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Emergency use authorization requests for anti-SARS-CoV-2 antibodies under FDA review

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On October 7, 2020, Eli Lilly and Company and Regeneron announced that they have submitted requests to the  U.S. Food and Drug Administration (FDA) for emergency use authorizations (EUA) of their anti-SARS-CoV-2 monoclonal antibodies.

Lilly’s EUA request is for bamlanivimab (LY-CoV555) monotherapy in higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19. According to the company, up to 100,000 doses of 700 mg LY-CoV555 monotherapy may be available in October, and one million doses available in Q4 2020.

The combination of LY-CoV555 and LY-CoV016, which bind complementary regions of the SARS-CoV-2 spike protein, for the treatment of symptomatic COVID-19 in an outpatient setting is also being evaluated. Lilly anticipates submission of an EUA request for combination therapy in November, and may have data to support a biologics license application submission for combination therapy as early as Q2 2021.

Regeneron’s EUA request is for REGN-COV2, which is a combination of two anti-SARS-CoV-2 monoclonal antibodies (REGN10933 and REGN10987). Regeneron was granted a $450 million contract to manufacture and supply REGN-COV2 by the US government, which has committed to making the doses available to Americans for free. The agreement covers a fixed number of bulk lots that are intended to be completed in the fall of 2020, as well as fill/finish and storage activities. At the time of the EUA request, Regeneron had doses available for ~ 50,000 patients, and expects to have doses available for a total of 300,000 patients within several months.

The Antibody Society is tracking the progress of recombinant biologic COVID-19 interventions in preclinical and clinical studies. Summary data for all anti-SARS-CoV-2 antibodies in clinical studies can be found here.

First study results for anti-SARS-CoV-2 antibody LY-CoV555

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On September 16, 2020, Eli Lilly and Company announced proof of concept data from an interim analysis of the Phase 2 BLAZE-1 clinical trial (NCT04427501) of LY-CoV555 (also known as LY3819253), an anti-SARS-CoV-2 IgG1 antibody. The randomized, double-blind, placebo-controlled study included 4 arms (placebo, 700 mg, 2800 mg, and 7000 mg administered intravenously (IV)), and enrolled mild-to-moderate recently diagnosed COVID-19 patients. Treatment is provided in an outpatient setting. The study was initiated on June 17, 2020 and has an estimated primary completion date of September 20, 2020.

  • The prespecified primary endpoint, change from baseline in viral load at day 11, was met at the 2800 mg dose level, but not the others. Additional analyses of viral data demonstrated that LY-CoV555 improved viral clearance at an earlier time point (day 3) and reduced the proportion of patients with persistently high viral load at later time points. Most patients, including those receiving placebo, demonstrated near complete viral clearance by day 11.
  • Analysis of pooled data from all dose groups indicated the rate of hospitalizations and ER visits was 1.7% (5/302) for LY-CoV555 vs. 6% (9/150) for placebo. Across all treatment groups (including placebo), no patients progressed to mechanical ventilation or died.
  • Viral RNA sequencing revealed putative LY-CoV555-resistance variants in placebo and all treatment arms. The rate of resistance variants was numerically higher in treated patients (8 percent) versus placebo (6 percent).
  • LY-CoV555 was well-tolerated, with no drug-related serious adverse events reported. Treatment emergent adverse events were similar across all dose groups and comparable to placebo.

Details for the BLAZE-1 study were updated on August 21, 2020 to include an experimental treatment arm comprising LY3819253 + LY3832479 (also known as LY-CoV016) administered IV.  LY-CoV016 binds a different epitope in the SARS-CoV-2 spike region compared to LY-CoV555. Across all treatment arms, the trial will enroll an estimated 800 participants.

Summary data for all anti-SARS-CoV-2 antibodies in clinical studies can be found here.

Fighting the Forever-war Against Infectious Diseases

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Author: Nick Hutchinson, Mammalian Cell Culture, Business Steering Group Lead, FUJIFILM Diosynth Biotechnologies (nick.hutchinson@fujifilm.com)

The COVID-19 crisis has had a devastating impact on populations across the world and caused the death of hundreds of thousands of people. The Antibody Society spoke to Dr. Jacob Glanville, CEO and President of Distributed Bio, Inc. to learn how his company has approached the development of new antibody therapeutics against the SARS-CoV-2 Coronavirus. He described how the crisis has stimulated innovation that may revolutionize the way we approach antibody discovery and development once the current pandemic is under control.

Dr Glanville explained, “The problem, when we think of every major outbreak, such as Ebola, SARS, MERS, Swine Flu, Avian Flu, is that the time it takes to develop a new drug is too long compared to the speed with which we need it. De novo discovery is too slow.”

To develop antibody therapeutics against COVID-19 as quickly as possible, Distributed Bio identified anti-SARS antibodies from almost 20 years ago that researchers had already shown would neutralize the SARS virus in vitro, protect mice from lethal challenge, and had known crystal structures. These antibodies have been studied extensively but were eventually too late to have an impact on the SARS crisis of 2003. It was Glanville’s idea to take advantage of the detailed functional research already performed on these antibodies and, try to retrofit them to bind to the new version of their original target the virus SARS-CoV-2. For this purpose, Distributed Bio applied their Tumbler technology, a computationally-guided antibody optimization method, capable of producing a library of billions of variants of individual antibodies exploring variations of all six complementarity-determining regions simultaneously.

“The novel coronavirus has around 74% homology in identity with the SARS receptor binding domain. I knew exactly how similar they were to the novel coronavirus as we had crystal structures of the SARS epitope. I believed that if we took five anti-SARS antibodies, there was going to be a pretty good chance that we would be able to adapt them to be a potent medicine against COVID-19,” said Glanville. “We already knew that they had the correct function, that they bound the right epitope in the right orientation with the right elbow angles. I believed that we could optimize them and enhance their affinity by making billions of versions of the antibodies within the library,” he continued.

According to Glanville, this is crucially important because historically, with outbreaks such as Ebola, the first antibodies launched were essentially prototypes with low potency or had inferior characteristics such as poor thermostability. It was the best-in-class not the first antibody that was successful, ultimately.

Distributed Bio were able to adapt all five antibodies in just nine weeks, a testament to the remarkable speed of these novel technologies. They sent a set of the most promising candidates to five laboratories which independently confirmed their ability to bind to the new SARS-CoV-2. The company then selected the two most potent antibodies for in-vivo testing, and two laboratories confirmed independently that both candidates protected healthy, as well as immuno-compromised animals using hamster models.

[Read more…]

SARS-CoV2, COVID-19 and the Cytokine Storm

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Written by Damani Bryant, Bio-Techne

The advent of a global pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has infected over 18 million people globally, as of August 2020. Of those infected, more than 700,000 people have been killed by coronavirus disease 2019 (COVID-19). Our current understanding is that the crisis began with several cases of pneumonia in Wuhan, China in early December 2019 (1). The World Health Organization (WHO) declared COVID-19 a public health emergency of international concern on January 30, 2020. COVID-19 was subsequently declared a pandemic by the WHO Director General on March 11. By August 2020, the WHO-documented distribution of COVID-19 infections is as follows: 9.9+ million cases in the Americas, 3+ million cases in Europe, 2+ million in South-East Asia, 1.5+ million cases in the Eastern Mediterranean, 800,000+ cases in Africa, and 300,000+ cases in the Western Pacific.

COVID-19 symptoms

Efforts to contain SARS-CoV2 are stymied by the fact that many of the infected are asymptomatic. One study estimates that up to 45% of those infected are asymptomatic (2). Symptomatic individuals have an onset between 2 and 14 days after exposure to the virus (3).  Relatively mild symptoms described by the  Centers for Disease Control (CDC) include: fever, chills, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headaches, loss of the sense of smell, sore throat, congestion or runny nose, nausea or vomiting and diarrhea. More severe responses to infection can progress from cytokine release syndrome (CRS), also known as the “cytokine storm”, to acute respiratory distress syndrome (ARDS), multiorgan failure, and death. CRS is thought to be an important step in the progression to ARDS in SARS-CoV2, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infections (1,4). The clinical presentation of CRS ranges from mild fever, arthralgia, myalgia to high fever, uncontrolled systemic inflammatory responses, vascular leakage to disseminated intravascular coagulation and organ failure among other symptoms (5).  ARDS is formally defined as a respiratory failure within a week of a known insult that is characterized by bilateral opacities that are not fully explained by cardiac function or volume overload, effusion (fluid buildup), lung collapse, nodules and oxygenation below a specific threshold (6).  The death rate associated with ARDs is 40%.

Biology of SARS-CoV2 and COVID-19

SARS-CoV2 is a member of the Coronaviridae family, specifically the Coronavirinae subfamily that includes 4 genera: α-coronavirus, β-coronavirus, γ-coronavirus and δ-coronavirus (7). SARS-CoV2, SARS-COV and MERS-CoV are all RNA β coronaviruses. SARS-CoV2 shares 80% sequence identity with SARS-COV and 50% sequence identity with MERS-CoV (1,8). SARS-COV emerged from China in 2002 and spread globally, infecting over 8,000 and killing more than 700 people (8,9). MERS-CoV emerged from Saudi Arabia in 2012 and was responsible for over 2,000 infections and over 800 deaths globally (9). All three coronaviruses cause severe respiratory disease in humans. Although the SARS-CoV2 symptoms are milder and the mortality rate is thought to be lower (~3%-6.7%) than SARS-CoV (9.6%) and MERS-CoV (35%), it has a faster transmission rate in humans (7,8,10).

SARS-CoV2 and SARS-CoV enter cells via the angiotensin-converting enzyme-related carboxypeptidase (ACE2) receptor, which is expressed on cardiopulmonary and hematopoietic tissues. (1,11-13). SARS-CoV2 has been reported to have a 10-20 times higher binding affinity for ACE2 than SARS-CoV (7). Receptor-mediated viral entry requires priming of the S1 region of the viral spike (S) by the transmembrane serine protease 2 (TMPRSS2) (8,11,12). The S1 region of the viral spike binds to ACE2 followed by S2 subunit-mediated fusion of the viral and cellular membrane. After membrane fusion, ACE2 and SARS-CoV2 are endocytosed into the cell. SARS-CoV2 internalization has been correlated with increased production of proinflammatory cytokines such as nuclear factor kappa B (NF-κB) and interleukin 6 (IL-6) (8).  IL-6 signals through a cis signaling pathway and a trans signaling pathway (13). The cis signaling pathway involves the binding of IL-6 to a complex containing IL-6 receptor (IL-6R) and glycoprotein 130 (gp130). This stimulates the downstream activation of the Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3) pathway. Activation of this pathway can promote CRS via activation of innate  and acquired immune mechanisms, including T cell differentiation and B cell activation and differentiation. In the trans signaling pathway, IL-6 forms a complex with soluble IL-6R and gp130 on many cell membranes due to the gp130’s ubiquitous expression. This propagates the CRS-stimulating signal to cells that do not express membrane IL-6R. Other cytokines and growth factors that are altered  in response to the trans signaling pathway include increased vascular endothelial growth factor (VEGF), monocyte chemoattractant protein 1 (MCP-1), IL-8, and decreased E-Cadherin in endothelial cells (13). As alluded to previously, CRS is characterized by the release of excessive amount of proinflammatory cytokines such as interferons, interleukins, chemokines, Colony stimulating factors, and tumor necrosis factor alpha, that are harmful to the host (8). Quantitative real time PCR studies of intensive care unit COVID-19 patients have documented elevated transcripts of a variety of cytokines including:  IL-2, IL-7, IL-10, G-CSF, IP-10,  MIP-1A, TNF  and CXCL-8 (14).

Methods for assessing the cytokine storm

A National Cancer Institute scale is commonly used to grade the severity of CRS in patients (5).  Other scales include: the Penn Grading Scale, Common Terminology Criteria for Adverse Events (CTCAE) v4.0, Lee et.al, 2014 and the MD Anderson Cancer Center (MDACC) scale (15). Grade 1 is characterized by fever. Symptoms are mild and not life threatening. Symptoms may or may not require treatment depending on the scale used. Grade 2 is characterized by hypotension that is responsive to fluids or low dose vasopressors. Symptoms are more moderate at this stage and may require hospitalization. All scales suggest an intervention. Organ toxicities may also be observed at this stage. Grade 3 is characterized by hypotension that requires high dose vasopressors, hypoxia and organ toxicities. Symptoms are more severe at this stage and require more aggressive interventions. Finally, grade 4 CRS is severe enough to require ventilation. CRS complications at this grade are life threatening.

Efficacy of COVID-19 therapeutic candidates

Circulating IL-6 has been correlated with COVID-19 severity in patients (16). Given the prominent role of IL-6, it is no surprise that tocilizumab, a human monoclonal anti-IL-6R antibody has been administered to patients with severe COVID-19 (17). Tocilizumab is approved for the treatment of CRS triggered by CAR T cell therapy by the Food and Drug Administration (13). Early data indicated that tocilizumab is associated with a shorter duration of vasomotor support and ventilation, shorter median time to recovery, improvement in CRS grade and computerized tomography imaging results in COVID-19 patients (17, 18). However, more recent data from Phase 3 clinical trials indicate that the human IL-6R antibodies tocilizumab and sarilumab are not associated with an overall benefit in COVID-19 patients. The Phase 3 sarilumab trial was recently halted because it failed to reach primary and secondary endpoints (19). A Phase 3 (global randomized, double blind, placebo controlled) tocilizumab trial was also halted because it failed to meet its primary endpoint of improved clinical status in patients hospitalized with severe COVID-19 pneumonia (20).

The corticosteroid dexamethasone, which is known for its anti-inflammatory and immunosuppressive effects, has recently been shown to reduce the mortality of COVID-19 patients on ventilators by one-third according to preliminary data presented to the WHO (21). Dexamethasone is now recommended standard of care for “patients with COVID-19 who are mechanically ventilated and in patients with COVID-19 who require supplemental oxygen but who are not mechanically ventilated” (22,23).  However, like tocilizumab, the anti-malarial drug hydroxychloroquine has fallen out of favor and clinical trials have been halted due to lack of efficacy (24).  As of mid-August 2020, there are over 3,000 COVID-19-related studies listed on the clinicaltrials.gov website, suggesting many other interventions are still being evaluated. Taken together, the rapid global transmission and high mortality rate of those infected underscores the urgent need to understand COVID’s mechanism of action and quickly pivot when a vaccine or therapeutic candidate is not efficacious.

References

  1. Coperchini, F. et al. (2020) The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 53:25
  2. Oran, D. P. and E. J. Topal (2020) Prevalence of Asymptomatic SARS-CoV-2 Infection A Narrative Review Ann Internal Med. [Epub ahead of print]
  3. Laur, S. A. et al. (2020) The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Int Med. 172:577
  4. Channappanavar, R. and S. Perlman (2017) Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 39:529
  5. Shimabukuro-Vornhagen, A. et al. (2018) Cytokine release syndrome.  J. Immunotherapy of Cancer. 6:56
  6. Matthay, M. A. et al. (2019) Acute Respiratory Distress Syndrome. Nat. Rev. Disease Primers. 5:18
  7. Fani, M. et al. (2020) Comparison of the COVID-2019 (SARS-CoV-2) pathogenesis with SARS-CoV and MERS-CoV infections. Future Virol. [Epub ahead of print]
  8. Hirano, T and M. Murakami (2020) COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome. Immunity. 52:731
  9. Lu, R. et al. (2020) Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 395:565
  10. Perlman, S. (2020) Another Decade, Another Coronavirus. N Engl J Med. 382:760
  11. Zhou, P. et al. (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature [Epub ahead of print].
  12. Hoffmann, M. et al. (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell [Epub ahead of print]
  13. Moore, J. B. and C. H. June (2020) Cytokine release syndrome in severe COVID-19. Science 368:6490
  14. Huang, C. et al. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395:497
  15. Liu, D. and J. Zhao (2018) Cytokine release syndrome: grading, modeling, and new therapy. J Hemat & Oncol. 11:121
  16. Ulhaq, Z. S. and G. V. Soraya (2020) Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect. 50:382
  17. Kewan, T. et al. (2020) Tocilizumab for treatment of patients with severe COVID–19: A retrospective cohort study. E Clinical Med. [Epub ahead of print]
  18. Mastroianni, A. et al. (2020) Subcutaneous tocilizumab treatment in patients with severe COVID-19–related cytokine release syndrome: An observational cohort study. E Clinical Med. [Epub ahead of print]
  19. https://www.sanofi.com/en/media-room/press-releases/2020/2020-07-02-22-30-00
  20. https://www.roche.com/media/releases/med-cor-2020-07-29.htm
  21. https://www.who.int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients
  22. https://www.sciencemag.org/news/2020/07/one-uk-trial-transforming-covid-19-treatment-why-haven-t-others-delivered-more-results
  23. https://www.covid19treatmentguidelines.nih.gov/dexamethasone/
  24. https://www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19

Will SARS-CoV-2 introduce a new era for subunit vaccines?

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Written by: Gunnveig Grødeland, PhD, University of Oslo and Oslo University Hospital.

Effective control of Covid-19 is dependent upon development of protective and safe vaccines. At present, there are many different vaccine formats against SARS-CoV-2 in clinical development, with the more advanced already in clinical Phase III studies. A remaining challenge, however, is that we still do not have a clear understanding of what constitutes the most relevant type of immunity for protection against Covid-19, and what would be the best strategy for induction of such protection.

A serological survey of over 35,000 households in Spain has demonstrated that an overall 5% of the population has antibodies against SARS-CoV-2, with a higher prevalence of 10% around Madrid and lower in coastal areas (1). Spain has been one of the more severely Covid-19 affected countries in Europe. The fairly low incidence of antibodies in the Spanish population therefore implies that we cannot rely on herd immunity to develop naturally from the present pandemic. Further, the prevalence of SARS-CoV-2 specific antibodies in populations from the epicenters of New York and Lombardy has been estimated to be about 20-25% (2,3). It is not yet clear which antigens and epitopes the induced antibodies are directed against, but there are indications that the antibodies may have a limited capacity for neutralization (4).

During the previous SARS-CoV-1 outbreak in 2002/03, it was demonstrated that antibodies induced against immunodominant sites of the Spike protein were not neutralizing (5). It is also known that when neutralizing antibodies are induced they typically bind to the receptor binding domain of Spike, but also that such antibodies could potentially induce conformational changes in Spike due to mimicking of the ACE-2 receptor and as such potentially enhance viral infection (6). Careful design would therefore be needed for utilization of Spike as a vaccine antigen.

While most vaccines presently in development against SARS-CoV-2 aim for induction of antibodies, cellular immunity can also award protection against disease. Interestingly, a large part of the population have T cells that are reactive against different SARS-CoV-2 proteins even in the absence of a SARS-CoV-2 infection. These T cells are mostly CD4+, and likely originated from previous infections with the “common cold” coronaviruses (7,8). However, it is not yet clear to what degree their presence can reduce development of severe Covid-19 disease.

How should we proceed with vaccine development in a situation where the correlate of protection is not clear?

Pandemics may emerge when a novel pathogen has acquired the ability to transmit efficiently from human to human. As is the case for SARS-CoV-2, we should expect many unknowns when a new pandemic erupts. Vaccination remains the best preventive strategy, but how can one efficiently design vaccines when it is not clear what type of immune responses will be more important for protection? The only answer today is to simultaneously develop many different vaccine formats, compare their strengths and weaknesses, and select the best-fit candidate for vaccination of the population. For this to work, it is important that researchers share both promising and negative results for their particular vaccine format. It is my hope that this strategy will secure a vaccine ready to be large-scale deployed against SARS-CoV-2 during 2021.

We can be certain that SARS-CoV-2 will not be the last pandemic challenge facing the world. It is still unclear what will happen during this fall, but alongside taming the present outbreak, we should try to generate knowledge and strategies that may be of use for quenching the next pandemic emergence caused by an unknown pathogen X. This includes both strategies for managing transmission in society, development of treatment strategies that can be used for limiting replication across different viral families, as well as development of vaccine platforms that can be readily adapted for tailored induction of particular types of immunity.

A new era for subunit vaccines?

Interestingly, a majority of the vaccine formats presently in development against SARS-CoV-2 are subunit vaccines, meaning that they contain only selected viral antigens. At present, there are no genetic subunit vaccine licensed for use in humans, but there are a few protein based subunit vaccines available (e.g., Flublok by Sanofi, Recombivax by Merck).

Subunit vaccines have typically been hampered by reduced immunogenicity, necessitating the combined use of an adjuvant or alternative strategies for enhancing vaccine efficacy. However, their safety profiles and ease of production nevertheless makes subunit vaccines ideal for pandemic prevention.

The large amount of research presently going into development and clinical evaluation of different subunit vaccines is unprecedented. Thus, the ongoing SARS-CoV-2 pandemic may turn out to be the breaking point where subunit vaccines establish themselves as the preferred alternative to conventional inactivated or attenuated vaccines.

Subunit vaccines rely on rational selection and design of selected antigens. As such, immune responses can be steered towards antigenic regions more relevant for development of protective immunity. The better we understand human immunology, the better subunit vaccines we can design. For the future, we could be able to assign the relevant correlate of protection by examining shared pathogen traits, and then design vaccines specifically tailored for induction of the corresponding type of immunity. In the meantime, we will likely fare better by aiming a bit more broadly, and develop subunit vaccines that can induce both antibody and T cell responses.

References

1.    Pollan, M., B. Perez-Gomez, R. Pastor-Barriuso, J. Oteo, M. A. Hernan, M. Perez-Olmeda, J. L. Sanmartin, A. Fernandez-Garcia, I. Cruz, L. N. Fernandez de, M. Molina, F. Rodriguez-Cabrera, M. Martin, P. Merino-Amador, P. J. Leon, J. F. Munoz-Montalvo, F. Blanco, and R. Yotti. 2020. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet.

2.    Percivalle, E., G. Cambie, I. Cassaniti, E. V. Nepita, R. Maserati, A. Ferrari, M. R. Di, P. Isernia, F. Mojoli, R. Bruno, M. Tirani, D. Cereda, C. Nicora, M. Lombardo, and F. Baldanti. 2020. Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020. Euro. Surveill 25.

3.    Stadlbauer D, Tan J, Jiang K, Hernandez M.M, Fabre S, Amanat F, Teo C, Arunkumar G, McMahon M, Jhang J, Nowak MD, Simon V, Sordillo EM, Bakel H, and Krammer F. 2020. Seroconversion of a city: Longitudinal monitoring of SARS-CoV-2 seroprevalence 1 in New York City. medRxiv preprint.

4.    Robbiani, D. F., C. Gaebler, F. Muecksch, J. C. C. Lorenzi, Z. Wang, A. Cho, M. Agudelo, C. O. Barnes, A. Gazumyan, S. Finkin, T. Hagglof, T. Y. Oliveira, C. Viant, A. Hurley, H. H. Hoffmann, K. G. Millard, R. G. Kost, M. Cipolla, K. Gordon, F. Bianchini, S. T. Chen, V. Ramos, R. Patel, J. Dizon, I. Shimeliovich, P. Mendoza, H. Hartweger, L. Nogueira, M. Pack, J. Horowitz, F. Schmidt, Y. Weisblum, E. Michailidis, A. W. Ashbrook, E. Waltari, J. E. Pak, K. E. Huey-Tubman, N. Koranda, P. R. Hoffman, A. P. West, Jr., C. M. Rice, T. Hatziioannou, P. J. Bjorkman, P. D. Bieniasz, M. Caskey, and M. C. Nussenzweig. 2020. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature.

5.    He, Y., Y. Zhou, H. Wu, B. Luo, J. Chen, W. Li, and S. Jiang. 2004. Identification of immunodominant sites on the spike protein of severe acute respiratory syndrome (SARS) coronavirus: implication for developing SARS diagnostics and vaccines. J. Immunol. 173: 4050-4057.

6.    Yang, Z. Y., H. C. Werner, W. P. Kong, K. Leung, E. Traggiai, A. Lanzavecchia, and G. J. Nabel. 2005. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc. Natl. Acad. Sci. U. S. A 102: 797-801.

7.    Grifoni, A., D. Weiskopf, S. I. Ramirez, J. Mateus, J. M. Dan, C. R. Moderbacher, S. A. Rawlings, A. Sutherland, L. Premkumar, R. S. Jadi, D. Marrama, A. M. de Silva, A. Frazier, A. F. Carlin, J. A. Greenbaum, B. Peters, F. Krammer, D. M. Smith, S. Crotty, and A. Sette. 2020. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181: 1489-1501.

8.    Le Bert N, Tan TA, Kunasegaran K, Tham CYL, Hafezi M, Chia A, Chng M, Lin M, Tan N, Linster M, Chia WN, Chen MIC, Wang LF, Ooi EE, Lalimuddin S, Tambyah PA, Low JGH, Tan YJ, and Bertoletti A. 2020. Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals. bioRxiv preprint.