Immunomodulator Stockpiling as a Means of Broad Defense From Biological Threats

At the start of a future novel pandemic, there may be no targeted therapies against the novel microbe behind it. In fact, for many of the viral families that are most likely to cause pandemics, there are no proven therapies. This fact should drive R&D for new vaccines and therapies to protect against these families. But at the same time, it should make clear that we need to build on the best possible medical strategies to save lives that have emerged in the response to COVID and prior infectious disease crises that have not depended on specific therapies. The class of medicines known as immunomodulator therapies should be a key component of that strategy.

The purpose of this article is to examine the potential role of immunomodulators as a means of protecting against a wide range of future biological threats—whether they are deliberately caused by bioweapons or naturally occurring epidemics or pandemics—and to provide policy recommendations for implementing this approach. In the current pandemic preparedness era, which is characterized by skepticism among a portion of the general public, it is critical to have a robust evidence-based method to guide preparedness plans and clinical care decisions so as to avoid anecdote-only approaches around the use of countermeasures.

BASIS FOR FOCUSING ON MODIFYING THE HUMAN IMMUNE SYSTEM

The symptoms and the severity of every infectious disease affecting people is the result of a complex interaction between the infecting pathogen and the human immune system. Sepsis is the final common pathway for a severe infection of any type, ranging in cause from malaria to fungi to viruses to bacteria. Myriad factors—including genetic elements, route of infection, dose of infection, other underlying medical conditions, and prescribed medications—influence the response of the host (human). A dysregulated immune human response to infection is what distinguishes an ordinary infection from the highly damaging physiologic state known as sepsis. Because the immune response is in disarray in states of sepsis, regulating and modifying that response has been an active area of investigation for decades.

Modulating the human immune response—as an adjunct to targeted antimicrobial therapy—is one means to mediate against the damage incurred by the human immune response and improve outcomes of illness. Earlier successes with this approach include the use of the broad-spectrum host-modulating corticosteroids in the treatment of certain types of meningitis (tuberculous, Hemophilus influenzae, Streptococcus pneumoniae) and severe Pneumocystis pneumonia (1–4). Macrolide antibiotics, because of their anti-inflammatory properties, have adjunctive immunomodulator value for S. pneumoniae bacteremia as has intravenous immunoglobulin (IVIG) for septic shock (5, 6). More recently, corticosteroids have shown benefit in severe community-acquired bacterial pneumonia and refractory septic shock (7, 8).

There have also been many prior attempts to use specific modulation of certain cytokines and proteins whose quantity increases during infection and causing, in more severe cases, a cascade of harmful effects during sepsis. These attempts at the use of specific immunomodulators to treat sepsis have not been successful in providing a benefit. For example, efforts to interrupt the effects of interleukin-1 and to use activated protein C ended unsuccessfully (9, 10). These failures may be due to sepsis being heterogenous and a brief window of time in the disease process where a specific immunomodulatory molecule may be beneficial.

By contrast, during the COVID-19 pandemic, primarily before the advent of vaccines and specific antiviral therapy, the first medication shown to have benefits by decreasing mortality was the nonspecific immunomodulatory corticosteroid dexamethasone (11). The rationale for use was extrapolated from success in severe cases of pneumonia and acute respiratory distress syndrome. Subsequently, medications that specifically targeted interleukin-6 (IL-6), or the pathways related to it, showed mortality benefit (after it was noted to be elevated in severe cases). These mortality benefits persisted even when combined with antiviral therapy (12).

Given that the greatest mortality benefits during COVID-19 arose, not from specific antiviral therapy, but via nonspecific immunomodulatory approaches provides compelling evidence that a strategy that uses widescale immunomodulatory products in the time period before targeted medications or vaccines can be developed would be a highly effective new element to national preparedness efforts.

In the early days of responding to a serious biological event, whether deliberate, accidental or naturally occurring, the only products that have therapeutic and lifesaving benefits beyond supportive medical care may be an immunomodulatory agent. Such agents may be the sole means of decreasing mortality among a pandemics’ earliest patients, many of whom may be healthcare workers and other front-line workers. The ability to decrease mortality in these groups, at the earliest stage of a pandemic, may have cascading and outsized benefits.

PRIOR PANDEMIC EXPERIENCE

Though immunomodulation has been used in individual cases and for specific infectious syndromes (as mentioned above), their use during infectious disease emergencies in which standard-of-care therapies are not yet available or established, has shown their value over time.

The 2009 H1N1 Influenza A Experience

During the swine-origin influenza pandemic in 2009, largely ad hoc efforts to trial immunomodulatory adjuncts occurred. These agents included macrolide antibiotics, statins, and corticosteroids (13). Macrolide antibiotics such as azithromycin and clarithromycin, in addition to their anti-bacterial effect, also possess properties that impact the immune response. Similarly, statins possess properties that extend beyond lipid-lowering effects and can also impact the immune system. Efforts to use convalescent plasma and IVIG were also used with positive results (14, 15). Very few of these interventions were studied rigorously enough during the pandemic to demonstrate unequivocal benefit.

These attempts were not a fully systemic approach to the use of immunomodulatory agents. A systemic approach would include multinational randomized controlled trials of various compounds. However, investigators performed formal prospective cohort study clinical trials of both convalescent plasma and IVIG.

In seasonal influenza, clinical trials studying the prior use of statins, the administration of non-steroidal anti-inflammatory agents, and the administration of macrolide antibiotics have occurred, with the latter two showing positive benefits (16, 17).

As it currently stands, immunomodulation for influenza infections is not standard of care—primarily due to lack of robust evidence—but may occur in select individual cases. Both naproxen and clarithromycin have shown promise in reducing mortality and morbidity (17).

The COVID-19 Experience

In the early days of the pandemic, there were no specific countermeasures available or known to be beneficial. However, the early cases reported from China had immunological characterization performed. Such studies revealed, for example, elevation of inflammatory markers such as C-reactive protein (CRP), as well as cytokines such as IL-6, which are likely to be elevated in most serious infections (18).

This early knowledge fostered trial-and-error approaches on individual patients and led to clinical trials of known immunomodulatory agents. The initial medications trialed were those thought to modulate the inflammatory cascade of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on prior usage or mechanism of action.

At the time that formal clinical trials were being conducted, somewhat haphazard use of immunomodulatory drugs such as tocilizimab, baricitinib, sarulimab, and tofacitinib were being administered in an ad hoc manner. Such usage was driven by clinician knowledge, health system availability, and case severity.

Rigorous clinical trials, by contrast, were conducted by consortiums such as Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) with specific and explicit criteria based on regulatory status, plausible mechanism of action (based on human data, animal data, logical parameters), and other factors such as safety, drug-drug interactions, and availability of supply (19, 20). Additionally, and notably, the Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) group conducted multiple immunomodulator clinical trials keyed to their focus on severe pneumonia as they quickly entered pandemic mode (21).

Because such drugs, at the time, were being used off-label and were not being distributed or purchased by health systems to be used for COVID-19 but for their on-label indications, supplies at individual hospital systems were limited. This often led to in-hospital competition with other services (e.g., rheumatology) for allocation of doses of such medications. Aggressive stewardship of the medications among COVID-19 patients was pursued with some hospital systems restricting use to those with markedly elevated CRP or ferritin levels; high oxygen requirements; or the need for ICU admission.

As more clinical evidence and experience accrued, eventual Food and Drug Administration (FDA) emergency-use authorization (EUA) was granted to baricitinib and tocilizumab. Both drugs were later granted full FDA approval for use in COVID-19 patients. Vilobielimab (22), an anti-complement agent, also received EUA as did extracorporeal blood purification devices, for which the data are mixed (23). Other medications such as interferon-lambda (for which a deficiency exists during COVID infection), abatacept, and infliximab have also been demonstrated to show benefit in COVID-19 (24–26). Convalescent plasma was also used for COVID-19 with mixed results, possibly dependent on the titer of antibodies present in the preparation (27).

Table 1 lists successful immunomodulation therapies for COVID.

TABLE 1.

Available Immunomodulatory Agents for COVID-19

	Mechanism	Original Uses
Dexamethasone	Corticosteroid	Multiple
Tocilizumab	IL-6 blocking monoclonal antibody	Rheumatoid arthritis, cytokine release syndrome, giant cell arteritis, and juvenile idiopathic arthritis
Baricitinib	Janus kinase inhibitor	Rheumatoid arthritis and alopecia areata
Tofacitinib	Janus kinase inhibitor	Ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis
Sarilumab	IL-6 blocking monoclonal antibody	Rheumatoid arthritis
Vilobielimab	Anti-C5a antibody
Abatacept	T-cell immunomodulation	Rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, graft vs. host disease prophylaxis
Infliximab	Tumor necrosis factor -alpha blocking monoclonal antibody

IL-6 = interleukin-6.

POLICY IMPLICATIONS FOR PREPAREDNESS FOR BIOLOGICAL THREATS

Immunomodulation is part of treatment pathways for various infections, including emerging infectious diseases, epidemic pathogens, pandemic pathogens, and routine severe respiratory infections. However, even with this kind of increased recognition and value of immunomodulatory treatment modalities for severe infections, there has been little apparent advanced preparedness planning around these products by national governments as yet.

This should change now, and the U.S. government and other governments, working together with partners in the private sector and research institutions, should take a series of steps to move forward toward inclusion of immunomodulatory products in national stockpiles dedicated to preparedness for future biological threats.

Research to Understand Immunomodulatory Pathways of Viral Families of Greatest Pandemic Potential

The success of the various immunomodulatory agents used in the treatment of COVID-19 was the result of a targeted approach that was based on an early understanding of relevant immunological pathways. This understanding is derived from data, which included basic immunoprofiling generated very early in China. These data pointed, for example, to the involvement of one of the fundamental viral defense pathways (Janus kinase/signal transducer and activator of transcription). These pathways were then matched to known medications that were already known to target those pathways.

This type of basic immunoprofiling to elucidate which pandemic pathogens (or pathogen families) activate which pathways can be done now in advance of future major biological events, and it should be pursued at a minimum for pathogens that are representative of the key viral families with pandemic potential ((28), see Table 2).

TABLE 2.

Pandemic Viral Families

Orthomyxoviridae

Coronaviridae

Adenoviridae

Picornaviridae

Paramyxoviridae

Pneumoviridae

These viral families of greatest pandemic potential include viruses that are continuously causing infections in humans on daily basis, so there are clear routine opportunities to do immunoprofiling to understand the immune disruptions caused by these viral families and the immunomodulatory approaches that can be taken to try to protect against their impact. The National Institutes of Health, Centers for Disease Control and Prevention, Biomedical Advanced Research Development Agency (BARDA), and other PHEMCE (Public Health Emergency Medical Countermeasure Enterprise) members should develop an enhanced and robust agenda to perform these tasks.

For example, immunoprofiling of the cohort of the yearly several thousand severe respiratory syncytial virus, severe parainfluenza, severe rhinovirus, and severe adenovirus infections that occur in the United States alone could provide important foundational knowledge that could serve as the basis for clinical investigation and clinical trials of immunomodulatory agents to improved clinical outcomes not only for the seasonal cases that occur perennially but also for potential pandemic pathogens that may emerge from these families (Table 2). Such profiling has occurred in a non-systemic fashion but could be more formalized or actively pursued with the aim of fostering immunomodulatory treatments. In the event that a pandemic pathogen emerges that triggers those same pathways, immunomodulatory therapies could be at the ready and rapidly deployed.

Of these families that should be studied, special priority should be made for influenza given its proven high pandemic potential over the last hundred years. The immunomodulation that is used on a case-by-case basis should graduate to a more generalized practice with a strong evidence base. Some severe influenza cases have been shown to be the result of over-exuberant immune response driving the progression of the disease, of both seasonal and zoonotic (i.e., avian origin). Immunoprofiling of these cases should be prioritized. Additionally, hundreds of thousands of people are hospitalized in the United States alone each season with influenza and offer an opportunity for both immunoprofiling and immunomodulation. The U.K. GenOMMIC study which since 2015 has been collected and analyzing the DNA of those with critical illness caused by SARS, Middle East Respiratory Syndrome, and influenza (and also emerging syndromes) is such an effort that should be expanded and replicated (29). Animal infection models could be used to develop an understanding of the immunological dysregulation that occurs in infections that are rare or not-occurring in humans.

Conduct Interpandemic Clinical Trials

The U.S. government and other governments should prioritize conducting clinical trials on the seasonal members of pandemic-prone families. Basic immunoprofiling should be used as a guide to match disease processes with repurposable molecules with potential beneficial mechanisms of action, providing a basis for clinical trials. Similar criteria to that which ACTIV successfully used in the pandemic should be used to create master protocols and maintain their clinical trial infrastructure (30). To this end, efforts such as the ACTIV-initiated Strategies and Treatments for Respiratory and Viral Emergencies clinical trial platform should be supported, augmented, and given specific tasks regarding immunomodulators and respiratory viral infections. The REMAP-CAP effort, by continuously operating in the severe pneumonia space will, by definition, be among the vanguard for any emergent respiratory virus that will be swept into their trials. Similarly, the U.K. RECOVERY trial group, which established the efficacy of dexamethasone as a COVID-19 treatment, has now expanded from COVID-19 to include influenza pneumonia and nonviral pneumonias. Both are models to emulate and augment. The Australian and New Zealand Intensive Care Society Research Center is also a platform that is instructive (and is now conducting REMAP-CAP trials) (31, 32).

COVID and Influenza Immunomodulators Should be Stockpiled Now

During COVID-19 production capacity of some immunomodulatory was constrained in the United States The manufacturer of tocilizumab noted that demand was 400X baseline prepandemic conditions during certain points during the COVID-19 pandemic which created a critical national shortage (33). This shortage then sparked demand to spike for the similar medication sarilumab causing yet another shortage.

As such it would be prudent to stockpile immunomodulatories that proved most valuable in the COVID response, as well as the potential anti-influenza molecules such as macrolide antibiotics and non-steroidal anti-inflammatory agents, now for both seasonal use and for future coronavirus or influenza pandemic threats.

Stockpiling Preemptively as a Hedge Against Capacity

When other promising, effective, and safe immunomodulatory agents are identified through clinical research studies, they should be also included in stockpile planning and preparedness. Given the urgency of an infectious disease emergency, clinical research need not be fully complete in order to begin the process of stockpiling. Molecules with a plausible mechanism of action and some level of clinical data—similar to the criteria ACTIV used in during COVID-19—could be included in stockpiles with the aim of doing more investigation as needed, similar to the process.

Because these medications have well-defined normal and predictable markets in oncology or rheumatology, manufacturers have little reason to produce in excess of their traditional markets. Hence, the shortages of tocilizumab that occurred during COVID-19. Government procurement and stockpiling of these medications, and biosimilars when available, would create demand for higher quantities to be produced. Consequently, such an activity would avoid the shortages, rationing, ad hoc usage, and onerous stewardship that occurred during COVID-19.

Given the promise of immunomodulatory molecules in diminishing the severity of human infection, the United States and other countries should pursue a strategy for preparing for biological threats—deliberate, accidental, or naturally occurring—that includes immunomodulatory therapies. This is a task that should be pursued by U.S. government agencies such as BARDA; the PHEMCE; clinical trial groups; and pharmaceutical companies. Such a policy would require partnership between the government, private sector partners, and the research community, as exemplified by ACTIV and REMAP-CAP. This work would prioritize: the immunoprofiling of seasonal severe respiratory viral infections, clinical trials of known immunomodulators for infections other than SARS-CoV-2, studying relevant animal model immunoprofiles of potential pandemic agents for which human cases are sporadic (e.g., Nipah, Hendra), matching existing molecules that interfere with identified pathways, and funding the stockpiling of such medical countermeasures.