key: cord-1041117-s6v4bgev
authors: Sariol, Alan; Perlman, Stanley
title: Lessons for COVID-19 immunity from other coronavirus infections
date: 2020-07-14
journal: Immunity
DOI: 10.1016/j.immuni.2020.07.005
sha: 2768ab08659b765b39d1ab39f837298cf5d2100a
doc_id: 1041117
cord_uid: s6v4bgev

Abstract A key goal to controlling COVID-19 is developing an effective vaccine. Development of a vaccine requires knowledge of what constitutes a protective immune response and also features that might be pathogenic. Protective and pathogenic aspects of the response to SARS-CoV-2 are not well understood, partly because the virus has infected humans for only 6 months. However, insight into coronavirus immunity can be informed by previous studies of immune responses to non-human coronaviruses, to common cold coronaviruses, and to SARS-CoV and MERS-CoV. Here we review the literature describing these responses and discuss their relevance to the SARS-CoV-2 immune response.

COVID-19, caused by a novel coronavirus (CoV), SARS-CoV-2 (severe acute respiratory 26 syndrome-coronavirus-2), is the cause of a worldwide pandemic that has infected over 27 10,000,000 people with a mortality of about 5% to date (World Health Organization, 2020a).

Two previously identified CoVs, SARS-CoV and MERS-CoV (Middle East respiratory syndrome-29 coronavirus), caused severe pneumonia, but unlike SARS-CoV-2 exhibited only limited person 30 to person spread, resulting in dramatically lower numbers of confirmed cases (about 8100 and 48 cell epitopes, which are known to confer protection, though little is known about the longevity of clearance, contributes to demyelination (Bergmann et al., 2004; Pewe and Perlman, 2002; Pewe et al., 2002) . Adding further to the complexity of the role of T cells in balancing viral 150 clearance and immunopathogenesis, some subsets of these T cells, including T regulatory 151 (Treg) cells and IL-10-producing CD8 + T cells, are necessary for protection against excessive 152 immune responses in the CNS (Anghelina et al., 2009; Cervantes-Barragán et al., 2012;  153 Trandem et al., 2011) . Interestingly, virus-specific Treg cells targeting the same 154 immunodominant epitope as effector T cells are particularly critical for suppressing 155 immunopathology (Zhao et al., 2011a (Zhao et al., , 2014a . Of particular relevance to SARS-CoV-2 and 156 other highly pathogenic human CoVs, T cells are essential to prevent cytokine storm in MHV-strains of these common cold CoVs are known to circulate globally, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, the latter two of which were discovered following heightened common colds, and it has been estimated that 90% or more of adults have serum antibodies 187 against these 4 viruses (Gorse et al., 2010; Perlman and McIntosh, 2019) . Because these CoVs 188 are the closest to SARS-CoV-2 in transmissibility and ability to replicate in the nasopharyngeal 189 tract, albeit without the same predilection for severe lower respiratory tract disease, studies of 190 the immune responses to these viruses may be of particular relevance to the current pandemic 191 ( Figure 2A ) (Dijkman et al., 2013; Sungnak et al., 2020) .

The majority of our understanding of immunity against these viruses comes from experimental (Bradburne et al., 1967) . Similar to studies of animal elevated serum angiotensin II compared to wild type mice (Yang et al., 2014; Zou et al., 2014) .

In IAV-infected mice and patients, elevated serum angiotensin II is correlated with disease 251 severity. Further, Ace2 -/mice develop more severe IAV-mediated disease than do their wild 252 type counterparts. These results support the notion that downregulation of ACE2 may contribute 253 to SARS-CoV pathogenesis.

Studies of the immune response to SARS-CoV have consisted of both direct study of human 256 SARS patients and animal models of SARS, including macaques, marmosets, and ferrets, as 257 well as smaller animals, such as hamsters and particularly mice (Gretebeck and Subbarao, 258 2015). While mice are susceptible to infection with SARS-CoV, young mice develop no illness, 259 and aged mice develop mild clinical disease (Roberts et al., 2005) . In order to address this 260 limitation, transgenic mice expressing the human ACE2 (hACE2) gene were developed; 261 however, though they develop pulmonary disease, they also develop a lethal encephalitis 262 (McCray et al., 2007; Tseng et al., 2007) . A different approach instead adapted SARS-CoV to 263 mice by serially passaging the virus in mouse lungs. MA15, the first of these mouse-adapted 264 SARS-CoV strains, caused severe pulmonary disease in young mice (Roberts et al., 2007) . This The cytokine response to SARS-CoV was frequently characterized by high level production of 274 pro-inflammatory chemokines and cytokines, such as CCL2, CCL3, CCL5, and CXCL10, and IL-275 6, TNF, and IL-8 production, all of which were further upregulated in patients with more severe 276 disease (He et al., 2006; Jiang et al., 2005; Zhang et al., 2004) . Similar findings were also 277 observed in SARS animal models and in vitro, both in human airway epithelial cells and in 278 human monocyte-derived macrophages and dendritic cells (DCs) after infection (Cheung et al., 279 2005; Law et al., 2005; Yen et al., 2006) . Interestingly, while macrophages and DCs can be 280 infected by SARS-CoV and produce cytokines following infection, replication is abortive in these cells. Of note, infected monocytes/macrophages and monocyte-derived DCs do not produce type I IFN, suggesting that SARS-CoV immune evasion strategies are effective in these cells (Cheung et al., 2005; Law et al., 2005; Yilla et al., 2005) . mechanisms to counter the type I IFN response, both via evasion and direct antagonism of 

The type I IFN response in SARS patients was observed to be dysregulated in patients that 301 experienced adverse outcomes and severe disease, with one report finding that IFN responses 302 persisted significantly longer than in those patients that went on to recover, and were 303 accompanied by the lack of a protective anti-virus neutralizing antibody response (Cameron et 304 al., 2007) . Other reports did not describe this persistent IFN expression, and instead found a 305 poor IFN response relative to other respiratory viruses, a pattern that seems to be reflected in 306 patients infected with SARS-CoV-2 (Blanco-Melo et al., 2020; Reghunathan et al., 2005) . A responsible for significant immunopathology. Together, these data suggest a role for dysregulated IFN signaling in the immunopathogenesis of SARS-CoV and other CoVs.

The antibody response to SARS-CoV is characterized by seroconversion as early as 4 days and 322 generally around 10-16 days post-onset, with titers peaking around 15-20 days post-infection 323 (Hsueh et al., 2004; Lee et al., 2006; Wu et al., 2007) . Several neutralizing antibody epitopes, 324 predominantly against the S1 and S2 subunits of the S protein, and particularly the RBD in the 325 S1 subunit, have been identified (Buchholz et al., 2004; Zhong et al., 2005) . While antibodies 326 against other structural proteins have been observed, these are largely non-neutralizing 327 (Åkerström et al., 2006; Qiu et al., 2005) . A positive correlation between N-and S protein-328 specific serum antibody titers and recovery from SARS-CoV was observed, and passive transfer 329 of neutralizing antibodies was found to prevent replication in mouse models of SARS (Bisht et 330 al., 2004; Subbarao et al., 2004; Zhang et al., 2006) . However, these antibody responses have 331 been found to lack longevity. While serum antibody titers remain high for the first 2 years after 

found that sub-optimal T cell responses result from an impairment of respiratory dendritic cell 363 migration from the lungs to the lymph nodes (Zhao et al., 2009 ). This inhibition of DC migration 364 was mediated, at least in part, by inhibitory alveolar macrophages, as depletion of these cells 365 prior to infection resulted in enhanced T cell responses, viral clearance, and survival in mice.

Aging is thought to play a significant role in this process, as expression of prostaglandin D2 367 (PGD 2 ) and an upstream phospholipase (PLA 2 G2D) increase with age and are strongly 368 correlated with this migration defect and sub-optimal T cell response. Inhibition or depletion of 369 these factors reverse these age-related impairments (Vijay et al., 2015; Zhao et al., 2011b) . both. Neutralizing antibody responses are protective in CoV infections and are thus a primary target for vaccine strategies. However, as described above, antibody responses to CoVs can wane rapidly following infection or immunization, allowing for potential reinfection, particularly in 522 mild or subclinical disease such as those caused by the common cold CoVs or mild MERS.

Because SARS-CoV-2 infection often presents with asymptomatic or mild disease similar to the 524 common cold viruses (Arashiro et al., 2020; Black et al., 2020) , this is of particular concern, as it 525 is possible that those cases will develop rapidly waning immunity relative to severe cases, have found enhanced protection correlated with intranasal immunization relative to parenteral routes (Jia et al., 2019; Kim et al., 2019; Zhao et al., 2016) .

non-human CoVs. Viruses associated with ADE shows a preferential tropism for macrophages, 561 unlike human respiratory CoVs. As SARS-CoV-2 primarily infects the respiratory tract and 562 lungs, a markedly different tropism than the macrophage-tropic FIPV, ADE is unlikely in our 563 estimation. ADE has also never been observed in SARS or MERS, and sera from rats , 2006) . These mouse studies also indicated that VAERD was most 570 prominent in aged mice. While vaccines need to be carefully evaluated for evidence of VAERD, 571 there is good reason to believe that proper vaccine and adjuvant formulation will minimize the 572 risks of this problem, yet will still induce a protective immune response (Iwata-Yoshikawa et al., 573 2014). Critical will be to identify a vaccine strategy that elicits long lasting immune responses.

Reaching these goals will require progress on several fronts. Much of our understanding of 576 immune responses in the context of MERS and SARS resulted from studies of experimentally 577 infected animals. Thus, the establishment of useful animal models of COVID-19 will be 578 instrumental in understanding COVID-19 immunity. Taking cues from prior knowledge of SARS-

CoV and MERS-CoV animal models, several of these models are currently being explored, 580 including non-human primates, ferrets, hamsters, and mice. Each of these models presents 581 unique advantages and disadvantages. (Chandrashekar et al., 2020; Gao et al., 2020; Williamson et al., was mild and restricted to aged mice (Sun et al., 2020b) . Based on previous studies of hDPP4-KI mice, it is likely that passage through mouse lungs will be required for the generation of adenoviral vector encoding for hACE2, a method also used for the generation of a mouse model 627 of MERS (Zhao et al., 2014b) . Because vector is instilled intranasally, this results in expression 628 of hACE2 exclusively in the respiratory tract of mice (Hassan et al., 2020; Sun et al., 2020a) .

Finally, another approach is to use reverse genetics to mutate residues in the receptor binding 630 domain, allowing for binding of the virus to mouse ACE2 and thereby facilitating viral entry into 631 mouse cells. One such mouse-adapted virus, generated via targeted mutation without serial 632 passage, is able to replicate in mice, though clinical disease was mild and observed primarily in 633 aged mice (Dinnon et al., 2020) . As in the case of hDPP4-KI mice, further passage of this virus 634 through mouse lungs will likely result in more virulent virus. Thus, it is probable that some 635 combination of mouse-adapted virus and wild type or hACE2-expressing mice will produce the 636 most robust mouse models for severe COVID-19, and these models will complement other 637 models of mild disease. 

determining whether a neutralizing antibody and/or SARS-CoV-2-specific T cell response is 644 sufficient to prevent clinical disease and transmission is critical. If so, it will also be important to 645 determine the magnitude of the responses required to provide protection in order to inform both 646 social measures and vaccine strategies that can limit spread. Second, it will be essential to 647 perform longitudinal studies to establish the longevity of these protective adaptive immune 648 responses, following natural infection or vaccination. Proper and detailed longitudinal studies 649 will require substantial investment of resources by governments, industry sources, non-650 governmental agencies, and others. Third, identifying factors that contribute to the dysregulated 651 immune response and immunopathology in patients with severe disease could inform early 652 therapeutic options to limit disease severity. A critical part of these endeavors will require 653 identification of biomarkers that identify patients predisposed to severe disease, so that they can minimize transmission, but also to identify vaccine-enhanced disease, so that vaccination is safe and widely accepted by the public.

Supported in part by grants from the NIH (PO1 060699, RO1 AI129269).

Åkerström, S., Tan, Y.-J., and Mirazimi, A. (2006) . Amino acids 15-28 in the ectodomain of Temperature-sensitive LAV (Fehr et al., 1997; Gerber et al., 1990) While the immune response to SARS-CoV-2 is not yet well understood, insights may be gained from studies of other coronavirus infections. Here, Sariol and Perlman review the literature on animal and human coronavirus infections and discuss the critical outstanding questions for understanding SARS-CoV-2 vaccination and protective immunity.

Antibody responses against SARS coronavirus are correlated with disease outcome of 1309 infected individuals

Analysis of serum cytokines in patients with severe acute respiratory syndrome

T cell responses are required for protection from 1320 clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-1321 infected mice

IFN-γ-and IL-1323 10-expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during 1324 encephalomyelitis

Acute Respiratory Syndrome Target a Dominant Site in the S2 Domain of the Surface Spike 1354

Active replication of Middle East respiratory 1357 syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in 1358 human macrophages: implications for pathogenesis

A pneumonia outbreak associated with a new coronavirus of 1361 probable bat origin

Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections

No, multiple phase I trials

Betacoronavirus Human Respiratory No, three recently concluded phase I trials

SARS-CoV-2 Betacoronavirus Human Respiratory No, several ongoing trials