key: cord-0952432-epxi6ylo authors: Ajmeriya, Swati; Kumar, Amit; Karmakar, Subhradip; Rana, Shweta; Singh, Harpreet title: Neutralizing Antibodies and Antibody-Dependent Enhancement in COVID-19: A Perspective date: 2022-02-04 journal: J Indian Inst Sci DOI: 10.1007/s41745-021-00268-8 sha: f0d647ea57f1594974f51c2f4ea33ec99399b792 doc_id: 952432 cord_uid: epxi6ylo Antibody-dependent enhancement (ADE) is an alternative route of viral entry in the susceptible host cell. In this process, antiviral antibodies enhance the entry access of virus in the cells via interaction with the complement or Fc receptors leading to the worsening of infection. SARS-CoV-2 variants pose a general concern for the efficacy of neutralizing antibodies that may fail to neutralize infection, raising the possibility of a more severe form of COVID-19. Data from various studies on respiratory viruses raise the speculation that antibodies elicited against SARS-CoV-2 and during COVID-19 recovery could potentially exacerbate the infection through ADE at sub-neutralizing concentrations; this may contribute to disease pathogenesis. It is, therefore, of utmost importance to study the effectiveness of the anti-SARS-CoV-2 antibodies in COVID-19-infected subjects. Theoretically, ADE remains a general concern for the efficacy of antibodies elicited during infection, most notably in convalescent plasma therapy and in response to vaccines where it could be counterproductive. enhancement (ADE), then the risk of aggravating the severity of infection increases. SARS-COV-2 infection leads to the production of neutralizing antibodies, but the extent to which these antibodies would be neutralizing and protective to the subsequent SARS-CoV-2 infection is still not clear. Some reports of SARS-COV-2 reinfection have been published, elucidating illness with the genetically distinct strain of SARS-CoV-2 with symptomatic reinfection [24] [25] [26] . There is a possibility of severe cases of infection during a secondary infection with SARS-COV-2, similar to DENV serotypes as reported previously, due to the risk of cross-reactive antibodies potentially capable of promoting ADE. This cross-reactivity of antibodies with different strains may give rise to the phenomenon of ADE and make the symptoms more severe; acute respiratory distress syndrome (ARDS) is majorly attributed to the severe cases of illness that have emerged to be the leading cause of death in COVID-19, similar to SARS and MERS 6 . Even though the link between ADE of infection and disease severity is yet to be established, in the past, the severity of infection and crossreactivity of antibodies to other viral serotypes have been linked and established in vitro for Zika, Dengue, and Influenza A viral infection [28] [29] [30] . These previous and current studies point towards the requirement of proactive research in the immunopathology caused by COVID-19. Because a large and variable group of people are getting infected with severity ranging from mild to severe cases of illness, therefore, the possibility of ADE is worth considering. Dengue virus (DENV) is a single positivestranded RNA virus of the family Flaviviridae and genus Flavivirus. ADE has been well documented in this disease. Dengue fever is caused by four antigenically distinct dengue virus serotypes (DENV 1-4). Live attenuated vaccine (LAV) for Dengue raised a serious concern due to their capacity to elicit an adverse immune response. The concern behind this limited approval is that this vaccine predisposed some of the denguenaïve recipients to severe dengue fever due to their cross-reactivity with other DENV serotypes, thereby contributing to ADE. Therefore, the major bottleneck with whole DENV-based vaccine strategies may be overcome using an antibody response serotype. ADE may be a significant concern in the case of COVID-19, not just due to a suboptimal response to different variant of concern (VoC) but also due to an inadequate viral neutralization. In this review, we aim to assess the hypothesis that non-neutralizing antibodies or antibodies that are neutralizing but possess a low affinity to critical regions of virus entry points may be associated with the severity of infection in COVID-19 that fails to neutralize the virus. These antibodies may be formed by infection or vaccination with a closely related serotype of SARS-CoV-2, previous exposure to other classes of coronaviruses. In this review, we discuss the phenomenon of ADE, its possible mechanism that may play a significant role in the pathogenesis of COVID-19 by relating the previous and some current findings with the COVID-19 pandemic and highlights the interplay of antibodies that may be neutralizing or nonneutralizing in nature with viral surface receptors that may lead to this condition. Phenomenon Virus entry into host cells is a primary obligate process in viral pathogenesis; this is usually mediated by hijacking the cellular mechanism. Neutralizing antibodies aid in inhibiting the attachment of the virus to the host cell receptors by targeting the viral surface proteins or glycoproteins and is considered to be a crucial mechanism to eliminate the virus 31-36 , and the attachment between viruses and target cells plays an essential role in most cases and may produce different outcomes. However, in some instances, paradoxically, binding of the antibodies at subneutralizing concentrations to non-critical sites of the virion can result in non-neutralization of the virion that may lead to virion entry and invasion into certain cell types via antibody Fc region present on the carboxyl-terminal domain of antibody with Fc gamma receptor IIa (FcRIIa)-expressing phagocytic cells like the monocytes, macrophages, or through interaction with complement receptors contributing in the enhancement of infection, a process known as antibody-dependent enhancement 37-41 during these instances, the binding of antibodies to these non-critical sites leaves the virus with retainment of its infectivity 37 . Virus possesses various kinds of different antigenic epitopes capable of inducing neutralizing antibodies, but some might induce non-neutralizing antibodies that may enhance the infection 42 . Despite the presence of multiple critical sites on the virus surface, immunoglobulins, after attaching to this area, may not neutralize the virus completely because the virus can utilize another site for interacting with the host cell 37 . Diluting concentrations of antibodies have been shown to increase lung pathology and infiltration of cells into the alveolar air space observed in vivo mouse model during the influenza virus life cycles 43 . In an experimental study, it was observed that lower levels of IgG could promote the uptake of human parvovirus (B19V) in endothelial cells showing an enhancing effect of lower levels of antibodies at the level of virus internalization 44 . Seropositive people who may have successfully eliminated one viral serotype may well be at increased risk of infection with other viral serotypes. The neutralizing antibodies preformed for one of these serotypes might often not be neutralizing for different serotypes that may cross-neutralize the epitopes, and these deficient and incompetent neutralizing antibodies may instead allow ADE mechanism to kick in, leading to enhanced infection [45] [46] [47] . Dengue viruses, one of the best studied, representing a classic example of flaviviruses exhibiting ADE cause infection through four distinct serotypes DENV1, DENV2, DENV3, and DENV4; antibodies raised for one Dengue serotype do not protect against other serotypes failing to block the virus entry into cells 42,48,49 ; the humoral response produced against one Dengue serotype provides protective serotype-specific antibodies; however, these antibodies do cross-react with other Dengue viral serotypes but do not neutralize them that may promote the entry of the virus via antibody Fc regions failing in protecting against different viral serotypes (Fig. 1) ; as a result, a second In secondary infection, neutralizing antibodies that are elicited successfully neutralize the virus when the DENV serotype is similar to the primary DENV infection. c Antibody-dependent enhancement of infection in DENV infection occurs when non-neutralizing antibodies formed from primary infection bind with different DENV serotypes during secondary infection, these Ab from a primary infection are unable to neutralize the different DENV serotype that enhances the virus entry and replicate into cells leading to a heightened risk of dengue viral infection severity. Image credit smart.servier.com. Dengue viral infection could arise, being more lethal, leading to dengue hemorrhagic fever and shock syndrome 42,50 , this similar instance of ADE can happen in COVID-19 in which RBD region of S protein of SARS-CoV-2 may get mutated as found in some studies 51,52 . Enhancement of disease and more severity has been described in infants who received inactivated respiratory syncytial virus (RSV) vaccine as well as inactivated measles vaccine after they encountered a secondary viral infection 53,54 . The virus-antibody complex binds with either Fc or complement receptors expressed on immune cells leading to the internalization of the virus-antibody complex that must follow the destruction of the virus. However, in some instances, the virus escapes the antigen-antibody complex and starts a replication cycle inside immune cells that possibly occurs when the virus is bound to low-affinity antibodies 38 . Although the exact mechanism of ADE remains to be understood, ADE has been reported to take place in two possible ways, first, internalization of virus-antibody immune complexes into phagocytic cells via interaction of the antibody Fc region with the cellular Fc receptors present on myeloid cells which then render immune system to trigger signal transduction, releasing inflammatory cytokines, superoxide burst, and antibody-dependent cell-mediated cytotoxicity (ADCC) leading to the heightened antibody-mediated uptake of the virus 27,38,55 (Fig. 2 ). This type of Fc-dependent mechanism has been documented in West Nile virus, dengue virus, and human immunodeficiency virus 42 . Fc receptors have been shown to play a pivotal in promoting antibody-dependent cell enhancement mechanisms 38 . Generally, cells that express Fc receptors lead to phagocytosis of antigen-antibody complexes as well as the direct killing of target cells by a process known as Antibody-dependent cellular cytotoxicity (ADCC) 56 . However, type 1 FcγR receptors are expressed by myeloid lineage cells such as monocytes, macrophages, dendritic cells, granulocytes including neutrophils and eosinophils, B and NK cells 57 , ADE is primarily observed in monocytes, macrophages, and dendritic cells 58-61 . CD32(FcγRII) in monomeric form has a low affinity for the Fc region of IgG antibodies but possesses a high affinity for IgG immune complexes 62 . FcγRI (CD64) binds with monomeric IgG with high affinity 63,64 . The second possible mechanism of ADE is the complementmediated enhancement of infection by complement protein C1q that is activated in the classical pathway or C3 that is activated in an alternative pathway followed by the binding of the antibody to the viral surface proteins forming the complex of virus-antibody-complement protein 65 (Fig. 3) . C1q binds to the Fc region of IgG1 and IgM that are complement-fixing antibodies attached to the viral proteins 65 followed by the interaction between the corresponding receptor and complement protein that increases viral adhesion leading to the formation of the virus, antibody, and complement complex 42,66 . ADE mediated by complement protein CIq has been found with Ebola virus in non-monocytic cells by endocytosis or enhancing virus attachment to the target cell; thus, this resulting complex consisting of virus-antibody-C1q binds to C1q cell surface receptors leading to either the binding of the virus to Ebola-specific receptors or endocytosis via C1q receptors 67-69 . The involvement of complement protein C1q has also been shown to mediate HIV-1 infection by binding to the Fc portion of antibodies that enhanced infection in vitro as immunocomplex as C1q binds with C1q receptors at the cell surface 38,70 . C3-mediated ADE is found in both the West Nile and HIV virus. Principally, IgG antibodies have been observed to mediate ADE; however, IgM as well as IgA along with Complement, have also been shown to be capable of ADE 71,72 ; for instance, IgM-dependent enhancement of West Nile virus mediated by complement protein CR3 has been found in macrophage immune cells 73 . As the virus utilizes its envelope proteins to attach to the target cell surface receptors or coreceptors, neutralizing antibodies targeted against viral proteins generally hinder this step by targeting critical regions of the viral proteins preventing the binding of the virus (Fig. 4) , this, in turn, reduces the infectivity of the virus leading to its neutralization 37 . The production of neutralizing antibodies is the desirable primary goal of vaccination, and therefore, antibodies that are secreted are expected to be neutralizing 74 . Neutralizing antibodies are secreted as part of the humoral response of the active immune system mediated by Ab secreting plasma cells. Pathogens disarmed by these antibodies are generally phagocytosed by macrophages; neutralization of viral infectivity can take place in some ways; they may either interfere with the binding of the virion to the cellular receptors, fusion with the host membrane in case of enveloped viruses, membrane penetration (for nonenveloped viruses), may block uptake into the cells, prevent uncoating of the genomes in the endosomes or cause aggregation of virus particles 37 . Antiviral antibodies lyse the enveloped viruses and serum complement disrupt membranes 36,74,75 . The neutralizing effect of antibodies depends on certain factors, for instance, the stoichiometry of antibody(Ab titer), that must exceed a particular threshold 75 ; the antibody affinity for viral epitopes regulates the fraction of epitopes on the viral particle occupied by antibodies at any given concentration that is referred to as occupancy that predominantly determines the neutralization potential, as well as the accessibility of epitope, are both obligatory to exceed the threshold requirements as the antibodies possessing poor accessibility to specific epitopes require a higher concentration to exceed the occupancy threshold for neutralization 36,76 . A similar observation has been made in a study, where 77 the diluted form of antisera against SARS-CoV spike protein has been found to promote ADE and enhanced apoptosis at the same time, while neutralizing antibodies against SARS-CoV neutralized infection 55 ; so, it is the avidity that is more important and not merely the affinity. An increasing body of evidence shows that crossreactive antibodies can have a crucial impact but greatly varied, these cross-reactive antibodies can perform neutralization if they bind viral epitopes with higher affinity 78-80 ; nonetheless, the longevity of neutralizing antibodies is found to be higher than cross-neutralizing antibodies; a study found neutralizing antibody IgG to last longer than cross-reactive antibody that declined over time specific against a dengue virus serotype 81 . Cross-neutralizing antibodies may bind to specific regions of antigen but fail to neutralize it. Similar results have shown that neutralizing antibodies (nAbs) when targeting SARS-CoV, binds to viral RBD epitope of the spike protein, but not the receptor-binding motif that culminated in the failure of crossneutralization of infection 82,83 . Kathleen et al. found that S-RBD-specific antibodies exhibited more neutralizing potential than N-proteinspecific antibodies 84 , this in vitro study explains that not all antibodies elicited are neutralizing. In an in vivo study, Syrian hamsters were tested for the efficacy of antibodies isolated from convalescent donors, it was found that despite their efficient binding to S and/or RBD proteins of SARS-CoV-2, antibodies not competitive with ACE2 failed to inhibit the virus from entering host cells 85 . The early presence of IgG subtypes has been observed in some patients 86 , indicative of a possible memory to a cross-reactive antigen in a secondary immune response that might increase disease severity due to ADE 86,87 . Mutations in the concerned viral proteins may render the immune system to preferentially utilize the immunological memory from a previous infection during the encounter with a slightly different strain of the virus and may boost nonneutralizing antibodies, these non-neutralizing antibodies may reduce the efficacy of vaccines and for this reason, the vaccine for Influenza requires to be developed every year 87-89 . Also, there is no evidence that the immune system elicits neutralizing antibodies during immune response against a pathogen over non-neutralizing ones 90 . Still, the factors responsible for an effective and long-lasting antibody response remains unclear. In the first report of ADE in 1964, enhancement of the infectivity of arboviruses such as Murray Valley encephalitis virus, West Nile virus, and Japanese encephalitis virus was observed during their neutralization in the presence of chicken antisera, all of which belong to the family Flaviviridae 91 , it was found afterwards that the IgG antibodies in the sera were responsible for this enhancement 27 ; however, no biological explanation was being given for this process of enhancement. Since then, flaviviruses have been intensively studied to elucidate ADE's mechanisms and clinical significance in viral pathogenesis. Among flaviviruses, Dengue was the first virus in which ADE was clearly established in 1977 27 , and the relationship between the secondary infection associated with antibody response and severe illness was recognized in Dengue viruses; studies showed that low concentrations of IgG Abs were able to enhance infection 30,39,47 . A probable role of ADE was speculated by a mathematical model that related the disease severity with enhancing effect of cross-reactive antibody to different DENV serotypes during secondary infection 92 In vivo studies done in rhesus monkeys reflecting the relationship between antibody response and increased Dengue viremia have added further evidence to ADE phenomenon 103, 118 . Complement-mediated ADE has been extensively studied in HIV and West Nile virus 73, 119 . In vitro studies have shown that sera from convalescent patients from Ebola virus disease contain antibodies capable of promoting ADE 120 . In vivo studies done in rhesus monkeys reflecting the relationship between antibody response and increased viremia to different DENV serotypes has been added to further evidence to the phenomenon of ADE 94, 103, 118, 121, 122 . Similarly, in an experimental finding, enhanced yellow fever immunogenicity upon yellow fever vaccination was observed in subjects with a specific range of cross-reactive antibody titers from a previous inactivated Japanese encephalitis vaccination 123 ; similar observations have been made when antibodies elicited after vaccination against Japanese encephalitis virus were found to enhance dengue virus infection 124 ; a study in COVID-19-affected patients reported that the higher antibody titers against SARS-CoV-2 were associated with more severe disease that raises the possibility of antibody-dependent disease enhancement effect 125 . A possible case of COVID-19 reinfection has been observed in a patient with two different COVID-19 infection who was found to be infected with two genetically different SARS-CoV-2 variants 126 . ADE of SARS pathogenesis has been shown to occur in different circulating immune cell types such as monocytes and macrophages; however, upon the induction of ADE, macrophages did not show any fruitful replication or modification of expression of proinflammatory cytokines or chemokines 127 . In a preprint study published by Fan Wu et al. ADE by SARS-CoV-2 has been detected from severely affected elderly patients plasma with high titers of SARS-CoV-2 spike protein-specific antibodies via FcγRII cellular receptor; a similar kind of result was obtained when ADE was shown to be mediated by S(spike) protein-specific antibodies in SARS 55 ; furthermore, in a study, anti-nucleocapsid antibody of SARS-CoV was found to be associated with severe cases of illness 128 ; these results offer insights into the possible role of ADE where N-specific antibodies may not be neutralizing leading to more severe disease outcomes. Antibody-dependent enhancement (ADE) might be one of the causes behind worsening in the severity of symptoms, and this process might have implications for Convalescent therapy used for patients. Due to epitope heterogeneity, there may be a chance that prior exposure to SARS-CoV-2 or other coronaviruses may trigger ADE 129, 130 . One such observation has been made in the study, which indicated the cross-reactivity of antibodies for previous coronaviruses endemic among the human population 131 , and recent studies have shown the presence of IgG seropositivity for OC43 and NL63 in individuals who have not been exposed to SARS-CoV-2 forming immune responses against SARS-CoV-2 132 . Thus, prior exposure to other coronaviruses may be a risk factor for ADE. Glycosylation of antibodies, particularly in the Fc region of IgG, has been extensively studied in health and disease. The Fc region of IgG1 antibodies binds with the FcγRIII receptor through interaction with the hinge region and the CH2 domain 133, 134 . The interaction of Fc with FcγRIII receptor is significantly influenced by the presence of glycans at the N-glycosylation site in each of the CH2 domains 135 . It has been widely studied that the absence of core fucose from N-glycans of antibodies leads to an enhanced ADCC activity that subsequently increases affinity for FcγRIIIa both in vitro and in vivo 136, 137 . Also, the researchers have developed non-fucosylated antibodies that, at lower concentrations was shown to exhibit strong ADCC deploying this glycosylation feature of antibodies 138 . Such a low level of fucosylation has been shown in S, and RBD-specific IgG antibodies in COVID affected symptomatic patients as compared to either asymptomatic or mildly infected patients mediating strong FcγRIIIa responses 139, 140 . ADE has been observed to potentially escalate multiple viral infections, such as in the case of respiratory syncytial virus (RSV) 53,141 and measles 142, 143 . The outcome of ADE has been shown to affect lungs, causing lung injury and cause enhancement of respiratory disease after a respiratory virus infection takes place with symptoms of monocytic infiltration and profusion of eosinophils in the respiratory tract 144 ; the other outcome observed is a vaccine-associated enhanced respiratory disease (VAERD) 143 . ADE has been known to be associated with a wider category of infections known as enhanced respiratory disease (ERD), including antibody-based mechanisms such as cytokine cascades and cellmediated immunopathology 145 . In non-macrophage tropic respiratory viruses, for instance, RSV and measles, non-neutralizing antibodies have been shown to induce ADE and ERD by the formation of immune complexes that get deposited in the airway tissues and activate cytokine and complement pathways that cause inflammation, airway obstruction, and acute respiratory distress syndrome leading to severe cases of illness [141] [142] [143] 146, 147 ; and these are some clinical observations of SARS-CoV-2 similar to RSV and measles in severe cases of COVID-19; inflammatory lung injury by activation of hyperactivation of the complement cascade has been observed prevailing in COVID-19 patients 148, 149 . These results collectively indicate that complement pathways can be aggressively activated in the lungs of COVID-19 patients, which may attribute to SARS-CoV-2N protein 150 . In vivo studies in BALB/c mice challenged with non-neutralizing antibodies for Influenza A virus demonstrated increased lung pathology and infiltration of cells into the alveolar air space on challenging with neutralizing antibodies 43 . SARS-CoV-2 may escape the antibody-virus complex at sub-neutralizing concentrations of antibodies progressing towards replication process that may be abortive without producing viable virus particles or nonabortive, in either case, massive death of immune cells can happen that can result in inflammation cascade and a cytokine storm 151 . As the surge in COVID-19 cases took place, children and adults have been observed to be infected with SARS-CoV-2 more than those observed in the early phase of the COVID-19 pandemic back in 2019. Children who were thought to be largely spared from SARS-CoV-2 had become more prone to multisystem inflammatory syndrome (MIS-C), a post-COVID-19 disorder, which was first recognized in the UK when children were found to be negative for SARS-CoV-2 but were seropositive, indicates the possibility of past infection; multisystem inflammatory syndrome in infants (MIS-C) and adults (MIS-A) associated with COVID-19 has certain implications such as multiple organ failure and shock 152, 153 , in this context, more further research is required to confirm the basis of ADE in MIS-C. According to some previous and present studies, cross-reactive non-neutralizing antibodies appear to hamper virus neutralization. However, extensive research on ADE remains to be done to prove its existence; in vitro and in vivo studies done so far underscore the chances of ADE in Flaviviruses infection. Future studies are required to study the immune system physiology of people before and after vaccination as pre-existing antibodies may provide some correlation with recovery as opposed to worsening of disease that may enlighten the type of antibodies to assess in vaccine studies and differences in the severity of COVID-19 illness and how it manifests in old versus young people. Whether the immune system is producing antibodies to the original viral strain from prior exposure or to the currently infecting viral strain needs to be studied. Thus, uncovering these facts and findings could help explain the largely varying response amongst COVID-19 patients with the disease ranging from mild and symptomless to severe infections requiring hospitalization in some cases that often result in death. ADE could be a potentially new avenue to explore in COVID-related fatality. Globally, new variants of SARS-CoV-2 have emerged that could potentially give rise to the phenomenon of ADE. It is a combination of several factors that may determine its resurgence but nevertheless could trigger reinfection with an enhanced severity and need for healthcare support. The other members of the beta coronavirus lineage, including SARS-CoV and the Middle East respiratory syndrome (MERS) virus, are already known to infect humans. Hence, it is conceivable that protective antibodies against them could initiate ADE in individuals infected with SARS-CoV-2. Maternally acquired SARS-CoV-2 antibodies bound to mast cells could also trigger ADE in children along with the development of MIS (multisystem inflammatory syndrome) via placental transport of these antibodies. However, in contrast to DENV, SARS, and MERS, CoVs infect predominantly the respiratory epithelium, not macrophages which actually expresses the FcγR receptors. Therefore, the chances of ADE are low in COVID cases, and no ADE has been observed in COVID-19 infection. But not just the virus variants; even vaccines against COVID-19 could initiate ADE response. However, the new vaccine technologies consider these facts at the vaccine design stages for any risk of ADE. These are as listed below: • Targeting a SARS-CoV-2 protein epitope for vaccine development that was the least likely to cause ADE, as evident from in silico studies. • Evaluating animal-based studies in pre-clinical and phase1 trials for ADE post-vaccination studies. Further to do the same in human clinical trials. • Epidemiological surveillances to register cases of ADE in a population It is, therefore, in the best of everyone's interest to ramp up the vaccination drive keeping a tab on the vaccinated populations for adverse response and hospitalization. Unvaccinated individuals are the breeding grounds for the emergence of variants of interest (VOI) and variants of concern (VOC), which are more harmful than ADE in terms of the rate of occurrence; this needs coordination between the government and the residents with a public awareness program describing the benefits of vaccines in containing the disease spread in the population. We need to understand that if not facilitating the virus entry, even antibody-mediated elevated effector functions or immune complex formation can also lead to ADE and inflammation. With more innovative algorithms, a vaccine against SARS-CoV-2 generated high neutralizing antibody titers and minimal risk of ADE. With many more vaccines coming up in the market against SARS-CoV-2, the government and regulatory bodies must verify the safety and efficacy of these vaccines for their own population. These necessities the requirement for vaccine bridging trials for the J. Indian Inst. Sci. | VOL xxx:x | xxx-xxx 2022 | journal.iisc.ernet.in foreign-made vaccines to look for ADE in the native population. Even if rare for COVID-19, the possibilities for ADE poses a theoretical risk and need to be addressed with utmost care. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Morbidity and mortality trends of Covid 19 in top 10 countries SARS-CoV-2 epidemic in India: epidemiological features and in silico analysis of the effect of interventions. F1000Re-search Early transmission dynamics in Wuhan, China, of novel coronavirusinfected pneumonia Clinical features of patients infected with 2019 novel coronavirus in Wuhan Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding SARS -CoV-2 receptor ACE 2 and TMPRSS 2 are primarily expressed in bronchial transient secretory cells Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): an overview of viral structure and host response Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study Clinical, laboratory and imaging features of COVID-19: a systematic review and metaanalysis Clinical symptom differences between mild and severe COVID-19 patients in China: a meta-analysis Respiratory virus infections: understanding COVID-19 Lower respiratory tract infection in the community: associations between viral aetiology and illness course SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor SARS-CoV-2 vaccines in development SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates Antibody-enhanced dengue virus infection in primate leukocytes In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells Antibody-dependent enhancement of human immunodeficiency virus type 1 infection Antibodyenhanced infection by HIV-1 via Fc receptor-mediated entry Antibodydependent enhancement of hantavirus infection in macrophage cell lines Infectivity-enhancing antibodies to Ebola virus glycoprotein Monoclonal antibodies to Sindbis virus glycoprotein E1 can neutralize, enhance infectivity, and independently inhibit haemagglutination or haemolysis Relationship between glycoproteins of the viral envelope of bunyaviruses and antibody-dependent plaque enhancement Antibody-mediated growth of Influenza A NWS virus in macrophagelike cell line P388D1 Infection enhancement of Influenza A NWS virus in primary murine macrophages by anti-hemagglutinin monoclonal antibody Antibody-mediated enhancement of disease in feline infectious peritonitis: comparisons with dengue hemorrhagic fever Antibodymediated enhancement of rabies virus infection in a mouse macrophage cell line (P388D1) Enhancing antibodies, macrophages and virulence in mouse cytomegalovirus infection Foot-and-mouth disease virus undergoes restricted replication in macrophage cell cultures following Fc receptor-mediated adsorption Antibody-dependent enhancement of coxsackievirus B3 infection of primary CD19+ B lymphocytes Studies on the pathogenesis of dengue infection in monkeys. II. Clinical laboratory responses to heterologous infection Neutralizing and enhancing antibodies measured in complementrestored serum samples from HIV-1-infected individuals correlate with immunosuppression and disease Fcγreceptor IIa-mediated Src signaling pathway is essential for the antibody-dependent enhancement of ebola virus infection Secondary infection as a risk factor for Dengue hemorrhagic fever/ dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity Japanese encephalitis vaccine-facilitated dengue virus infection-enhancement antibody in adults Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease 2019 Genomic evidence for reinfection with SARS-CoV-2: a case study Antibody-dependent enhancement of SARS coronavirus infection and its role in the pathogenesis of SARS | HKMJ Antibody response of patients with Severe Acute Respiratory Syndrome (SARS) targets the viral nucleocapsid Hypothesis to explain the severe form of COVID-19 in Northern Italy Is COVID-19 receiving ADE from other coronaviruses? Epitoperesolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with an endemic human CoV Cross-reactivity towards SARS-CoV-2: the potential role of low-pathogenic human coronaviruses The structure of a human type III Fcγ receptor in complex with Fc The 3.2-Å crystal structure of the human IgG1 Fc fragment-FcγRIII complex Structural analysis of human IgG-Fc glycoforms reveals a correlation between glycosylation and structural integrity Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity Production of therapeutic antibodies with controlled fucosylation Symptomatic SARS-CoV-2 infections display specific IgG Fc structures Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity Vaccines against respiratory syncytial virus: the time has finally come Atypical exanthem following exposure to natural measles: eleven cases in children previously inoculated with killed vaccine Atypical measles and enhanced respiratory syncytial virus disease (ERD) made simple Learning from the past: development of safe and effective COVID-19 vaccines Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies A role for immune complexes in enhanced respiratory syncytial virus disease A role for nonprotective complement-fixing antibodies with low avidity for measles virus in atypical measles Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation Change of antigenic determinants of SARS-CoV-2 virus S-protein as a possible cause of antibody-dependent enhancement of virus infection and cytokine storm COVID-19 and multisystem inflammatory syndrome in children and adolescents Two different antibody-dependent enhancement (ADE) risks for SARS-CoV-2 antibodies Authors acknowledge the support extended by This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no declarations of interest. Not applicable.Received: 9 August 2021 Accepted: 28 September 2021 Singh is actively working on rationalizing data systems and integrated data platform. Dr. Singh has led teams developing data portals for many programs of ICMR such as ICMR Antimicrobial Resistance Surveillance Network, Nikusth for National Leprosy Eradication Program (NLEP), i-Mann for implementation research in mental health, etc. Recently, Dr. Singh's team has developed and maintaining National COVID-19 testing database. Singh has 89 peer-reviewed publications and 14 copyrights for developed tools.