Having started his career in immunology, Dr. Mark Soloski began to apply his expertise to Lyme disease more than a decade ago when he joined the Johns Hopkins Lyme Disease Research Center. His work looks at the role the immune system plays in human Lyme disease, with a focus on trying to understand how it may contribute to the different outcomes of infection. Alongside Dr. John Aucott, he is engaged in the Study of Lyme disease Immunology and Clinical Events (SLICE), a longitudinal study of patients diagnosed with early-untreated Lyme disease and matched controls. As a scientific advisor for the LymeX Diagnostics Prize, a prize competition to accelerate the development of Lyme disease diagnostics, Dr. Soloski is helping mentor participating teams through office hours and webinars.

Through October 2023, the 10 teams in Phase 2 of the LymeX Diagnostics Prize are participating in a virtual accelerator designed to help them refine their concepts for detecting active Lyme disease infections in people. As part of the accelerator, teams have access to scientific advisors who provide valuable insight and feedback from their extensive experience in Lyme disease diagnostics. Note these scientific advisors are not official representatives of LymeX and are not in any way involved with submission evaluation or award decisions.

We spoke with Dr. Soloski to learn more about the barriers to diagnostics development, the need for collaboration, and the future of Lyme disease research.

Your research in Lyme disease focuses on the immune response to infection. Based on what you’ve found, what is the need for new diagnostics?
Dr. Soloski: “I’m an immunologist. My studies started at a very basic molecular level, evolved into an interest in the immune response to bacteria using mouse models, and now have focused on human Lyme disease. When I look at problems, I look at them through the lens of an immunologist.

We clearly need to have more effective diagnostics for early Lyme disease—the stage when the physician is trying to make the right call. Some physicians can make the call very easily based on clinical symptoms; sometimes there are gray areas, and that’s when diagnostics really need to help. We know that if you’re diagnosed early and treated properly early, you reduce long-term consequences, you reduce the probability of long-term persistent symptomatology.

To do that, we must apply next-gen approaches to develop new diagnostic approaches for Lyme disease. We need to have direct diagnostics that determine that this bacterium is in the host and causing symptomatology. Now we do this by measuring the immune response; that’s the basis of the current two-tier antibody testing. But these tests all rely on measuring a detectable immune response. If we can make antibody-based tests more sensitive, that’s great. Our tests are highly specific, and we don’t get many false positives. What we get is the negatives because the immune response hasn’t ramped up strongly in many individuals in early acute disease. 

Direct detection of the bacteria the blood is also very challenging, because Borrelia burgdorferi [the bacteria responsible for Lyme disease] is there for a very short period of time, and there’s not a lot there. It’s almost like gambling to see whether you can win and detect it. Most people know that the odds are against finding it. Anything that takes advantage of new approaches directly detecting the presence of the bacteria should be welcomed and supported and championed.”

It’s clear that patients and clinicians need innovation in diagnostics and treatment. What are the barriers to research and development when it comes to Lyme disease?
Dr. Soloski: “I think one of the challenges is that B. burgdorferi has an uncanny ability to evade the immune system. It does this in so many different ways: By slipping away from cells that like to phagocytize and destroy it, by changing structures on the surface so that an initial immune response will be evaded. It has many methods to interfere with the innate and adaptive immune response in profound ways. This is possibly why so many people with Lyme disease have weak or no detectable antibody response, especially at the early stages of disease when correct diagnosis is needed.

I find it amazing how this bacteria has co-evolved with its natural host of wild mammals, such as mice. Remember, we humans are unfortunately accidental hosts. We have not been part of the evolutionary story of B. burgdorferi. The primary reservoir for the Lyme bacterium is mice: Many mice in the wild are infected with B. burgdorferi, and those mice seem to be doing just fine. They’re not slow, they’re not sickly. If they were, the fox or the owl would’ve wiped them out. There’s this funny bargain that’s been made between the host and the bacteria as if, ’Well, I’m not going to make you sick. I’m going to replicate a little bit. I’m going to just make sure your immune system doesn’t really recognize me very well and I’m going to delay any kind of response you have until I get picked up by another tick and then moved on to the next host.’

It’s been a longstanding co-evolution. We humans did not participate in that co-evolution—we are a dead-end host, and perhaps that is why there are so many different perplexing disease outcomes. We know that there are people who get infected who just don’t make a good antibody response. For example, we know there are people who weren’t diagnosed or treated, perhaps symptoms were mild and/or they didn’t see a rash. These folks very often will show up, especially in North America, with something called Lyme arthritis. They’ll have a swollen knee and they’ll be diagnosed as having Lyme arthritis because they have a strong antibody response. But remember, that antibody response, while detectable, was not good enough to get rid of the bacteria. The bacteria still reside in the joint tissue. So even if you make an immune response, it’s not robust enough to get rid of the pathogen.

The other thing that’s interesting—and this is also very concerning—is that there are many different disease outcomes. Some people get diagnosed and treated properly and they do just fine. Those are the good outcomes. But we all know that there are many people who get diagnosed, treated, and develop long-term symptoms that can certainly impact the quality of life. That’s the outcome that, as a research team here in our Lyme Disease Research Center at Johns Hopkins, we’re very interested in trying to understand and trying to develop new approaches to treatment.”

The LymeX Diagnostics Prize is designed to help entrants overcome diagnostic development barriers, providing funding and technical assistance while fostering cross-disciplinary collaboration and partnerships. What has made you most excited about the prize competition?
Dr. Soloski: “The LymeX Diagnostics Prize gives people the freedom to be creative, the freedom to be bold. Plus, it also provides financial support. And I have to say, it’s been challenging in the human Lyme disease funding space to get support for these kinds of initiatives. That may be changing at the federal level. It’s happening kind of slowly, but it is happening. Not only does the NIH fund research in Lyme disease, so does the Department of Defense, and rightly so. There are also a number of private foundations that support Lyme disease research.

But the funding pales in comparison to many other infectious diseases. Considering that we have 300,000 to 400,000 new cases every year, that number should demand more attention in both the public and private sectors. This prize initiative, which is a collaborative effort between the Steven & Alexandra Cohen Foundation and the U.S. Department of Health and Human Services, can provide the kind of support that allows both academic and private industry investigators to be free to be creative and pursue ideas that maybe are high risk, but will certainly have the possibility of having a high impact.”

If the teams are successful, their work will mark the first major breakthroughs in Lyme disease diagnostics over the past 25 years. What are the potential implications for research into Lyme disease overall?
Dr. Soloski: “Whenever you develop or apply new technologies, you get insights into disease pathogenesis. So, for example, some groups are developing more sensitive antibody tests using arrays of bacteria proteins (antigens). Perhaps they may find that for some of those proteins, only 30% of people develop detectable antibody responses. What’s special about those 30% of people? How can we understand why they’re targeting this protein while these other people are targeting other antigens? That’s a clue as to how the host and the pathogen are interacting with each other.

B. burgdorferi in the Northeast, B. burgdorferi in the mid-Atlantic, and B. burgdorferi in the Midwest are genetically different from each other. Their overall structure and composition are the same, but there are subtle variations that we must appreciate. We may find out that the reason this test works on 80% of the people is that maybe the other 20% of the people are being infected by a certain bacterial strain that we’re just missing. This is not just a North American problem, it’s a European problem and Eurasian problem, too. And those strains are different than our B. burgdorferi strains. So, what we can learn here has not just the ability to impact what happens in the United States, but also elsewhere, since Lyme disease is in Canada, Europe, and Asia as well.

The teams’ work can help our understanding of the complexity of the bacteria and the complexity of the host response. Remember, as humans we’re genetically very heterogeneous. Our genetic output, our way in which we respond to pathogens, is not just influenced by the genes we inherited from our parents, but it’s also influenced by the experiences that we’ve had throughout our life. And we refer to that as epigenetic influences. Who knows, perhaps new diagnostic approaches can provide new insights into that as well. 

The new diagnostic approaches might also be of great value for the diagnosis of other tick-borne diseases. B. burgdorferi is not the only pathogen that is transmitted by the blacklegged tick, Ixodes scapularis. There could be some other pathogens that are driving febrile illnesses that overlap with Lyme disease and may be driving Lyme-like symptoms but are not Lyme disease. In one of the studies we did, we found that when we used a highly sensitive molecular detection approach and interrogated patients’ erythema migrans and blood, we found a set of patients that we could find no evidence that B. burgdorferi was present. They never—up to a year later—made a detectable antibody response against B. burgdorferi. So, these individuals clinically looked like Lyme, smells like Lyme, but as far as we can tell, is not Lyme. One of our puzzles is, what is that? Is that important? Shouldn’t we find out what’s driving the illness in these people too?

There’s a lot happening in the Lyme disease space that should give people a lot of hope. Not only the LymeX Diagnostics Prize, which is working to bring a cutting-edge, highly sensitive new diagnostic onto the landscape, but there’s development of a vaccine against Lyme disease. There are other ideas in the pipeline for other kinds of vaccine approaches. There are monoclonal antibody-based therapies, which are kind of similar in concept to what was developed for COVID. There’s a lot of things that people are investing their time and energy, their treasure, and their talent in.”

Phase 2 accelerator offers access to a range of expert resources.

Over the course of the Phase 2 accelerator, the cohort has access to virtual learning, mentorship, biorepository subject matter expertise, and networking opportunities designed to help the teams progress toward Food and Drug Administration review. A selection of accelerator resources will be made available to the public on the competition website to support broader innovation in Lyme disease diagnostics and treatment. Following the conclusion of the accelerator in October 2023, the cohort will submit concept papers that detail solution refinement, clinical and patient input, and a roadmap from lab to market.

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