Host-directed Therapeutics for the Next Pandemic: What They Are and Why We’ll Need Them
The current pandemic has been labeled a “starter pandemic” by many because the mortality rate could have been much worse, as compared to what was seen in the 1918 influenza and the more recent SARS outbreaks. Over the past two years, the scientific community has been challenged with how to treat this novel virus. Now the focus needs to shift to preparing for what comes next.
In severe COVID19, we now know that injury caused by the patient’s own body (the ‘host’) — -rather than the virus per se — — is the major problem. For reasons that are still poorly understood, the immune response becomes excessive and out of control (‘dysregulated’), causing harmful inflammation that damages the lungs and other key organs.
The same problem of dysregulated and dysfunctional host responses is also seen in severe or fatal cases of many other infections and autoimmune disease. This has sparked efforts to develop drugs that can target (treat) these undesirable and harmful host responses, a quest captured in the term Host-Directed Therapeutics (HDTs). The dream of research in HDTs is to find drugs that can enhance a person’s protective immune responses against a pathogen, to reduce excessive inflammation and to optimize immune reactivity at the sites of disease.
For future pandemics, it would be highly desirable to identify in advance effective HDTs and have them ready for any outbreak. They would also be useful in the many non-pandemic cases of severe disease where runaway inflammation is a key factor. With this in mind, let’s review the state of the search for Host-Directed Therapeutics.
The good news: HDT works! In COVID19, the poster child for a successful HDT is the anti-inflammatory corticosteroid drug dexamethasone. After a rigorous randomized clinical trial (the RECOVERY study in the UK) showed that it reduces mortality and improves overall outcomes, this drug has become part of standard therapy for severe COVID19 cases. There are also other (non-COVID) examples of effective HDTs, particularly in autoimmune disease. For example, severe rheumatoid arthritis is often treated with agents that interfere with molecules responsible for excessive inflammation, e.g., anakinra is a recombinant normal human protein that blocks responses to the pro-inflammatory cytokine Interleukin 1.
The bad news: The number of approved HDTs is quite small. Finding effective and safe HDTs is hard. Researchers have identified hundreds of molecules that are overactive or are deficient inside excessive inflammation. However, knowing which one(s) we should target with drugs is challenging to say the least. Testing drugs in severely ill patients must be done cautiously so as to not make things worse, and with rigorous comparison groups (‘controls’). This ensures that any benefits seen are real, rather than better outcomes due to younger age or fewer accompanying diseases. These challenges and the need for a large number of patients in any trial make the investigation of possible HDTs expensive. A final sad truth is that many drugs that look promising in the lab or in mice don’t work when ultimately tested in patients. For example, numerous HDT drugs tested for control of the dysregulated inflammation in sepsis failed. This has also been the case for some HDTs tested in COVID19 (e.g. colchicine, hydroxychloroquine). Hence, we must be prepared for some failures along the way.
Back to good news: There is an abundance of ‘candidate’ agents that look like promising HDTs, based on laboratory and animal studies. We have a wealth of laboratory and animal model tools to prioritize agents and to test for safety before proceeding to human trials. A promising subset of the candidate agents use human proteins that are normally present in the body and are less likely to have any toxic side effects. One example is human plasma gelsolin. This abundant protein, which is depleted by inflammatory disease and infection, has many desirable immunomodulatory properties, improves outcomes in bacterial and viral pneumonias in animal models and has passed initial safety testing in human patients. It is currently being tested for benefit in COVID19 in Europe. Fingers crossed!
Finally, expanding our drug cabinet of effective immunomodulatory HDTs is very feasible (and needed) before the next pandemic. Although most people with garden variety (non-COVID) bacterial or viral pneumonias have mild disease and get better, a still substantial number get the same kind of severe disease that requires artificial ventilation and ICU-level care. These patients also suffer from excess and dysregulated inflammation, and they could certainly benefit from an effective HDT. Finding good HDTs for severe pneumonias will have direct benefits for a major need in the present.
It will also prepare us for the next pandemic.
Written by Dr. Lester Kobzik, Chief Scientific Advisor, BioAegis Therapeutics and Professor (emeritus) of Pathology at the Harvard Medical School and the Harvard T.H. Chan School of Public Health.