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Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop (2024)

Chapter: 5 Potential Research Priorities and Opportunities in Therapeutics

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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
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5

Potential Research Priorities and Opportunities in Therapeutics

Key Points from Individual Speakers and Participants1

  • An altered zonulin pathway and the presence of the spike protein in blood does not necessarily mean an individual will have long COVID. There also needs to be a genetic predisposition, which explains why only some people with the spike in their blood suffer from long COVID symptoms and others do not. (Fasano)
  • There are likely interactive feedback mechanisms between the immune system and microbiome. Developing alternative treatments for Lyme disease that do not wipe out good flora can help patients with acute disease but decrease probability of developing long Lyme by avoiding microbiota disruption. (Lewis)
  • Learning from different complex chronic illnesses is key, and it is important to know how they are similar and different in order to properly train clinicians and improve precision and personalized treatment approaches. (Putrino)
  • Infection-associated chronic illnesses are complex conditions that often require novel combinations of treatments to address multiple underlying causes. (Putrino)

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1 This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect a consensus among workshop participants.

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

Several speakers in this session emphasized the need for new treatment approaches and therapeutics that can be made available quickly for patients who have been suffering. This chapter focuses on several priorities for developing therapeutics for infection-associated chronic diseases, such as antiviral development (including drug development and repurposing), using combination therapeutics, and developing treatments specifically for children suffering from chronic symptoms following COVID-19 infection. Speakers also highlighted the potential for better treatments that do not disrupt the microbiome, as well as a variety of treatment approaches within a clinic setting.

ANTIVIRAL DEVELOPMENT

This section reviews current evidence on the development of antivirals for acute COVID infections and long COVID, and the understanding that informed the need for combinations of therapeutics.

Development of Paxlovid

Ravi Shankar Singh, Pfizer, provided remarks on the development of Paxlovid,2 an antiviral drug that is used to treat COVID-19 patients. While drug development is typically a very long process, the process for nirmatrelvir, the antiviral component of Paxlovid, took less than 2 years from concept to treating patients. Pfizer made a few innovative changes to expedite the process in an emergency situation, he said, including expedited drug design and manufacturing of the drug product, at-risk investment in commercial batches, and rapid internal decision making and regulatory interactions. Pfizer had worked on drug development during the 2003

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2 Disclaimer from the manufacturer: Paxlovid is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. Paxlovid has not been approved, but has been authorized for emergency use by FDA under an EUA, for the treatment of mild-to-moderate COVID-19 in pediatric patients (12 years of age and older weighing at least 40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death; and the emergency use of Paxlovid is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Act, 21 U.S.C. §360bbb-3(b)(1), unless the declaration is terminated or authorization revoked sooner. Paxlovid includes ritonavir, a strong CYP3Ainhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events. Prior to prescribing Paxlovid: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3Ainhibitor like Paxlovid and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring. Consider the benefit of Paxlovid treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed.

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

severe acute respiratory syndrome (SARS) outbreak and was able to draw from that experience to design a new drug candidate molecule for SARS-CoV-2 relatively quickly since the two viruses are structurally similar, Singh explained. One of the weaknesses of the molecule designed in 2003 for SARS-CoV-1 was that it had poor intestinal permeability; to address this, the drug design group altered some functional groups in the chemical structure to improve the oral bioavailability.

To enable the rapid timeline that was needed during the pandemic, the Pfizer team leveraged a machine learning/artificial intelligence design tool against a large dataset of drug molecules to predict antiviral efficacy and pharmacokinetic (PK) properties. Nirmatrelvir was then selected over 600 other potential therapeutic molecules flagged in this analysis. Pfizer used an innovative “first in human” study design, which efficiently informed and accelerated the launch of the clinical trial.3 Ritonavir, a protease inhibitor, was added after determining that it significantly increased the half-life of nirmatrelvir. Next, the team developed and used population PK and quantitative structural pharmacology models to project drug concentration and effect on the viral load in the blood to determine appropriate dosage and duration of treatment. As 5- and 10-day regimens had similar projected viral load reduction, they recommended a 5-day regimen to reduce the burden on patients.

With this information and data in hand, they moved toward testing the formulation in clinical trials. Early on, results showed that patients treated with Paxlovid were significantly less likely to experience hospitalization related to COVID-19 or death from any cause within 28 days of beginning treatment. The trial was stopped prematurely because of the exceptional efficacy.

Summarizing the lessons from this expedited effort, Singh shared the following lessons for future drug development:

  • Being bold and holding different stages of drug development in parallel, rather than in sequence, to expedite the process.
  • Sharing prior and emerging clinical development knowledge from other diseases or pathogens.
  • Increasing collaboration, flexibility, mutual regulatory recognition, and reliance.
  • Enabling rapid decision making through streamlined and timely interactions between sponsors and regulators.
  • Embracing digital tools to enhance access, speed, quality, and the patient experience.

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3 For details on the Paxlovid clinical trial design, see https://classic.clinicaltrials.gov/ProvidedDocs/31/NCT04756531/Prot_000.pdf (accessed December 10, 2023).

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

Development of Antivirals and Combination Therapies for Infection-Associated Chronic Illnesses

Sara Cherry, University of Pennsylvania, shared her work exploring antiviral therapeutics and using established virology knowledge to advance therapeutics for long COVID. She noted that the initial infection of SARS-CoV-2 was largely confined to the upper respiratory tract, even in people without symptoms. But once the virus moves into the lower respiratory tract, it tends to cause more severe symptoms and progress to acute illness. Symptoms of long COVID are highly variable, and there is a need to understand the connection between these symptoms and the initial infection, Cherry stated. The focus in developing antivirals is typically on blocking the acute infection through a number of different mechanisms. The largest class of antivirals is direct-acting molecules that prevent viral replication (e.g., Paxlovid, remdesivir). But viruses are intracellular parasites, and rely on intracellular host pathways to replicate, she said, so there have also been efforts to develop host-directed therapeutics such as halting viral replication by blocking a host enzyme that the virus needs to replicate. Lastly, there are immunomodulators that work to boost an early immune response that can also block viral replication.

As the pandemic emerged in 2020, Cherry said her team utilized their existing pipeline to focus on identifying antiviral small molecules with specific activity against SARS-CoV-2. They collaborated across the world to obtain drug repurposing libraries, which contain large numbers of small molecules originally developed to combat other pathogens. The largest class of approved antivirals resemble human nucleosides, the building blocks used to make RNA, which block viral replication when incorporated by the virus. Another large category they found from the library was inhibitors of human enzymes that make the nucleosides, which works by “starving” the virus of these building blocks for replication and thereby blocking infection.

Modeling some of the successes of HIV antivirals, she said her team understood that they could combine different agents to create a “cocktail” of small molecule inhibitors and increase the potency while also decreasing the likelihood of resistance. Their testing demonstrated synergistic outcomes when molnupiravir, a nucleoside analog, is combined with inhibitors of host nucleoside biosynthesis. They then used air–liquid interface cultures that mimic the human respiratory system where most of the viral replication occurs to test whether these drug combinations that worked well in cell culture assays were effective in an environment that resembles real-world infections. Using the air–liquid interface models, they were also able to find that treatment with interferons or small molecule activators of innate immunity was able to reduce the viral load. Using animal models, they found that adding brequinar to molnupiravir could decrease the viral

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

titers more than molnupiravir alone. This also led to significant decrease in pathogenesis in the lungs, added Cherry.

However, all these tests were focused on the acute infection, and her team was interested in what is causing the long COVID symptoms—whether there is viral antigen or whether the infection is similar or different in different compartments. Based on existing data, they focused this effort on the gastrointestinal (GI) tract. Given the widespread use of wastewater testing throughout the pandemic, she said it is clear that at least some stage of the infection cycle is affecting or being shed through the GI tract. While they mostly detected viral antigen in the respiratory tract in autopsy samples taken from patients with acute disease, samples from patients in the postacute phase revealed viral antigen within the GI tract of many individuals.

She shared some of their data from testing the activity of small molecule drugs used clinically, such as Paxlovid or interferon beta in a human intestinal cell line. They found that Paxlovid and interferon beta retained activity in the human intestinal cell line, while molnupiravir had decreased activity. Furthermore, prophylactic treatment by all three compounds showed antiviral activity in preventing infection, but there was significantly reduced activity with single-dose treatment regimens after the infection is established. Moving forward, she said they are beginning to test for a variety of regimen timelines and different combinations; it is hoped that doing so will inform the understanding of treatment strategies that might be helpful in long COVID patients.

CLINICAL TRIALS FOR MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN AND LONG COVID

Alessio Fasano, Harvard University, recalled his surprise as a pediatrician at the beginning of the COVID-19 pandemic when many were suggesting that children would be spared from the COVID-19 pandemic, which would be unusual for a viral infection While the virus travels from upper to lower airways in adults, it does not do that in children for reasons that are still unknown. Because of this, many children remained asymptomatic even though the virus attack rate is the same as in adults, so a proportion of children suffer from the same kinds of long-term effects seen in adults. Meta-analyses have since revealed the prevalence of more than 40 long COVID symptoms in children and adolescents, with more than 25 percent reporting the presence of one or more symptoms after 12 weeks (Zheng et al., 2023).

Fasano stated his belief that long COVID is a consequence of a virus that (1) persists in biological niches and (2) leads to chronic inflammation, eventually resulting in (3) autoimmune response. Solid evidence shows that this virus can be found in the gut even months after acute infection, he said.

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

His team also found that the immune response to the viral spike protein is a surrogate biomarker of multisystem inflammatory syndrome in children (MIS-C) when compared to healthy children (Yonker et al., 2021).

One of the consequences of viral persistence is dysbiosis of some host pathways, such as the zonulin pathway that modulates the intercellular tight junctions in the GI tract. When this pathway is upregulated the tight junctions are disrupted and there is uncontrolled antigen trafficking from the gut lumen into the bloodstream. Fasano shared the first study they did in children with MIS-C, where they found an elevation of serum zonulin, and participants had systemic symptoms including microbiota dysbiosis and tight junction disruption (Yonker et al., 2021) (see Figure 5-1). The viral spike protein is then able to enter the bloodstream as a result of zonulin upregulation, he explained, leading to cytokine storm, activation of specific T cells, production of proinflammatory cytokines, and formation of microclots that eventually result in more severe consequences for those individuals, such as long COVID and MIS-C. The presence of SARS-CoV-2 in the GI tract can precipitate this chain reaction. Zonulin has been associated with many chronic inflammatory diseases, he added, and the common element between these chronic inflammations is dysbiosis.

Through this study, Fasano and colleagues identified evidence of inflammation. His team detected SARS-CoV-2 in the stool weeks or months after initial COVID-19 infection, and its presence in the GI tract caused

Two images depict the impact of multisystem inflammatory syndrome in children on the gut mucosal barrier. The first image, representing healthy children, shows a tightly connected barrier, with zonulin linking the barrier together. The barrier separates the commensal microbiome from the homeostatic immune cells. The contrasting image shows the gut mucosal barrier is disconnected due to zonulin release in children with MIS-C resulting in SARS-CoV-2 translocation and inflammatory immune cells.
FIGURE 5-1 Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.
SOURCE: Alessio Fasano presentation, June 30, 2023; Hensley-McBain and Manuzak, 2021.
Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

imbalance to the microbiome, an increase in zonulin, and a leakage of highly inflammatory viral particles and antigens into circulation (Yonker et al., 2021). With this information, they theorized that instead of treating the consequence of the hyperinflammation, there might be an opportunity to treat the cause, i.e., the zonulin-mediated dysbiosis, barrier integrity alteration, and antigen trafficking that may be causing the spike protein to circulate. The same findings emerged with long COVID patients, when researchers found that zonulin levels were higher in long COVID patients, compared to those who were COVID-positive but did not develop long COVID symptoms and healthy controls. Additionally, low-density lipoprotein (LDL) levels were used as a biomarker surrogate of oxidative stress and inflammation, and there is a direct correlation between zonulin levels and this oxidative LDL, he explained (Mouchati et al., 2023).

Autoimmune response is also tied to viral persistence and inflammation. The spike protein of SARS-CoV-2 is a super antigen, Fasano said, with the capability to stimulate T cell expansion leading to autoimmunity, implying that individuals with a certain T cell receptor mutation would be at risk (Porritt et al., 2021). Simply having the altered zonulin pathway and having the viral spike protein in your bloodstream does not necessarily mean that the individual will develop long COVID, he clarified, as a genetic predisposition is also needed. This explains why only some people with the spike protein in their blood suffer from long COVID symptoms and others do not.

Thinking of clinical translation, Fasano theorized they could stop the pathway leading to MIS-C manifestation by stopping the passage of elements from the virus into circulation. Because there was no effective or approved treatment for children suffering from MIS-C at the time, they requested compassionate use approval from the U.S. Food and Drug Administration to administer larazotide and zonulin in these patients. This treatment was found to shorten the time to resolution for GI symptoms (from 6.7 to 2.3 days) and cleared the spike antigen very quickly (from 10 days to 1 day) (Yonker et al., 2022). This led to a phase 2 trial, which was halfway completed at the time of the workshop, but Fasano remarked on the favorable safety profile so far.4

Finally, in terms of a surrogate marker, Fasano shared an example from a young patient who was in the intensive care unit, and, along with other children at the time, was given the standard of care of intravenous immunoglobulin (IVIG), steroids, and Anakinra,5 but with little clinical

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4 For information about the clinical trial, see https://clinicaltrials.gov/study/NCT05022303 (accessed December 10, 2023).

5 Anakinra is an interleukin-1 receptor antagonist and an immunosuppressive drug approved to treat rheumatoid arthritis in adults.

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

improvement. When larazotide was administered in this patient, levels of the viral spike protein and C-reactive protein (an established marker of inflammation) both dropped. Taking this to the next level, Fasano said they just received approval for a phase 2 trial for treatment of long COVID, focused on pediatric populations who have spike protein or S1 in their blood as an indication of disrupted intestinal barrier integrity.

OPPORTUNITIES FOR PREVENTION AND TREATMENT OF LYME DISEASE ASSOCIATED CHRONIC ILLNESSES

Given the overlap in symptoms between chronic Lyme and other autoimmune disease, Kim Lewis, Northeastern University, wanted to investigate whether there was also an overlap between alterations in the microbiome in these disease states. Looking at different subgroups of patients compared with healthy controls, his team identified distinct signatures in the gut microbiomes for each group. There are also different gut microbiome signatures depending on treatment with certain antibiotics and the time point of treatment in relation to when the sample was taken. A typical marker of dysbiosis is expansion of the bacterial family Enterobacteriaceae, he said, which are associated with a proinflammatory state. This led his team to a working hypothesis that there are interactive feedback mechanisms between Borrelia burgdorferi, the human microbiome, and the immune system. He called attention to the routine treatment of acute Lyme disease with broad spectrum antibiotics, noting that while it is the only current treatment for Lyme, these antibiotics also disrupt the microbiome and may increase the probability of developing chronic Lyme-related symptoms. He suggested treating with a selective antibiotic that only kills Borrelia, helping patients with acute disease but also decreasing the probability of long Lyme by avoiding disruption of the microbiome that can be connected to many other conditions (see Figure 5-2).

A word map shows a variety of health conditions that are related to the microbiome. “Microbiome” is written in black text on the left side of the image. Nine diagonal black arrows connect “microbiome” to a variety of health conditions listed on the right side of the image. This image demonstrates the significant impact of the microbiome on many facets of human health.
FIGURE 5-2 Health and disease manifestations affected by the microbiome.
SOURCE: Kim Lewis presentation, June 30, 2023.
Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

Lewis described the process for identifying a selective compound for B. burgdorferi. He initially focused on ADEP4, a semi-synthetic acyldepsipeptide that activates a protease inside bacterial cells to kill the cell. Since ADEP4 and related compounds can kill both regular bacterial cells and persisters, it would be especially useful for any chronic infection. However, none of these compounds turned out to be effective against B. burgdorferi. Surprisingly, an antibiotic called hygromycin A that was first discovered in 1953 but never developed for clinical use, showed promise for specificity to B. burgdorferi, Lewis said. While hygromycin A has low activity against standard other bacterial pathogens, it is very potent against spirochetes.

Following this discovery, Lewis and colleagues tested hygromycin A in mouse models and found it was effective in clearing B. burgdorferi infection at different doses and administered through different routes. A single dose of hygromycin A at 1,500 mg/kg was able to eradicate B. burgdorferi in mice, Lewis noted. Importantly, hygromycin A did not disrupt the mouse microbiota. Lewis shared that his lab is currently advancing this drug toward a clinical trial and working with partners to increase development and build manufacturing capacity. He is aiming for a clinical trial endpoint of the alleviation of symptoms 6 months after treatment.

CLINICAL CARE ACROSS ILLNESSES

David Putrino, Mount Sinai Health System, started a clinic primarily focused on long COVID, but recognizing the overlap with so many other complex chronic illnesses, his team has also started to treat patients with other conditions, such as Ehlers-Danlos syndrome, myalgic encephalitis/chronic fatigue syndrome (ME/CFS), and Lyme disease. Putrino specified that this hybrid clinic and research center treats complex chronic illness, but it does not treat functional disorders. He reviewed some of the proposed underlying causes of long COVID pathology, including immune dysregulation, microbiota dysbiosis, autoimmunity, blood clotting, and dysfunctional neurological signaling. These types of complex illnesses often require novel combinations of treatments to address multiple underlying causes, he said.

He presented steps they took toward creating a comprehensive clinical pipeline, with a robust preintake process to ensure the physician has all the necessary information by the time the patient is seen and to reduce strain on patients by limiting the number of in-person appointments. During the preintake process they perform several blood testing panels to look for coinfections; measure hormone, vitamin, and mineral levels; and perform coagulopathy and platelet activation to measure interleukins, inflammatory cytokines, and other symptoms of inflammation. They also document patient-reported outcomes using validated questionnaires. The next stage is a clinical intake exam that begins the treatment phase. It includes a discus-

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

sion of results from the preintake sessions, a personalized intervention plan, and postintake evaluations. These evaluations may include other patient-specific tests, such as electrocardiograms, endoscopy, or autonomic testing.

The next stage of the pipeline is “prehab,” which includes symptom management resources and conversations and lessons on how to best avoid symptom flare-ups, as well as breath work programs specifically focused on improving blood carbon dioxide balances. In conducting internal research, Putrino said his team found that 90 percent of patients who used their breath work platform for at least 3 months had improvement across indicators such as sleep quality and stress control. Next in the pipeline, is autonomic rehabilitation to promote more regulated autonomic nervous system through limb movements so patients can better tolerate upright body positions and movement. Putrino clarified that this rehabilitation is not a cure for the underlying disease but focuses on reducing severity of symptoms. The clinic also provides peer support and mental health services.

The clinic is also exploring innovative partnerships to enhance patient care, such as seeking grants from Uber to make ridesharing available for patients to come to appointments. It also makes referrals to additional health services and works with a compounding pharmacy to make medications more accessible. In closing, Putrino said they firmly believe that learning from different complex chronic illnesses is key, and it is important to know how they are similar and different to properly train clinicians and improve precision and personalized treatment approaches. He also noted that the clinic has a lived experience advisory board that provides guidance on all patient care and research initiatives.

DISCUSSION

The discussion covered use of Paxlovid, potential biomarkers for therapeutics development, the balance between specific and more general investments in therapeutics development, and lastly a call for increased patient-centered care models. In the context of long COVID, a participant asked about whether a longer treatment window, such as using a single therapeutic agent for 15 days, would reduce the risk of developing long-term symptoms. Cherry responded that starting with Paxlovid is reasonable, but that 15 days may or may not be enough. Having biomarkers to help follow the patient for efficacy and detect viral antigens would be helpful. Another participant asked how Paxlovid might work in a persistent infection, since it prevents the viral particle from replicating but does not clear the original viral reservoir. Cherry replied that the viral RNA cannot persist forever, as the RNA would eventually be metabolized with cell senescence and turnover. The GI epithelium especially turns over every 2 weeks, so that might clear the viral RNA more quickly. However, Avindra Nath,

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

National Institutes of Health, added that viral persistence would still be an issue if present in the brain, as brain cells do not turn over.

Regarding using the spike protein as a biomarker for viral persistence, Fasano said that he is not aware of any other source besides a virus that produces the spike protein. So, if it is present in the bloodstream, Fasano interprets this as an indication that (1) SARS-CoV-2 is still in the body, (2) the spike protein is circulating in the bloodstream, and (3) if there are specific T cell receptor mutations and the host is predisposed, then clinical symptoms of long COVID could result.

One participant asked about the balance between targeting pathogen- or disease-specific molecules for development and the more general investment from government agencies and policies right now toward disease-agnostic platforms. Putrino thought more information needs to be gathered in a highly stepwise and deliberate manner to understand the similarities and differences between conditions, which will inform the decision making between the two ends of this balance. He lamented the idea of running a well-designed randomized clinical trial on a highly specific therapeutic lead compound, but having very general inclusion criteria that impedes the effort to characterize a specific type of an illness and will likely lead to apparent failure of the trial. In this scenario, when the trial readout is negative, the potential therapeutic compound is often quickly given up. Instead, he called for a concerted effort to set up these registry style clinics around the country to get very detailed, well-classified data.

Finally, an attendee asked how the Mt. Sinai model of informed, compassionate, patient-centric clinical care can be exported and developed elsewhere for more people to access. Putrino replied that they are working to build curricular and training materials and will also be creating a complex chronic illness medical curriculum through Icahn School of Medicine. There needs to be a concerted effort to teach and reteach a new generation of clinicians, he concluded, as these illnesses caused by infections are treatable only if you know where to look.

Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"5 Potential Research Priorities and Opportunities in Therapeutics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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The National Academies Forum on Microbial Threats and Forum on Neuroscience and Nervous System Disorders hosted a hybrid public workshop in June 2023 to explore opportunities to advance research and treatment of infection-associated chronic illnesses. The illnesses discussed in this workshop, including COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), persistent or posttreatment Lyme disease syndrome (PTLDS), and multiple sclerosis (MS), share overlapping mechanisms and symptoms and have been inadequately researched. Recognizing these commonalities, speakers identified the need to advance research more comprehensively, translating to improved diagnostic and treatment options for patients across multiple conditions.

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