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 Table of Contents  
Year : 2021  |  Volume : 23  |  Issue : 1  |  Page : 107-108

Is antibody-dependent enhancement a cause for COVID Vaccine hesitancy

1 Associate Professor, Department of Community Medicine, INHS Asvini, Mumbai, Maharashtra, India
2 Associate Professor, Department of Microbiology, INHS Kalyani, Visakhapatnam, Andhra Pradesh, India
3 Professor, Department of Community Medicine, INHS Asvini, Mumbai, Maharashtra, India

Date of Submission14-Jun-2021
Date of Decision23-Jun-2021
Date of Acceptance23-Jun-2021
Date of Web Publication05-Jul-2021

Correspondence Address:
Dr Shabeena Tawar
Associate Professor, Department of Community Medicine, INHS Asvini, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_93_21

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How to cite this article:
Tawar S, Chandola P, Ray S. Is antibody-dependent enhancement a cause for COVID Vaccine hesitancy. J Mar Med Soc 2021;23:107-8

How to cite this URL:
Tawar S, Chandola P, Ray S. Is antibody-dependent enhancement a cause for COVID Vaccine hesitancy. J Mar Med Soc [serial online] 2021 [cited 2022 Jul 2];23:107-8. Available from: https://www.marinemedicalsociety.in/text.asp?2021/23/1/107/320582

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread rapidly resulting in considerable morbidity and mortality among those infected with the virus. The disease has been an enigma – right from its origin, nature of transmission, pathogenesis associated with severity to a definitive treatment. Predictive mathematical models have failed miserably; and the disease is continuing to make its presence in all the countries. To manage the pandemic globally, several candidate vaccines have been accorded Emergency Use Authorization (EUA), and investigational drugs are being used without clear efficacy trial data. Recently, few reports have suggested the role of antibody-dependent enhancement (ADE) with increased severity of symptoms related to early high levels of SARS-CoV-2 antibodies in patients and have created serious vaccine hesitancy.[1]

It is known that entry of SARS-CoV-2 is facilitated by the binding of the viral spike (S) protein to its cellular receptor, angiotensin-converting enzyme 2 (ACE2). An important objective of vaccine and therapeutic development is to produce antibodies that prevent the entry of SARS-CoV-2 into cells by blocking either ACE2-receptor binding interactions or S-protein mediated membrane fusion. A potential hurdle for the vaccines and the antibody generating drugs is the risk of exacerbating COVID-19 severity ADE.[2] However, the extent to which ADE contributes to COVID-19 immunopathology is being actively analyzed and debated.[3]

  Pathogenesis of Antibody-Dependent Enhancement Top

The viral genome encodes various structural spike (S), nucleocapsid (N), membrane (M), envelope (E), and nonstructural proteins.[4] The spike protein (S) is the most immunogenic, comprising 2 subunits, subunit 1 containing a receptor-binding domain (RBD) and subunit 2. RBD binds to the main host cell receptor for SARS-CoV-2, ACE2, resulting in viral entry into the cells, namely lungs, heart, and gastrointestinal tract.[5] Antibodies against RBD of S protein are neutralizing but wane rapidly with time. Antibodies against other epitopes of S protein are nonneutralizing and may even cause more severe disease upon secondary or reinfection.[6]

Middle East respiratory syndrome coronavirus (CoV), SARS-CoV and seasonal human coronaviruses commonly produce nonneutralizing antibodies during the course of infection.[7] Such individuals also tend to have more severe form of illness when infected with SARS-CoV-2. The above has led to the hypothesis of ADE, a process by which nonneutralizing or subneutralizing antibodies trigger Fcγ receptor-mediated uptake of the virus into the cell, facilitating viral cell entry by intermediation of Fcγ receptors (FcγRs) and/or complement receptors and lead to more severe infection and illness.[8],[9] ADE is thus a process where antibodies developed against a disease lead to over-activation of the immune system against that disease the next time the body encounters the pathogen. In such cases, the antibodies, instead of improving the body's reaction to the disease, might lead to a more severe condition.

  Antibody-Dependent Enhancement and COVID-19 Vaccines Top

Vaccine-induced ADE in SARS-CoV 2 has been hypothesized in recent times and has been raising potential safety concerns. The basic mechanism of action of current COVID vaccines is to encourage the immune system to react to the spike protein and create neutralizing antibodies and memory cells against the protein without acting against the virus itself. If the body gets infected with the virus, it will already have the required cells and antibodies to fight it in a precise and efficient manner, thereby preventing it. Evidence from research studies have also suggested that vaccines that elicit neutralizing antibodies against the S protein, protected animals from SARS-CoV without any evidence of exaggeration of severity of the disease and have a high chance of success with minimal risk of ADE. Moreover, although SARS-CoV 2 can invade macrophages, they cannot replicate within them.[1],[3] Hence, it can be presumed that the present scare of ADE is not relevant to the current COVID disease.

  Antibody-Dependent Enhancement and Monoclonal Antibodies Top

Monoclonal antibodies that bind and “neutralize” SARS-CoV-2 are derived from B-cells of convalescent patients. At present, EUA for treatment of nonhospitalized patients with mild-to-moderate COVID-19 has been accorded in the United States – these are bamlanivimab as a monotherapy and bamlanivimab together with etesevimab or casirivimab with imdevimab as a combination therapy. Being derived from B-cells and eliciting neutralizing antibody, chances of ADE after administration of mAbs seem to be quite less.[10]

  Conclusion Top

ADE is a known phenomenon in vaccine research. ADE risks may be associated with the formation of antibody levels over time after vaccination, and also, if the antibodies are derived from prior exposures to other coronaviruses. Clinical data have not yet fully established a role for ADE in human COVID-19 pathology. While SARS-CoV-2 represents a possible risk of ADE in a subset of COVID-19 patients with disease progression beyond the mild stage of the disease, it will be crucial to evaluate animal and clinical data for signs of ADE and to analyze ADE-related safety risks if clinical ADE is observed in vaccinated individuals and or those administered with mAb treatment from COVID-19.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Ricke DO. Two different antibody-dependent enhancement (ADE) risks for SARS-CoV-2 antibodies. Front Immunol 2021;12:640093.  Back to cited text no. 1
Coish JM, MacNeil AJ. Out of the frying pan and into the fire? Due diligence warranted for ADE in COVID-19. Microbes Infect 2020;22:405-6.  Back to cited text no. 2
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.  Back to cited text no. 3
Lee WS, Wheatley AK, Kent SJ, DeKosky BJ. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat Microbiol 2020;5:1185-91.  Back to cited text no. 4
Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol 2020;92:418-23.  Back to cited text no. 5
Chowdhury MA, Hossain N, Kashem MA, Shahid MA, Alam A. Immune response in COVID-19: A review. J Infect Public Health 2020;13:1619-29.  Back to cited text no. 6
Iwasaki A, Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev Immunol 2020;20:339-41.  Back to cited text no. 7
Shokri S, Mahmoudvand S, Taherkhani R, Farshadpour F. Modulation of the immune response by Middle East Respiratory syndrome coronavirus. J Cell Physiol 2019;234:2143-51.  Back to cited text no. 8
Yager EJ. Antibody-dependent enhancement and COVID-19: Moving toward acquittal. Clin Immunol 2020;217:108496.  Back to cited text no. 9
US Food and Drug Administration. Fact Sheet for Health Care Providers Emergency use Authorization (EUA) of Bamlanivimab and Etesevimab. 2021. Available from: https://www.fda.gov/media/145802/download. [Last accessed on 2021 Jun 13].  Back to cited text no. 10


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