking at about, let's say, for example, 2020 where we have pretty good numbers, about 600,000 deaths worldwide and about 200 million clinical cases. Now to emphasize is these are people that go to Hospi, go to the hospital with malaria, so 200 million people in the hospital every year with malaria.
And the tragic part of this is that it affects mostly in Africa, children under the age of. And pregnant women. And that's where the majority of the mortality is.
Kevin Folta: And I think in the manuscript that was recently published, a paper that was recently published says that there's a, a, a death from the [00:03:00] infection every 60 seconds.
That's
Stefan Kappe: about
Kevin Folta: right. Yeah, so this is a, a really major problem. The, the vectors in the pathogens here are really complex though. And can you give us a walkthrough of how malaria spreads?
Stefan Kappe: Yes. So first of all, to emphasize it's the parasitic infection. So we are looking at a single cell ucar organism. Quite more complex than a virus, more complex than bacteria.
And this parasite is transmitted by mosquitoes to humans. And it sits in the salivary lens of the mosquito as a form called SPO wide stage. And that spo OID stage when a mosquito takes a blood meal and during the blood meal, the mosquito spits to release saliva. That parasite is injected into the human.
Vicious bit and then immediately makes its way to a blood vessel penetrates a blood vessel in the skin, and then it's transported to the liver by blood flow. And when the parasite reaches the liver, it exits the bloodstream and infects liver cells, heide, and [00:04:00] within the heide. It makes itself at home and starts growing and replicating to ultimately produce over a period to six.
About 60,000 progeny that then are released as invasive forms called OIDs into the bloodstream where they infect breath blood cells. And here they replicate again over a 48 hour cycle. Psychically infecting and destroying red blood cells. Growing to billions of parasites within a couple of weeks, and that phase in the blood is what causes all symptoms and ultimately causes death.
In an infected human, the face of the parasite in the liver is completely asymptomatic. And as I mentioned, it lasts for about six to seven days. So after you get bitten by a mosquito for seven days, you don't know that you are infected and you're completely asymptomatic. Only on day eight and onward, you start feeling the symptoms of malaria.
And then the parasite ultimately when it wants to reach another host, makes sexual forms. And these sexual forms are taken up by the mosquito virtualized in the. [00:05:00] And form new forms that can then infect and replicate in the mosquito to ultimately colonize the salivary glance to upon a next bite infects the next host.
Kevin Folta: And, and doesn't the at least the parasite, does it have some unusual characteristics that allow it to evade immune detection?
Stefan Kappe: Yes. In the bloodstream it certainly has mechanisms to evade immune detection, and that's something called we call antigenic variations. So it has a gene families that are.
Highly variant in terms of the protein sequence, and these gene families allows the parasite to adhere to the vasculature and actually not get cleared by the spleens. Or it's an advantage for the parasite to adhere to the vasculature. But on the other hand, because these proteins are ex exposed on the infected red cell surface, they're also recognized by the immune system.
And because they are, the parasite has to vary, has to keep them varying. So they are not, Easily caught up in the immune response that is elicited in an infect individual. So the parasite puts new [00:06:00] versions of this molecule on the surface and escapes the immune response, and that's a major issue with developing vaccines against the bloodstream form of the parasite.
And that's one of the reasons why we are focusing our vaccine on the initial stage of infection in. Okay.
Kevin Folta: That helps a lot. So what are the current ways in which malaria is controlled? How, how is it mitigated in, in reality, and how effective are these approaches? Yeah,
Stefan Kappe: so because malaria is transmitted by mosquitoes, one way to preventing malaria is obviously preventing mosquitoes, infecting mosquitoes from biting humans.
And one way of doing this is using insecticides and spraying insecticides and killing mosquitoes Now, In the past we have used environmental spraying to control mosquitoes, but that came with problems, remember d d t. And now it's more focused on in-house spraying. So it's called indoor residual spraying.
The spraying is focused on actual dwellings where people live, and in addition we have insecticide implicated pet nets that can be used to. [00:07:00] Infection by just physically preventing the parasite from biting an individual, but also killing the mosquitoes when they get in touch with the best net by the insecticide.
And then ultimately, if you are infected and suffer symptoms of malaria, you can get treated. So there are anti-malarial treatments and that saves millions of life of lives each year. If we wouldn't have these treatments, many more people would die of. However, the parasite develops resistance against these treatments, and so far, the parasite has developed resistance against every single drug that has been developed to eliminate it.
Kevin Folta: Wow. And then it's also a question of access. Do all people in the developing world have access to those
Stefan Kappe: treatments? Yes, absolutely. That's a great question. Although treatments are sold relatively cheaply and are available in the developing countries, I think access is a problem and making them available for everyone.
It is a challenge to get the drugs to everyone. It's a challenge to have everyone treated if they are infected and if the hospital doesn't have some necessary drugs, people go untreated. But it's the challenge all across the board. It's the [00:08:00] challenge with Benets as well. Look, I mean, an interesting anecdote is, If you give someone a bat net, who has to make a decision?
Do they when to prevent, say a child from getting ma malaria, or do they wanna catch fish with a bat net and provide some food on the table? That's a hard decision to make. And this, these are the kind of socioeconomic conditions under which ma malaria thrives.
Kevin Folta: Yeah. It's another reason I really appreciate you taking the time to do this today, because people need to understand those decisions and, and what's actually happening in, in that context of where malaria is happening.
You know, the, the real life situation. And there have been because the mitigation strategies even seem a little bit primitive. We're using chemistry and nets. There's been several attempts to create vaccines that target the plasmodium, but how effective are they?
Stefan Kappe: So there is one vaccine that is actually now recommended by w h O for use in Suba in Africa.
It's called RTSs, and that's what we call a subunit vaccine. It's basically made of one protein component of the parasite that is on the [00:09:00] surface of the infectious form that get transmitted by, that gets transmitted by mosquitoes OID stage. And, and this vaccine has been under development for nearly 30 years and is finally, On the market, so to speak, and it can be used.
The unfortunate fact is that the levels of protection it achieves are modest at best. And although it will save lives, it is definitely not a vaccine that will change the epidemiology and transmission dynamics of ma malaria, I believe. So it's a good start you know, with a between 20 and 30% protection against clinical disease.
But we need to do better than this if we really want to address the. Just catastrophes that happens every year worldwide with malaria.
Kevin Folta: Okay, so that one's more of a traditional protein based subunit vaccine. So what about attenuated parasite where you just, you know inactivate or severely impair the entire parasite and use that?
Stefan Kappe: Yeah, so the history of using attenuated parasites as a vaccine goes all the [00:10:00] way back to the 1960s and seventies when it was first demonstrated that if you immunize laboratory animals with irradiation, attenuated, spur wide stages, this form that is transmitted by mosquito, you can. Illicit protection in, in, in laboratory animals against subsequent infection.
And that was then tested in humans in the 1970s by vaccinating individuals with irradiated OIDs back then in the seventies, it was also done by mosquito bite administration, and that showed that you can get fairly robust protection against malaria infection. I, I have to explain one more thing, and the way this is tested is by something we call control human malaria infection.
So we can actually. Recruit subjects and expose them to malaria, to test vaccine efficacy. And that has been used in the seventies and it's still used today. And it's a great way of quickly assessing vaccine efficacy or drug efficacy to malaria. And we can do this because we can safely treat the infection if we challenge with laboratory strains.
So the radiants, pero has really, lets. Historically, [00:11:00] the, the, the attenuated parasite form that has been used most in, in, in research and has more recently over the last 12 year been developed as a vaccine by a company called Scenario. And they have mastered the ability to grow these OID stages in mosquitoes, isolates, and purifies them, preserves them, and then have an injectable form of this vaccine for clinical studies.
And they have done numerous clinical studies. That irradiated OIDs can protect against controlled human MA malaria infection. And they have also shown that it can protect in clinical settings in malaria endemic areas. The issue I see with irradiation attenuated OIDs is that they have to ma be made every time and irradiated every time.
And it's an uncontrolled process in certain ways. And you don't have a true genetic identity of this organism that you're using as a vaccine because. Introducing random DNA damage. So that's where our work comes in, where we decided it's a good start, but we want to really go with more modern ways of [00:12:00] attenuation.
And so that's why we decided to use genetic modification to attenuate the parasite during the liver stage of infection.
Kevin Folta: And that's a perfect transition, so very, very nice. So we're speaking with Dr. Stefan Kapa. He's a professor in the Department of Pediatric at the University of Washington, and principal investigator at Seattle's Children Research Institute.
This is Collaborate's talking Biotech podcast, and we'll be back in just a moment. And now we're back on the Talking Biotech podcast. We're speaking with Dr. Stefan Kapa. He's a professor in the Department of Pediatrics at the University of Washington, and the principal investigator at Seattle's Children Research Institute.
And we're talking about modern strategies to mitigate the problem of malaria, an incredibly complex and challenging problem. That affects primarily the developing world, and we've spoken already about the complexities of the infection, the problems with trying to meet it, and maybe a [00:13:00] way in which it may be able to be approached using genetic engineering.
How is this done? In the latest approach.
Stefan Kappe: So this is a parasitic organism. It has u periodic cell makeups. It has about 5,000 genes. So very difficult to envision how you choose genes for attenuation, right? So what we did is we Generate a gene expression, profiles of the parasite when it infects the liver.
And this is really key here, right? Because as I pointed out, the liver stage infection is the foot is the first step that creates a foot wall of the parasite in the human host, so to speak. And if we can eliminate the parasite, at this stage, you do not get the onset of blood stage infection, which causes all clinical symptoms and ultimate death, but you also.
Do not get onward transmission of the parasite by the mosquito to a next person. So we wanna stop the parasite in the liver. How do we do this? We attenuate the parasite by using genes that we defined as being critical for the parasite replication in the liver. We delete those genes using [00:14:00] crispr carcine, gene deletion strategies, and then we create a parasite that can infect liver.
It has to be alive and infect, deliver in order to be immunogenic. We use, we, we, we nose. Because we have done experiments that demonstrates that dead parasites or non-infectious parasites do not induce protection. So the parasite, it affects the liver and then it replicates to a certain degree and then it dies in the liver.
It does not on its own cause infection, but what it does is it elicits a very potent immune response, both an antibody response as well as a T-cell response that eliminates on incoming parasites subsequently. So if you are immunized with these attenuated parasites, The T cells recognize is a next infected cell upon parasite transmission and eliminated.
And that is key. So you get what we call sterilizing protection. You don't protect necessarily against disease only, but you actually protect against the infection taking of what told in the
Kevin Folta: person. No, that's very good. How much of that is due to the fact that you're using a very [00:15:00] complex organism that has a large number of antigens, which are actually being responded to by the body?
Stefan Kappe: That's exactly right. That's the key aspect of this. So when, when we compare the subunit vaccine approach with a single antigen such as a surface protein of the parasite to our approach using the whole parasite and immunogen, it is intuitively clear why a whole parasite is better. You get a much more multi-pronged immune response against many different antigens that I express in the parasite, potentially thousands of antigens versus one antigen.
So the immune response, Much better educated on multiple components of the parasite. And that creates this much more potent, much more protective immune response that we are looking for if you ultimately want to really prevent ma malaria infections, the majority of people that are vaccinated.
Kevin Folta: Yeah. And if I can take a step back, you know, this kind of work I should mention that it was published recently in Science Translational Medicine and has a significant research team.
So who else played a role in
Stefan Kappe: this? So in this study that was [00:16:00] published recently, we had a team of individuals, well first as a research team in my group, mainly Dr. Ashley Vaughn, who is a senior scientist in my group, or was a senior scientist, is now a professor as well at the research institute and then team members other team members that played a role in my group as well as collaborators at the University of Washington, Sean Murphy, who is a professor of medicine There.
As well as the Fred Hutcherson Cancer Research Center. Jim Colin, I need to mention who participated in getting this study done. So this study is just the beginning of our work because what we did there is we created a parasite form by genetic engineering that is what we call replication deficient.
So this is a parasite that infects a liver cell and then dies off and it induces a quite good immune response. And we have shown in our trials that it can. Protect about 50% of the vaccines with a very I would say irregular immunization schedule with bio mosquito bite. And we can get to that in a minute.
But we are already thinking ahead and we are realizing [00:17:00] that replication deficient parasites are not yet the ideal life attenuated immunogen. What we really want to have is the parasites that can infect. Replicate to the mo to the largest extent possible, but cannot get into the bloodstream. And we have be recently been able to create these parasites, which we call replication competent parasite vaccines.
And these will go into clinical trials in the early I would say summer of next year.
Kevin Folta: And what, what kind of genes do you need to disrupt to cause the replication deficiency versus the replication competent inability to infect red blood cells? What are they, Are they different
Stefan Kappe: suites of. They are absolutely different suites of genes and, and we only recently have been able to identify the genes which, which, with which we can upon deletion, create replication, competent parasite vaccines.
So the genes that we create that we use for creating the first generation of replication deficient parasite vaccines are important for the parasite. To establish its intracellular niche in the, in the infected cell. [00:18:00] So when you delete these genes, the parasite cannot form a membrane around its compartment and protect itself against the host cell side of PAs.
So that's why these parasites die of rapidly and eliminated by the infected cell. But Ill elicit an immune response on the way. The replication competent parasites are generated by genes that are only important in the latest stages of development in the liver. When the parasite makes new infectious forms and these gene lesions prevents the parasite from making.
New infectious forms is OID stages that can infect, infect red blood cells when they get released from the liver. So as the parasite grows to an enormous size compared to the replication deficient parasite, think about a p and a watermelon. But It creates so much more antigen, but it cannot, and, and more antigen and a more greater diversity of antigen, but it cannot escape into the blood and in infect red cells.
So that's the perfect attenuated vaccine that targets the liver form of the
Kevin Folta: parasite. This is really neat stuff, but one, one of the really interesting parts of this is the way [00:19:00] in which the. Examined its ability to function by by how it was administered. So it, this wasn't a vaccine that was injected, right.
At least through traditional methods. So how, how is this tested and how does that play a role in ultimately, maybe the way it would be delivered in its real context.
Stefan Kappe: Yeah, so we chose for the trial that we just published for the replication deficient parasite vaccine, we chose to immunize by mosquito bite because frankly, we didn't have the ability to make the parasite and buy it and have an injectable form.
So, just for experimental medicine purposes and getting data on the protect, safety, and protective efficacy of this parasite vaccine, we immunized by mosquito bite. and we did this by giving subjects either three times or five times 200 bytes carrying this attenuated vaccine in the mosquito salivary gland.
And that was a delivery method. And then, you know, after four weeks we challenged the subjects and that's how we [00:20:00] determined that 50% of them were completely protected against this challenge. I was one of the subjects and I can tell you that 200 mosquito bites is not a pleasant way to get a vaccine.
And we certainly do not think that this is a viable. Vaccine platform for your immunizing. Hundreds of millions of individuals who need this vaccine. That's why we are collaborating with a biotech company, which I mentioned earlier scenario that has developed methodologies to actually purify these vaccines from the mosquito salivary clans and clean them up so we can inject them directly into individuals and.
This will be done in our next trial next year, where we actually now have an injectable form of this parasite vaccines, a replication competent parasite vaccine, our latest generation strains that we generated. So to your question, is there an advantage to give it by mosquito? By I. Think there might be immunological advantages, but I think it's impractical to do this obviously large scale, so we have to go [00:21:00] with an injectable fault.
Kevin Folta: Yeah, I understand now because originally when I read the paper, I, I kind of thought that maybe this would be a way in which the, you would be able to spread the. The plasmodium from, from individual to indivi, individual, from individual to individual, and spread the non replicating type. But if it's not replicating, it wouldn't really be there for the mosquito to pick up anyway.
That is
Stefan Kappe: correct, and I can tell you that we would never get approval for using such a vaccine that is spread by mosquitoes. I think it would be very difficult to convince governments, countries that they would have a malaria parasite strain that spreads by mosquito and vaccinates individuals involuntarily, so to speak.
Right. Because that's a, that's a thing, right? When you, when you think about vaccines today, look at, look about the vaccine hesitancy we have in this country with covid vaccines we have in other countries with covid vaccines. Can you imagine telling people that the vaccine is spread by mosquito bite and they don't even know if they get it?
I don't think that would be a, a wise decision. [00:22:00] So we need to have an injectable form that we can give people and ask for their permission to give
Kevin Folta: it to them. No, I, I understand that now. Yeah, it's, it seems really brilliant in some ways, but when you look at the practical aspects, I totally understand. So, but, but the other practical aspect is that vaccines typically rely on adjuvants and other types.
Immune stimulatory molecules or, or, or ions or whatever that help to generate that immune response. So is that another reason to go with a formulated type of Xing?
Stefan Kappe: Yeah, so that's that. It could be another reason. The main reason is practicality of immunization, as I alluded to earlier. So when you think about vaccines that have adjuvants, these are mostly subunit vaccines like proteins, for example, protein based vaccines used with an adjuvant because in themselves they are not immunogenic enough to stimulates the immune response.
That's why you use these adjuvants to tickle the immune response a little bit more and get a more I potent response now. Whole attenuate parasites that we are using. The parasite is basically already self adjuvant, [00:23:00] as I call it. It brings everything in that is needed to stimulate a very potent immune response.
And we know this based on animal studies. You get very potent antibody and CDA to TCE responses. These are the, the cellular part of the immune system that eliminate infected aides. But we are thinking ahead and there are adjuvants that we are, we are, we could potentially consider using together with c life attenuated vaccine product.
Now these have have to be adjuvants that don't affect the viability of the vaccine strain, but certainly we can envision certain types of adjuvant such as glycolipids, and that's something that we and our partner company scenario is
Kevin Folta: considering. And you mentioned the results of the human trials were about 50% had conferred immunity, but is that really a good benchmark or can you tell us a little bit more about maybe the details of the outcomes of the first experiments?
Stefan Kappe: Yeah, so 50% is good. It's a good start and as I said, we immunized by mosquito bite. It's a very difficult to control system. You don't know how much [00:24:00] vaccine you actually administer, so we were quite pleased with 50% protection. That's hard to achieve with any type of vaccine in this kind of setting.
But we want to think ahead and honestly, we want to get to a hundred percent protection against controlled malaria infection before we even consider going into malaria endemic areas with this vaccine and testing it a. Testing it for protection against natural acquisition of infection. You have to, you have to get high levels of protection, otherwise you will not make a dent in the transmission of the parasite and really will not make a dent, not a big dent in the clinical epidemiology of the, of the parasite.
So I think that a hundred percent is what we are going for with our next attenuated strain. We'll see. Fingers cross, it will work. We have believe, we have good reason to believe it will. Though. And let me explain this a little bit more carefully. So, there have been experiments I I would say experimental clinical studies where individuals have received completely unadulterated parasites.
So fully infectious parasites. They can infect an individual, they go through the liver, they replicate [00:25:00] in the liver, and then they are released the bloodstream. But in these clinical studies, they. Administered these parasites, two subjects, and then they killed the parasite with a drug in a bloodstream. So you allow full replication and the liver and you kill the para.
Immediately when it comes out of the liver and the bloodstream, if you use this type of immunization, it is extremely potent in, in protection. So it achieves 100% protection with three immunizations in subjects, and that is an amazing result that has never been achieved with any other vaccine. And that's our, I would say, our guidepost by which we want to go.
Of course, this is not a vaccination. You give para infectious parasites to individuals and treats them with a drug, but it gives us scientific evidence that the type of vaccines that we are, we are developing will be very potent in humans.
Kevin Folta: Well, that method does demonstrate that this approach could be efficacious, but does it also have a, your method, does it have a lot less [00:26:00] risk of potential breakthrough infection
Stefan Kappe: that is daily on our mind breakthrough infection?
So we were very worried about this because the number one, Priority with a vaccine is safety and it has to be absolutely safe. It cannot break through into the blood. So what did we do? So we created this replication deficient parasite, and more recently, this replication competent parasite attenuated at liver stage during the liver infection.
And short of going into humans, how do we test this? Well do the rescue come humanize mice. So we are using mice. Who have a humanized liver. They carry human liver cells, he parasites in their liver and they have also human red blood cells because we have humanized them for human red blood cells. So for our purposes, they're like little human.
And for the ma malaria parasites, they look like a little human. So we take our vaccine strains and we inject very high doses, millions of parasites into this humanized mice. And then we test if the parasite can complete liver [00:27:00] stage development and escaping into the blood. And in these studies, it turned out they cannot.
So the parasite was fully attenuated at liver stage. We like to call this that check in, but they don't check out a little bit like the cockroach motel. And so, so that showed that likely in humans we won't see breakthrough infections because in my carrying human heide, the whole cell of the parasite in the liver and human red blood cells, the host cell of the parasite in the bloodstream that these mice do not show braso infection.
Kevin Folta: Well, that's really exciting. So what happens next in terms of development? Is it really just the clinical trials and tests of this the, of the parasite that can replicate it's replication competent, but unable to perform the other stages of the lifestyle? The life cycle infection?
Stefan Kappe: Yes. So that will be next.
We will conduct a clinical trial in humans next year in Germany, actually with collaborators at the University of Tubing. That will recruit subjects and immunize them three times with 200,000 parasite forms vied in a vile, [00:28:00] and then challenge them three months later with a different strain of parasites.
So this is also important because we have great strain diversity of this parasite plus more falciparum, and I don't think I mentioned that name yet. That's the parasite we are actually targeting. The biggest killer of people in Africa plus modal. So we'll immunize with our vaccine strain and then challenge with a different strains that is genetically more distant.
And, and this is a big issue, remember Covid, right? You had great vaccines that worked against Alpha and then they didn't work so well against. You know all the other strains that came subsequently and exactly with malaria, there are so many strains out there that we have to protect against them all.
And so we'll test if these vaccines protect against other strains by challenging subjects with different strains of parasite, and if that gives us the desired. High levels of protection, a hundred percent then will move the product into testing in sub-Saharan Africa as quickly as possible. And hopefully if that works, then we'll have a licensed product on the market in five to seven years.
[00:29:00] But let me tell you about one more problem. You know, as scientists, we always think about problems, and this is a big one, and that is, can we. Hundreds of millions of doses of this vaccine in mosquitoes. Right? That's a real challenge. And the company scenario that that I mentioned is very good at doing this, but I think realistically, we have to think about this as a manufacturing.
Bottleneck. And so what they did recently, that's a very exciting development. They are actually now able to make these parasite vaccines in a culture dish or in a Biore reactor, and that will allow us to make very large numbers of doses in a relatively small facility. Big breakthrough for us this, this development because it really.
Now we have a vaccine strain that will work hopefully, and we have a manufacturing platform that can make hundreds of millions of doses. And those two combined might be the solution for malaria.
Kevin Folta: Yeah, I didn't think about that before. The, there's gotta be a lot of very strong. [00:30:00] Bottle, You don't wanna say bottlenecks, but barriers in culturing these things in the salivary glands of mosquitoes, you'd have to raise Jills of mosquitoes and have lots of blood to feed 'em and everything else, right?
So this is actually being done in culture in Biore reactors. Now it is
Stefan Kappe: being so it, so the vaccines before were made in mosquitoes, it actually. Colonize mosquitoes that are sterile so they don't have any microbial burden. So we can use them to basically generate these parasite vaccines and accumulate them in the celebrate lens from which they are extracted.
And then purified and vi. But now the company can make these vaccines and Biore reactors, and that is big breaks, as I said. Hopefully will solve the issue of vaccine shortages that we might face with this type of vaccine. Because ultimately vaccines can induce high levels of protection. But if we don't get them to everyone who needs them, it's a problem.
So we need not only to have an effective vaccine, but we also need to have a. Method of generating it that allows us to reach [00:31:00] all the people who need it.
Kevin Folta: Well, that brings up the other problem of logistics, that this is an attenuated ucar organism, and this is a, this is a plasmodium. So how lay is that in terms of its ability to be shipped and maybe not be on ice or be kept cold?
Is this something that could realistically be shipped around the world and be administered success?
Stefan Kappe: Yeah, so right now the preservation is actually done in liquid nitrogen. So we'll use liquid nitrogen shippers to distributes a vaccine. And that sounded rather difficult, you know, initially, but it turns out it's actually quite possible.
And there have been studies that have been done to look at this and it's, it's feasible to do this. And you know, with the covid vaccines, we all realize that cold chains for vaccines. Big issue. Right? And vaccines that are refrigerated are easier to store and deliver, but they come with a big issue. And that's vaccine spoilers, right?
So they're basically, you know, they're not perfectly refrigerated. They spoil. And now with the Covid vaccines being stored at [00:32:00] minus 80, that showed us, well, you know, it's possible to deliver vaccines that are kept at very low temperatures. It's possible to deliver them to, well by now. People. Correct. So liquid nitrogen I think is feasible and we'll, we'll, we'll see where it goes, but I think it can be done.
Kevin Folta: Well, maybe this is the worst question I'll ask all night, but how much of a step would the successful vaccine be in this global flight fight against malaria?
Stefan Kappe: Well, if we achieves the efficacy levels that we are aiming at 70 to a hundred percent, and if we can get the vaccine to all the people who need it, we would hopefully be able.
Eliminate malaria from large areas of the world within 10 to 15. And that means no more transmission. This is something that, that you have to think about as well. If you have the sterilizing vaccine of vaccines that didn't use a sterilizing protection, you breaks a transmission cycle. Think of, again, covid is a good example.
You know, initially we thought it protects against infections and we were talking about does it protect against disease? [00:33:00] But people can still transmit. No, we don't want a vaccine that protects only against disease, pulmon, malaria. We want a vaccine that protects against infection and breaks the infection cycle.
So if the parasite cannot be spread anymore, the transmission breaks down and the parasite is eliminated from a geographic area.
Kevin Folta: Oh, that's really great. Well, here's a question that comes from Covid though. Are there zoonotic reservoirs that that can harbor malaria or the, the, at least the plasmodium stage that can then be tapped to reintroduce to.
Stefan Kappe: That's a complex question. Let me try to give you an easy answer for PCI plus modal syrum, the parasites that we are targeting currently because it's the biggest killer in Africa and across the world, there's no no zoonotic reservoir as we know. But there other malaria parasite species that can infect humans, particularly in South East Asia where there are zoonotic reservoirs, and that's non-human primates.
So we haven't wrapped our mind yet around this problem because it's less of a, I would say, global. [00:34:00] Issue. It's more of a local issue in Southeast Asia, these parasites. But you know, maybe our vaccine will protect against those parasites as well. But to reiterate with PFA the parasites that we really need to eliminate zoonotic reservoirs are not an issue.
Kevin Folta: Well, this is all so exciting. And, and if people want more information, where should they look online or is there any presence in social media that describes what this process.
Stefan Kappe: Yeah, so I'm not big on social media. I'm a little bit of an older guy, but they can certainly go to our website at Seattle Children's Research Institute, KA Lab, and find information there and that can lead them to all relevant other sources.
If people want to learn more about malaria, the Centers for Disease Control has excellent information about malaria as well as the World Health Organization website. For our particular vaccine type, just come to our website at seattle children's dot org and you can read all about our
Kevin Folta: work.
Excellent. Now I'll include links inside the show notes. So, Dr. Stefan Kapa, thank you so much for your time tonight [00:35:00] on this. I feel a million times more enlightened about not just what malaria is, the extent of the problem, but really feel a sense of hope in the solutions that seem to be not that far away.
So thank you very much for joining. Thank you for having me, and as always, thank you for listening to Collabs Talking Biotech podcast. This is one to share widely because people need to understand what malaria is and the number of people it affects. It's a tragedy that this goes on as in such a broad context as it does, but at the same time, it seems like we're setting up for a success story in a new way to use genetic.
To disable that plasmodium that is the infectious agent, to be able to render modern techniques that could be able to almost eliminate the problem. This is Collaborate Talking Biotech podcast, and we'll talk to you again next week.