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SARS-CoV-2 viral load and antibody responses: the case for convalescent plasma therapy
Arturo Casadevall,1 Michael J. Joyner,2 and Liise-anne Pirofski3
1Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA.
2Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
3Division of Infectious Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.
Address correspondence to: Arturo Casadevall, Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Room E5132, 615 North Wolfe Street, Baltimore, Maryland 21205, USA. Phone: 410.955.3457; Email: acasade1@jhu.edu.
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1Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA.
2Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
3Division of Infectious Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.
Address correspondence to: Arturo Casadevall, Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Room E5132, 615 North Wolfe Street, Baltimore, Maryland 21205, USA. Phone: 410.955.3457; Email: acasade1@jhu.edu.
Find articles by Joyner, M. in: JCI | PubMed | Google Scholar
1Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA.
2Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
3Division of Infectious Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.
Address correspondence to: Arturo Casadevall, Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Room E5132, 615 North Wolfe Street, Baltimore, Maryland 21205, USA. Phone: 410.955.3457; Email: acasade1@jhu.edu.
Find articles by Pirofski, L. in: JCI | PubMed | Google Scholar
Published July 7, 2020 - More info
J Clin Invest. 2020;130(10):5112–5114. https://doi.org/10.1172/JCI139760.
© 2020 American Society for Clinical Investigation
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR–confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20–40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti–SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients’ plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.
Authors
Yanqun Wang, Lu Zhang, Ling Sang, Feng Ye, Shicong Ruan, Bei Zhong, Tie Song, Abeer N. Alshukairi, Rongchang Chen, Zhaoyong Zhang, Mian Gan, Airu Zhu, Yongbo Huang, Ling Luo, Chris Ka Pun Mok, Manal M. Al Gethamy, Haitao Tan, Zhengtu Li, Xiaofang Huang, Fang Li, Jing Sun, Yanjun Zhang, Liyan Wen, Yuming Li, Zhao Chen, Zhen Zhuang, Jianfen Zhuo, Chunke Chen, Lijun Kuang, Junxiang Wang, Huibin Lv, Yongliang Jiang, Min Li, Yimin Lin, Ying Deng, Lan Tang, Jieling Liang, Jicheng Huang, Stanley Perlman, Nanshan Zhong, Jingxian Zhao, J.S. Malik Peiris, Yimin Li, Jincun Zhao
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A history of success
Convalescent plasma has emerged as a major investigational therapy for COVID-19 (1). Although at the time of this writing its efficacy is uncertain, there are encouraging signs that it reduces mortality and hastens recovery in certain groups of patients, notably those who are treated early in disease and do not require mechanical ventilation (2–4). The rationale for the use of convalescent plasma for COVID-19 is that it will have a therapeutic effect by providing affected individuals with specific antibodies from a host who has recovered. This strategy has a long history of success for other respiratory viral diseases (5–7). Thus, knowledge of the time of appearance and quality of specific antibody responses to SARS-CoV-2 in individuals with COVID-19 can provide a rational basis to determine when the administration of exogenous antibody may have the greatest beneficial effect in patients who are ill. The observation that patients may not mount measurable antibody responses before day 10 of illness, which then peak around day 15, suggests that convalescent plasma may be most beneficial early in the course of COVID-19, before an endogenous antibody response develops (Figure 1).
Figure 1Early and later administration of convalescent plasma in the context of the developing antibody response. Patients with COVID-19 mount measurable antibody responses around day 10, which peaks by day 15, suggesting that convalescent plasma may benefit patients early in the disease course.
Historically, convalescent plasma was used to treat a range of different illnesses from bacterial meningitis to the 1918 influenza pandemic and H1N1, as well as SARS in 2009 (8–10). Plasma was most effective when given early in these illnesses. In the preantibiotic era, the time of the appearance of a specific antibody in pneumococcal pneumonia was used to support the administration of serum therapy early in the course of disease (11). This was based on the correlation between the appearance of specific serum antibody and clinical improvement in patients who recovered. Hence, the administration of convalescent plasma in the period before a patient develops their own antibody to SARS-CoV-2 may provide ready-made antibodies that mediate antiviral activity and augment the developing immune response.
Antibodies may mediate antiviral effects through numerous mechanisms, including direct antimicrobial effects such as viral neutralization as well as antibody-dependent cellular cytotoxicity (ADCC) and modulation of the inflammatory response (12). In fact, convalescent plasma therapy in patients with COVID-19, including those with severe disease, was shown to mediate viral clearance in several case studies and in a randomized controlled trial in which it led to rapid viral clearance from infected tissues (2, 13, 14).
The observation that patients with severe COVID-19 disease produced higher antibody titers than patients with mild disease is consistent with what is described in other diseases such as tuberculosis, where symptomatic patients have higher titer responses (15). Although some may question the functional significance of high antibody levels in individuals with severe disease and this may raise the concern of detrimental antibody effects, such as antibody-dependent enhancement (16), we caution against such interpretations. Instead, the generation of more antibody is likely to reflect the strong inflammatory response associated with severe disease that contributes to the pathogenesis of COVID-19 (17).
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