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ON THE UNPREDICTABILITY OF OUTCOMES OF IMMUNOTHERAPY AND PREVENTIVE IMMUNIZATION AGAINST COVID-19
Chebotar IV Shagin DA
Pirogov Russian National Research Medical University, Moscow Pirogov Russian National Research Medical University, Moscow
This article analyzes the possibility of employing immunotherapy and preventive immunization to fight COVID-19. The authors think that treatment and prevention of the infection with anti-SARS-CoV-2 antibodies can have unpredictable outcomes. Although these antibodies can neutralize virus antigens (S-proteins), they also have the ability to enhance virus entry into the host cell. The article emphasizes the importance of solid evidence of efficacy and safety for candidate anti-COVID-19 therapies and protective measures.
Keywords: coronavirus, COVID-19, SARS-CoV-2, antibodies, preventive immunization, immunotherapy
Author contribution: the authors equally contributed to the manuscript
ÇK1 Correspondence should be addressed: Igor V. Chebotar Ostrovityanova, 1, Moscow, 117997; nizarnn@yandex.ru
Received: 21.04.2020 Accepted: 28.04.2020 Published online: 30.04.2020
DOI: 10.24075/brsmu.2020.025
О НЕПРЕДСКАЗУЕМОСТИ РЕЗУЛЬТАТОВ ИММУНОТЕРАПИИ И ИММУНОПРОФИЛАКТИКИ COVID-19
И. В. Чеботарь Д. А. Шагин
Российский национальный исследовательский медицинский университет имени Н. И. Пирогова, Москва, Россия
В работе проведен анализ возможности использования иммунотерапии и иммунопрофилактики в борьбе с COVID-19. Результаты, к которым может привести профилактическое или терапевтическое применение препаратов, содержащих антитела против вируса SARS-CoV-2, на наш взгляд, неоднозначны, а взаимодействие антител с коронавирусными антигенами (S-протеинами) может повлечь за собой не только нейтрализацию вируса, но и усиление его способности проникать в клетку хозяина. В работе сделан акцент на необходимости научного доказательства эффективности и безопасности планируемых к применению методов терапии и профилактики COVID-19.
Ключевые слова: коронавирус, COVID-19, SARS-CoV-2, антитела, иммунопрофилактика, иммунотерапия
Вклад авторов: авторы внесли равный вклад в написание статьи.
1X1 Для корреспонденции: Игорь Викторович Чеботарь
ул. Островитянова, д. 1, г Москва, 117997; nizarnn@yandex.ru
Статья получена: 21.04.2020 Статья принята к печати: 28.04.2020 Опубликована онлайн: 30.04.2020 DOI: 10.24075/vrgmu.2020.025
Finding effective treatment and developing protective measures against the novel coronavirus infection COVID-19 is a critical challenge facing medical science. Today, many candidate approaches to managing this infection are under scrutiny. Obviously, the effective treatment is expected to directly block the virus and prevent it from replicating or entering the cell. Drugs designed to inhibit HIV (ritonavir, lopinavir) and Ebola virus (remdesivir) are now being evaluated for their potential to inhibit coronavirus replication [1, 2]. However, so far there is no solid evidence of their efficacy against COVID-12; this is true for both approved drugs and those still in clinical trials [3]. The possible anticoronaviral effect of quinolines and the unclear underlying mechanism of action need further investigation.
Immunotherapy and preventive immunization might hold promise for countering COVID-19. Indeed, vaccines and passive immunization have been successful in fighting various infections, including viral infections. However, because of the features demonstrated by the causative agent of COVID-1 SARS-CoV-2, extreme caution should be exercised when using active or passive immunization approaches.
This article is an attempt to point to the unpredictability of outcomes of using anti-SARS-CoV-2 antibodies for treating and preventing COVID-19.
Interaction with viral S-proteins
Spike-glycoproteins (S-proteins) responsible for latching onto receptors of the host cell have long been identified as the primary
surface target for neutralizing antibodies. Using cell and animal models of severe acute respiratory syndrome (SARS-CoV) and Middle-East respiratory syndrome (MERS-CoV), researchers have demonstrated that antibodies can bind to and neutralize S-proteins [4, 5]. It is reported that anti-S-IgG for neutralizing MERS-CoV promote survival of viral clones that carry mutations in the S-protein encoding genes; as a result, the antibodies can no longer recognize the S-protein and neutralize the virus [6].
Antibody-dependent enhancement of virus entry
Unfortunately, the emergence of clones unrecognizable to antibodies is not the only drawback of passive immunization/ immunotherapy. Therapies with anticoronaviral antibodies can be devastating due to the phenomenon of antibody-dependent enhancement of virus entry. Briefly, some IgG variants can accelerate penetration of the virus into the cell because their Fab fragments can bind to the S protein of SARS-CoV, whereas other IgG domains, like Fc or unidentified sites, bind to a number of host cell receptors, including angiotensin-converting enzyme 2, dipeptidyl peptidase-4 and the FcY-receptor (see Figure). This phenomenon has been demonstrated in the models of some coronavirus-related infections, including SARS and MERS [7, 8]. Considering the similarity of pathogenesis between SARS, MERS and COVID-19, there is a high probability that SARS-CoV-2 will also provoke IgG-dependent enhancement of virus entry. Some authors believe that IgG-enhancement of virus entry is not limited to epithelial cells and can also occur
МНЕНИЕ I ВИРУСОЛОГИЯ
M-protein
Nucleoprotein
Receptor for S-protein or Fcr II receptor (CD32)
E-protein
lgG
Coronavirus virion
Fig. A schematic representation of antibody-dependent enhancement of virus entry
in immune cells via immunoglobulin FcYII receptors (CD32) [9]. IgG-dependent damage to immune cells might underlie the pathogenesis of uncontrolled immune system activation and cytokine storm in patients with SARS.
It is believed that antibodies do not always enhance virus entry, depending on the antibody binding site on the S protein, the IgG subclass, IgG concentrations and expression of cell receptors. This unpredictability means that convalescent serum and synthetic anti-S antibodies should not be used in COVID-19 patients without thorough thought. The same applies to preventive immunization against COVID-19. It cannot be ruled out that vaccination will stimulate production of polyclonal antibody variants responsible for antibody-dependent virus entry.
As COVID-19 is continuing its global rampage, a worrying trend is being born: scientists are engaged in a race to develop diagnostic, therapeutic and preventive tools for the novel infection at all costs. A similar situation unfolded in the USSR shortly after HIV was discovered. In an attempt to get ahead
Host cell
of their foreign counterparts, some medical teams decided to treat AIDS patients with immunostimulants. The formal yet erroneous logic behind the decision dictated that a patient who developed immunodeficiency should be treated by stimulating the immune system. Dozens of patients fell victim to the ambitions of their doctors because immunostimulation provoked the irreversible progression of the disease. We hope that the story will not repeat itself with COVID-19 and that treatments for this infection will be evidence-based.
CONCLUSIONS
1. On the one hand, antibodies against coronaviral S-proteins can neutralize the virion; on the other hand, they are also capable of enhancing virus entry into the host cell. 2. Although COVID-12 is an epidemiological emergency, its treatment and prevention should be based on solid evidence of safety and efficacy.
References
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2. Cao YC, Deng QX, Dai SX. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: an evaluation of the evidence. Travel Med Infect Dis. 2020; 2: 101647. DOI: 10.1016/j. tmaid.2020.101647.
3. Centers for Disease Control and Prevention. Information for Clinicians on Investigational Therapeutics for Patients with COVID-19. Available from: https://www.cdc.gov/coronavirus/2019-ncov.
4. Greenough TC, Babcock GJ, Roberts A, Hernandez HJ, Thomas WD Jr, Coccia JA, et al. Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice. J Infect Dis. 2005; 191 (4): 507-14. DOI: 10.1086/427242.
5. Chen Z, Bao L, Chen C, Zou T, Xue Y, Li F, et al. Human
Neutralizing Monoclonal Antibody Inhibition of Middle East Respiratory Syndrome Coronavirus Replication in the Common Marmoset. J Infect Dis. 2017; 215 (12): 1807-15. DOI: 10.1093/ infdis/jix209.
6. Kleine-Weber H, Elzayat MT, Wang L, Graham BS, Müller MA, Drosten C, et al. Mutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated Neutralization. J Virol. 2019; 93 (2): pii: e01381-18. DOI: 10.1128/JVI.01381-18.
7. Yang ZY, Werner HC, Kong WP, Leung K, Traggiai E, Lanzavecchia A, et al. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc Natl Acad Sci USA. 2005; 102 (3): 797-01. DOI: 10.1073/pnas.0409065102.
8. Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol. 2020; 94 (5): pii: e02015-19. DOI: 10.1128/ JVI.02015-19 .
9. Yip MS, Leung HL, Li PH, Cheung CY, Dutry I, Li D, et al. Antibody-dependent enhancement of SARS coronavirus infection and its role in the pathogenesis of SARS. Hong Kong Med J. 2016; 22 (3 Suppl 4): 25-31.
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ВЕСТНИК РГМУ | 2, 2020 | VESTNIKRGMU.RU
Литература
1. Временные методические рекомендации Министерства здравоохранения Российской Федерации «Лекарственная терапия острых респираторных вирусных инфекций (ОРВИ) в амбулаторной практике в период эпидемии COVID-19». Версия 5 (08.04.2020). Доступно по ссылке: https://static-1. 6. rosmlnzdrav.ru/system/attachments/attaches/000/049/986/ 0riginal/09042020_%D0%9C%D0%A0_C0VID-19_v5.pdf.
2. Cao YC, Deng QX, Dai SX. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: an evaluation of the evidence. Travel Med Infect Dis. 2020; 2: 101647. DOI: 10.1016/j. 7. tmaid.2020.101647.
3. Centers for Disease Control and Prevention. Information for Clinicians on Investigational Therapeutics for Patients with COVID-19. Available from: https://www.cdc.gov/coronavirus/2019-ncov. 8.
4. Greenough TC, Babcock GJ, Roberts A, Hernandez HJ, Thomas WD Jr, Coccia JA, et al. Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective 9. immunoprophylaxis in mice. J Infect Dis. 2005; 191 (4): 507-14. DOI: 10.1086/427242.
5. Chen Z, Bao L, Chen C, Zou T, Xue Y, Li F, et al. Human
Neutralizing Monoclonal Antibody Inhibition of Middle East Respiratory Syndrome Coronavirus Replication in the Common Marmoset. J Infect Dis. 2017; 215 (12): 1807-15. DOI: 10.1093/ infdis/jix209.
Kleine-Weber H, Elzayat MT, Wang L, Graham BS, Müller MA, Drosten C, et al. Mutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated Neutralization. J Virol. 2019; 93 (2): pii: e01381-18. DOI: 10.1128/JVI.01381-18. Yang ZY, Werner HC, Kong WP, Leung K, Traggiai E, Lanzavecchia A, et al. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc Natl Acad Sci USA. 2005; 102 (3): 797-01. DOI: 10.1073/pnas.0409065102. Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol. 2020; 94 (5): pii: e02015-19. DOI: 10.1128/ JVI.02015-19 .
Yip MS, Leung HL, Li PH, Cheung CY, Dutry I, Li D, et al. Antibody-dependent enhancement of SARS coronavirus infection and its role in the pathogenesis of SARS. Hong Kong Med J. 2016; 22 (3 Suppl 4): 25-31.
