VIEWPOINT The Journal of Clinical Investigation Is innate immunity our best weapon for flattening the curve?

Leonard Angka,1,2 Marisa Market,1,2 Michele Ardolino,1,2,3 and Rebecca C. Auer1,4 1Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 2Department of Biochemistry, Microbiology, and Immunology, 3Centre for Infection, Immunity, and Inflammation, and 4Division of General Surgery, Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada.

The COVID-19 pandemic is a stern re­ Ideally, alternative strategies to social penia, and a protracted clinical course (6). minder not to take our immune system for distancing should (a) still protect high- These similarities should raise a caution­ granted. The fact that some individuals con­ risk individuals, (b) accelerate the glob­ ary flag, since humoral responses against tract and clear the SARS–CoV-2 virus without al recovery, and (c) easily be adapted to this feline coronavirus, rather than being apparent symptoms stands in sharp contrast tackle future pandemics. Here, we move protective, result in a more severe disease to the damage that this virus has brought forward the hypothesis that harnessing course. In these cases, subneutralizing lev­ upon more vulnerable populations, including innate immunity is our best weapon for els of spike S protein antibodies opsonize the elderly and patients with chronic con­ fighting novel viral outbreaks by prevent­ the virus and promote infection of immune ditions or cancer. While the differences in ing a productive infection or by accelerat­ cells expressing Fc receptors (antibody-de­ severity of infection between these popula­ ing viral clearance. pendent enhancement of disease). It is tions are multifactorial, it is likely that innate Active immunization provides pro­ likely that current vaccine endeavors will immunity provides the underpinning, given tection against a specific vaccination tar­ overcome these barriers, but this will take its central role in the early response to viral get through antigen-specific responses time and the vaccine may be ineffective infections. Within two decades, there have by adaptive lymphocytes. An effective against future coronaviruses (7). been three known coronavirus zoonoses antigen-specific vaccine can completely An intriguing alternate strategy to (SARS–CoV-1, MERS, and SARS–CoV-2), all protect the majority of healthy individu­ vaccination relies on enhancing innate of which have taken a devastating toll on the als, so it is not surprising that the world is immunity, which has been successfully human and economic health of affected soci­ waiting for this panacea with bated breath. adopted in veterinary medicine to prevent eties. Unfortunately, with the frequency and It is important to remember, however, that the transmission of respiratory viruses in diffusion of novel zoonoses, this is unlikely human endemic coronaviruses, which cattle housed in close quarters (8). Spe­ to be our last battle. As we begin the long and are responsible for up to 35% of common cifically, administration of an inactivated daunting recovery from this pandemic, we colds, often reinfect individuals, some­ Parapoxvirus ovis virus broadly activates must take the opportunity to think about how times even in the same year (2), despite innate immune components, including to exploit our innate immune system to better 90% of individuals developing corona­ dendritic cells, NK cells, and type I IFNs, prepare us to fight the next virus. virus-specific antibodies (3). Even when and protects livestock from many respira­ infection yields high antibody titers, the tory illnesses unrelated to Parapoxvirus. Harnessing innate immunity titer half-life is, in some cases, short (4). Innate immunity acts as our body’s “One may know how to conquer without Further undermining the hope for an front-line troops. Pattern-recognition being able to do it” (1). effective respiratory/coronavirus vaccine receptors recognize viral components and In most countries, interventions have been are examples from veterinary medicine, prompt IFN production. IFNs have direct put in place to flatten the curve. The goal where coronaviruses are scourges that antiviral activity and choreograph the of these interventions is to slow the spread have eluded eradication despite vaccina­ innate and adaptive lymphocyte respons­ of the virus so that capacity of medical tion. This is surely not for a lack of trying, es. They are so central to antiviral respons­ resources, such as hospital beds, ventilators, as bovine coronaviruses cause several dis­ es that zoonotic coronaviruses dedicate and personal protective equipment, is not eases, including shipping fever: a deadly much of their genome to suppressing them exceeded and we can adequately care for respiratory disease common in commer­ (9), lending credence to the hypothesis the sick. While social distancing has proven cial feedlots that is responsible for an that prophylactic or early IFN treatment highly effective in flattening the curve, it is estimated loss of $900 million annually will circumvent immune evasion and often impossible for essential workers or vul­ (5). Another example is the highly lethal promote viral clearance (10). Based on nerable patients. Moreover, the ripple effects feline coronavirus, which shares similari­ this rationale, clinical trials with recom­ of social distancing on our economy and ties to SARS–CoV-1/2, including viral per­ binant IFNs are underway. One clinical well-being are not sustainable long term. sistence, induction of profound lympho­ trial (ClinicalTrials.gov NCT04320238) is using nasally administered recombinant IFN-α1β to prevent SARS–CoV-2 infection Authorship note: LA and MM contributed equally. MA and RCA contributed equally. among medical workers. A second clinical Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. trial (NCT04293887) will administer IFN- Reference information: J Clin Invest. 2020;130(8):3954–3956. https://doi.org/10.1172/JCI140530. α1β to newly diagnosed patients within 7

3954 jci.org Volume 130 Number 8 August 2020 The Journal of Clinical Investigation VIEWPOINT days of symptoms onset, while a third trial against COVID-19. Unfortunately, BCG infected cells, and present higher expres­ (NCT04331899) will treat mild COVID-19 is contraindicated in many vulnerable sion of inhibitory receptors, e.g., NKG2A, cases with type III IFN, which has partially patients, such as those undergoing chemo­ which increases the threshold of activa­ overlapping functions, but reduced toxici­ therapy. However, the IMM-101 vaccine tion for NK cells (19). However, in more ty compared with type I IFN. If successful, (heat-killed Mycobacterium obuense) has severe COVID-19 infections, myeloid these trials will provide the proof of con­ a mechanism of action similar to that of cells accumulate in the lungs and pro­ cept that prophylactic/early stimulation of BCG, with an established safety profile in mote the recruitment and activation of the innate immune system provides pro­ cancer patients (16). The Canadian Cancer lymphocytes, including NK cells. Once in tection against SARS–CoV-2 and, in theo­ Trials Group has proposed testing IMM- the lungs, NK cells are likely to be among ry, against future coronaviruses. 101 in a clinical trial to protect high-risk the main producers of IFN-γ, which con­ cancer patients who cannot self-isolate tributes to immunopathology and the Training innate immunity due to their treatment (CCTG ID IC8). development of acute respiratory distress “He who is prudent and lies in wait for an When considering the mechanism of syndrome (20). enemy who is not, will be victorious” (1). action of IFNs and heterologous vaccines, The discordance in our assertions that Like any army, our innate immune sys­ NK cells emerge as important mediators of innate immunity eradicates COVID-19 tem will respond more effectively when the therapeutic response. NK cells are key while having a pathological role in severe primed. Recent studies have highlighted components of the antiviral response due disease can be explained by whom we how the adaptive immune response as to their ability to eliminate virally infect­ study and when we study them. Most cor­ well as innate immunity can be trained ed cells and produce antiviral cytokines relative clinical studies are undertaken to respond to pathogenic insults. Trained upon activation (17). NK cell function is in patients who are already hospitalized immunity refers to a more potent inflam­ heavily dependent on the cytokine milieu or critically ill because those are the ones matory response caused by long-lasting that these cells act on, and both IFNs and accessible for blood samples, while mild­ epigenetic modifications in myeloid pro­ other proinflammatory cytokines pro­ ly symptomatic or asymptomatic patients genitors (11). The lack of specificity of duced by trained myeloid cells can prime have not been properly studied because the secondary response may be the key to and boost NK antiviral functions. Viral they remain at home in self-quarantine. successfully exploiting trained immunity infections, particularly with cytomeg­ Murine studies, which are highly con­ against COVID-19 and future pandemics. alovirus, generate a subset of memory trolled, will therefore be very informative The bacille Calmette-Guérin (BCG, NK cells that respond more potently to a when contemplating when to therapeuti­ live attenuated Mycobacterium bovis) vac­ secondary exposure to the pathogen (18). cally boost innate immune responses (21). cine was developed against tuberculosis Although NK memory responses have not A case in point is that IFN treatment with­ and in many countries is part of a child’s been studied in the context of coronavirus in 6 hours after infection was curative in immunization schedule. Epidemiological infections, therapeutic strategies that pro­ mice infected with SARS–COV-1, whereas studies have shown that BCG vaccina­ mote beneficial inflammation could lever­ delayed administration, at 12 hours, was tion is associated with an approximately age the additional benefits provided by the ineffective (22), revealing that timing is a 30%–40% reduction in unrelated respi­ establishment of a memory NK cell pool. key determinant of efficacy. ratory infections and reduced infectious The data point to a model where­ mortality in childhood (12). Corrobo­ Timing becomes the key by prophylactic or early innate immune ration for this effect was obtained in a determinant activation can prevent or attenuate the randomized controlled trial where BCG “He will win who knows when to fight symptoms following COVID-19, but when vaccination protected against experi­ and when not to fight” (1). ineffective, viral-induced innate immune mental infection of an attenuated yellow If an early and strong innate immune dysfunction, followed by a dysregulat­ fever virus (13). Accordingly, there were response is the key to protection and ed innate immune response, may wors­ fewer confirmed COVID-19 cases and effective viral clearance, why do reports en immunopathology and the severity of deaths in countries with mandatory BCG of innate immune dysregulation leading infection. We must take into account that vaccination (14), although a contrasting to severe pathophysiology dominate the innate immune cells, including myeloid report was recently published (15), high­ clinical SARS–CoV literature? Initially, and NK cells, have been implicated in lighting that more studies are required to immune suppression may be required to immunopathology when therapeutically clarify whether BCG vaccination confers establish a productive infection. This has eliciting an antiviral response. Therefore, long-term protection. However, given been confirmed in hospitalized patients therapeutic interventions need to be effec­ the abundance of mechanistic evidence in whom severe symptomatic illness was tive and well timed, as an untimely admin­ showing that heterologous vaccination associated with innate immune suppres­ istration of immunostimulating agents can results in trained immunity, BCG immu­ sion (19). Clinical studies have shown that exacerbate immunopathology and aggra­ nization is currently being explored in the coronavirus infections reduce the number vate disease (23). Netherlands (NCT04328441), Australia of circulating NK cells and alter their func­ How then can we determine when to (NCT04327206), Egypt (NCT04350931), tional status. NK cells in patients infected exploit immune activation, and in which and the USA (NCT04348370) in an with coronaviruses are less functional, patients? A simple and direct solution to attempt to protect health care workers indicating a reduced ability to eliminate this problem could once again come from

jci.org Volume 130 Number 8 August 2020 3955 VIEWPOINT The Journal of Clinical Investigation innate immunity and particularly from the our faith in the innate immune system — May 27, 2020]. Cell Host Microbe. https://doi. measurement of NK cell reactivity. NK after all, organisms have been doing it for org/10.1016/j.chom.2020.05.008. 11. Netea MG, et al. Trained immunity: a tool cells’ responsiveness is finely tuned by the over half a billion years. for reducing susceptibility to and the inflammatory milieu, of which IFNs are an severity of SARS-CoV-2 infection. Cell. essential part. While it can be challenging Acknowledgments 2020;181(5):969–977. to accurately assess the levels of different Research in the Ardolino lab is funded 12. Higgins JP, et al. Association of BCG, DTP, cytokines in COVID-19 patients, measur­ by grants from the Canadian Institute and measles containing vaccines with child­ hood mortality: systematic review. BMJ. ing NK cell responsiveness is straightfor­ for Health Research (CIHR), the Can­ 2016;355:i5170. ward. NK-Vue measures IFN-γ released cer Research Society (CRS), and the Joan 13. Arts RJW, et al. BCG vaccination protects by NK cells stimulated with a proprietary Sealy Trust, and research in the Auer lab against experimental viral infection in humans stimulating cocktail and is currently used is funded by grants from CIHR, CRS, the through the induction of cytokines associat­ in cancer patients to assess NK cell activ­ Ontario Institute of Cancer Research, the ed with trained immunity. Cell Host Microbe. 2018;23(1):89–100.e5. ity before treatment (24). A similar con­ Terry Fox Foundation, and BioCanRx. 14. Miller A, Reandelar MJ, Fasciliogne K, Rou­ cept could be translated to viral infections. menova V, Li Y, Otazu GH. Correlation between Interestingly, NK cell activity is strikingly Address correspondence to: Michele universal BCG vaccination policy and reduced low in patients who are particularly vul­ Ardolino, 501 Smyth Road, Cancer Center, morbidity and mortality for COVID-19: an epi­ nerable to COVID-19, such as the elderly, 3-328, Ottawa, Ontario K1H 8M2, Canada. demiological study [preprint]. https://doi.org/ 10.1101/2020.03.24.20042937. Posted on cancer patients, and patients recovering Phone: 613.737.8899 ext. 77257; Email: medRxiv March 28, 2020. from surgery (24). This assay could there­ [email protected]. 15. Hamiel U, Kozer E, Youngster I. SARS-CoV-2 fore be used to identify patients at high rates in BCG-vaccinated and unvaccinated risk of symptomatic and severe COVID-19 1. Giles L. Sun Tzǔ on the Art of War: The Oldest young adults. JAMA. 2020;323(22):2340–2341. and those that would benefit from innate Military Treatise in the World. London, United 16. Dalgleish AG, et al. 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