Antibody-dependent enhancement

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In antibody-dependent enhancement, sub-optimal antibodies (the blue Y-shaped structures in the graphic) bind to both viruses and Fc gamma receptors (labeled FcγRII) expressed on immune cells promoting infection of these cells.

Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication.[1][2] Antiviral antibodies promote viral infection of target immune cells by exploiting the phagocytic FcγR or complement pathway.[3] After interaction with the virus the antibody binds Fc receptors (FcR) expressed on certain immune cells or some of the complement proteins. FcγR binds antibody via its fragment crystallizable region (Fc). This interaction facilitates phagocytosis of the virus-antibody complex by the immune cells. Usually this phagocytosis is accompanied by the virus degradation, but in the case of ADE, it can, on the contrary, cause viral replication, with the subsequent death of immune cells. Thus, the virus “deceives” the process of phagocytosis of immune cells and uses the host's antibodies as a “Trojan horse”. ADE can be induced when the strength of antibody-antigen interaction is below the certain threshold.[4][5] This phenomenon might lead to both increased virus infectivity and virulence. The viruses that can cause ADE frequently share some common features such as antigenic diversity, abilities to replicate and establish persistence in immune cells.[1] ADE can occur during the development of a primary or secondary viral infection, as well as after vaccination with a subsequent virus challenge.[1][6] It has been observed mainly with positive-strand RNA viruses. Among them are Flaviviruses such as Dengue virus,[7] Yellow fever virus, Zika virus,[8][9] Coronaviruses, including alpha- and betacoronaviruses,[10][11] Orthomyxoviruses such as influenza,[12] Retroviruses such as HIV,[13] and Orthopneumoviruses such as RSV.[14][15][16]

The mechanism that involves phagocytosis of immune complexes via FcγRII / CD32 receptor is better understood compared to the complement receptor pathway.[17][18] Cells that express this receptor are represented by monocytes, macrophages, some categories of dendritic cells and B-cells. Antibody-dependent enhancement can hamper vaccine development, as a vaccine may cause the production of antibodies which, via ADE, worsen the disease the vaccine is designed to protect against. This is a decisive issue during late clinical stages of vaccine development against COVID-19.[19][20][21][22][23][24] Some vaccine candidates that targeted coronaviruses, RSV virus and Dengue virus elicited ADE, and were terminated from further development or became approved for use only for patients who have had those viruses before.

In coronavirus infection[edit]

The phenomenon of antibody-dependent enhancement of infection has been suggested for alpha- and betacoronaviruses,[25][26] although no definitive role for ADE in human coronavirus infection diseases has been established so far.[22] Nevertheless, some researches [25][27][28][29][30] hypothesize that the pathogenesis of SARS and MERS diseases may be associated with ADE, manifested in the infection of monocytes, macrophages and B-cells during primary infection. It has been suggested that ADE could play a role in COVID-19 evolution from the mild to severe form of disease.[31][5][32][33][34]

Mechanism[edit]

There are various hypotheses about how ADE triggered by coronaviruses occurs, and it is likely that more than one mechanism exists. Fc receptors are playing crucial role.[2][35] The mechanism that involves interaction of the Spike protein of coronaviruses with FcγRII/CD32 receptors of the immune cells is most well supported by experimental data. The data suggests that virus-antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry into CD32+ target cell.[36] ADE allows SARS-CoV to infect macrophages. Virus infected macrophages induce little or no IFN-β, suggesting that suppression of the immune response leads to uncontrolled viral replication in the respiratory epithelium cells.[37]

Viral antigens[edit]

S-protein[edit]

In coronaviruses ADE can be promoted by antibodies to the spike (S) glycoprotein.[10][38][26][39][40][41] This observation was done for alphacoronaviruses such as FIPV[40][39][42] as well as for betacoronaviruses such as SARS-CoV-1[26][43][30][44][25][11] and MERS-CoV.[36] So far, it has been shown that only antibodies targeting this protein, but not other viral proteins, form complexes with coronaviruses, which are phagocytosed by immune cells via the FcγRII pathway and cause viral replication rather than viral destruction. Anti S-protein immune serum, while inhibiting viral entry into a permissive cell line, increases infection of human monocyte-derived macrophages[38] and cultured B-cells[44] by SARS-CoV.

Epitopes[edit]

Human immunodominant epitopes of the SARS coronavirus have been shown to cause both enhancing and neutralizing effects in non-human primates. Thus, in rhesus macaques, the S-protein peptides S471–503, S604–625, and S1164–1191 triggered antibodies that efficiently prevented infection. In contrast, peptide S597–603 elicited antibodies that enhanced infection both in vitro and in vivo. [26] Antibodies targeting S-protein that neutralized most variants of SARS-CoV-1 viruses enhanced immune cell entry of the mutant virus.

The mechanism of enhancement might involve the interaction of antibodies with conformational epitopes in the viral ACE-2-binding domain.[41] Antibodies that neutralize human S-proteins of SARS-CoV-1 enhance a cell entry mediated by the civet adapted virus S-proteins. The ACE-2-binding Domain of S-protein mediates ADE dependent virus entry.[41] The five amino acid differences between amino-acids 248 and 501 in S-protein region of human and civet viruses are responsible for ADE the differential ACE-2 affinity and the sensitivity to neutralizing antibodies.[41] ADE may happen due to an antigenic drift of S-protein that occurs as a result of mutations of the gene encoding this viral protein.[45]

Conformations[edit]

S-protein of coronaviruses, forms homotrimers protruding from the viral surface. It mediates a receptor recognition as well as membrane fusion and it represents the primary target of the humoral immune response during viral infection. The states and transitions of S-protein suggest conformational changes that promote viral entry into host cells.[46][47] Spike protein characteristics contribute to its antigenic diversity and may be associated with ADE. Some of these characteristics hypothetically can be related to a change of binding constants with relevant antibodies. The S-protein of SARS-CoV-1, MERS-CoV and SARS-CoV-2 have at least two conformations that are antigenically different. S-protein receptor binding domain (RBD) in S1 subunit can be in a receptor inaccessible (closed) or accessible (open) state.[48][49][50] Therefore the RBD can be in up or down positions. The RBD up states can be observed in MERS-CoV, SARS-CoV-1 and SARS-CoV-2, however, they can not be observed in coronaviruses that are causing common cold OC43, MHV or HKU1.[51][52] Several investigators have identified significant conformational heterogeneity in coronavirus S-proteins, especially in the RBD region.[52][53] Only open state of S-protein is highly immunogenic, while closed state of RBD is hidden from antibodies.[54] Conformational change of S-protein from open to closed can affect multiple antibodies binding constants and it can promote ADE. The pathogenesis of SARS, MERS and COVID-19 diseases, may be associated with ADE, manifested in the infection of some immune cells during primary infection. Some researchers[31][5][32][33][34] believe that ADE is a key step in COVID-19 evolution from the mild to severe form. A hypothesis has been formulated that changes in the antigenic determinants of the S-protein in SARS-CoV-2 are a possible cause of the pathogenesis of ADE and COVID-19 diseases.[55]

An S-protein of SARS-CoV-2, at left, and a protective coating of sugars (glycosylation), at right. Casalino, Amaro Lab, U.C. San Diego.
Glycosylation[edit]

S-proteins of SARS-CoV-1, MERS-CoV and SARS-CoV-2 have multiple glycosylation sites.[56][57][58][59][60] Therefore, in these viruses N-linked glycans are protruding from the protein's trimer surface. A glycan shield can modify humoral immune response[61] and protect the virus from antibodies by decreasing their neutralization capacity. It is known that carbohydrate chains of proteins affect the binding of antibodies to epitopes and, consequently can promote the formation of low-affinity antibody-virus complexes that can trigger ADE. Moreover, the carbohydrate chains themselves can be part of antigenic determinants, and their disappearance in the protein will again lead to a decrease in the binding affinity of the antibody to the antigen - and this is again creating risk of ADE.

N-protein[edit]

Prior immunization with N-protein encoding vector constructs promotes severe pneumonia in mice infected with SARS-CoV-1.[62][63] However, N-protein did not trigger a detectable serum SARS-CoV-neutralizing antibody production.[64] Therefore, it participation in ADE is unlikely.

Cellular receptors[edit]

Experimental evidence suggests that betacoronaviruses can enter immune cells via FcyRII/CD32 receptors. The virus-antibody complex is phagocytosed by CD32+ cells after binding with FcγRII.[10][65][66][38][26] It was specifically shown that the expression of two types of receptors by immune cells: FcγRIIa and FcγRIIb (but not FcγRI or FcγRIIIa) induces ADE by SARS-CoV-1.[44] Along with this finding authors of another study, while observing SARS patients, found that the severity of the disease correlates with the FcγRIIa allelic polymorphism. In patients with FcγRIIa allelic isoform that can interact with both IgG1 and IgG2, the disease is more severe compared to patients with the FcγRIIa isoform capable of binding only IgG2.[67] As shown in the table below expression of FcyRII is present in basophils, neutrophils, eosinophils and platelets.[3] So far, the infection of these cells has not been demonstrated, but it cannot be ruled out.

FcyRIIa FcyRIIb
Neutrophils + +
Eosinophils + +
Monocytes + +
Macrophages + +
Dendritic cells + +
NK cells - -
B cells - +
T cell - -
Platelets + -
Basophiles + +

Types of infected immune cells[edit]

Antibodies targeted S-protein of SARS-CoV-1 promote virus entry into cells bearing Fc𝛾RIIγ (CD32+ cells) such as B-cells,[27][68] monocytes[43][69] and macrophages.[27][30][11][69] In these cells, the virus replicates but does not promote a productive infection. This may be due to the fact that these cells of myeloid lineage do not express enough of serine proteases[70] required for the virion activation. However, viral replication, even without the formation of infectious virions, can lead to a massive death of immune cells bearing the Fc𝛾RII. Established cell lines[25][44][69] and primary humans[30][11] macrophages were vulnerable to antibody mediated SARS-CoV-1 infection. Primary feline macrophages were also vulnerable to antibody mediated feline infectious peritonitis viral (FIPV) infection.[69]

Antibodies[edit]

FcγRII bind only IgG antibodies.[3] In some experiments it has been shown that ADE was mainly caused by antibodies of the IgG2a subclass, while the tested antibodies of the IgG1 subclass did not cause such an effect.[42]

Alphacoronavirus[edit]

The feline infectious peritonitis virus (FIPV) is an alphacoronavirus that is a very common pathogen in both domestic and wild cats.[71] FIPV can cause antibody-dependent enhancement (ADE). Thus, vaccination against FIPV increases the disease seriousness.[72] It has been shown that infection of macrophages by FIPV in vitro can be triggered by non-neutralising monoclonal antibodies targeting the Spike (S)-protein, and this phenomenon can also occur with diluted neutralizing antibodies.[39] Some data indicate that ADE is likely to be promoted by re-infection with the same serotype of FIPS virus.[69][73] ADE explains why half of cats develop peritonitis after being passively immunized with antivirus antibodies and being challenged with the same FIPV serotype.[10] In several countries an attenuated virus vaccine is available in a form of nasal drops; however, its application is still considered controversial by many experts, both in terms of safety and efficacy.[74]

Betacoronavirus[edit]

Vaccine mediated immunopathology[edit]

Antibody-dependent enhancement during SARS-CoV-1 infection
S-protein and N-protein models of SARS-CoV-2 virus. Both models are reproduced with modifications from Ricke et al.[5] It is likely that the amino acids variability of the S-protein represents a result of antigenic drift.

There are multiple examples of immunopathological reactions triggered by betacoronaviruses. These reactions upon viral exposure have been a major challenge for coronavirus vaccine development[75] and may similarly impact SARS-CoV-2 vaccine research.[76] The ADE phenomenon has been demonstrated in both cell cultures and animal models. ADE related acute lung injury has been documented in both severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) animal models.[36] It can occur during a primary infection, reinfection or infection after vaccination. For example, rabbits intranasally infected with MERS-CoV developed a pulmonary infection characterized by viremia and perivascular inflammation of the lung along with an antibody response that lacked neutralizing antibodies.[77] The rabbits produced neutralizing antibodies after the initial virus challenge, however re-exposure to MERS-CoV triggered more severe lung disease.[77] Similar observation were done with re-infected or vaccinated mice with SARS-CoV. Thus, mice were capable to develop neutralizing antibodies after re-infection with SARS-CoV itself or after vaccination with four types of vaccines. However, they all developed immunopathologic-type lung damage after SARS-CoV virus challenge, despite being protected from the virus compared to control.[75] Similar problems were observed with hamsters [68] and non-human primates. For example, vaccinated macaques due to ADE suffered from acute lung injury after the virus challenge despite having the lower viral loads after vaccination.[78][79] In these animals, lung injury occurred with both type of vaccinations such as inactivated virus[78] or vector construct based on modified vaccinia Ankara virus that encoded full-length SARS-CoV spike (S) protein.[79][80] However, ferrets – after vaccination with a similar construct that was followed by the virus challenge – developed severe hepatitis, instead of lung damage.[81] Below is a table from a published review that summarizes model animal vaccine research against SARS-CoV-1 and MERS-CoV-2 viruses.[82] Additional information about vaccine candidates tests in murine models is in another review article.[80]

Virus Animal Vaccine type Vaccination Protective Immuno-pathology Ref.
MERS_CoV Mice Whole Inactivated Virus No Adjuvant Yes Yes [83]
Alum Yes Yes
MF59 Yes Yes
Adenovirus Vector S1 Yes Pulmonary perivascular hemorrhage [84]
S1 + CD40L Yes No
SARS-CoV Mice Whole Inactivated Virus No Adjuvant Yes Th2-type immunopathology with prominent eosinophil lung infiltration [75][85][86]
Alum Yes Th2-type immunopathology with prominent eosinophil lung infiltration [85][87][75]
TLR agonist Yes Mild [85]
delta inulin adjuvant [88] Yes No [86]
No Adjuvant – Aged Mice Partial Yes [87]
Alum – Aged Mice
DNA vaccines These vaccines are described in a separate review [80]
Venezuelan Equine Encephalitis Vector S protein
Young mice Yes No [89]
Aged mice Partial
N protein
Young mice No Yes [89]
Aged mice
S + N protein
Young mice Yes Mild [89]
Old mice No
Recombinant Vaccinia Virus Vector S protein Yes No [90]
N Protein No Yes
S + N Protein Yes Yes
E, M No No
Variable Virus vectors More vaccines are described in a separate review [80]
Virus Like Particle Alum Yes No [91]
Subunit S protein
No Adjuvant Yes Yes [75][86]
Alum
Delta inulin adjuvant Yes No [86]
TLR agonist Yes No [92]
S1 RBD
hFCA Adjuvant Yes No [93]
Proteins More vaccines are described in a separate review [80]
Ferret Whole Inactivated Virus No adjuvant Infection delay, multiple organ damage Not clear [94]
Alum
Adenovirus Vector S + N protein
Intra-nasal Infection delay, multiple organ damage Not clear [94]
Intra-muscular
Modified Vaccinia Virus Ankara Vector S protein Partial Liver damage [81]
Hamster Live Attenuated Virus Yes Mild [95]
Whole Inactivated Virus No Adjuvant Yes Mild [96]
AS01 Yes Mild
Subunit S protein trimer
No Adjuvant Yes No [68]
Alum Yes No
Non Human Primate Modified Vaccinia Virus Ankara

Vector

S protein Yes Acute lung injury [79]
Whole Inactivated Virus No No [78]
B-cell peptide- epitopes Three peptides from Spike protein (S471-503, S604-625, and S1164-1191) Yes No [26]
One peptide from Spike protein (S597-603) No Yes
Potential link between COVID-19 pathogenesis and conformational change of S-protein

ADE and disease pathogenesis[edit]

Primary infection[edit]

The pathogenesis of SARS, MERS and COVID-19 diseases, may be associated with ADE, manifested in the infection of monocytes, macrophages and B-cells during primary infection. Some researchers[31][5][32][33][34] believe that ADE is a key step in COVID-19 evolution from the mild to severe form with critical symptoms. ADE goes along with reduction of Th1 cytokines IL2, TNF-α and IFN-γ and increase of Th2 cytokines IL-10, IL-6, PGE-2 and INF-α, as well as with inhibition of STAT pathway.[97] This process can trigger generalized infection of immune cells in multiple organs and cytokine storm that characterizes COVID-19 infection .[98][99] ADE may explain the observed dysregulation of immune system, including apoptosis of immune cells, T-cell lymphopenia an inflammatory cascade with accumulation of macrophages and neutrophils in the lungs, as well as a cytokine storm that is an immune response, in which the body releases too many cytokines into the blood too quickly. Previously, other researchers have also put forward a similar hypothesis regarding SARS and MERS.[25][27][28][29][30]

The SARS-CoV and MERS-CoV viruses contribute to acute lung damage by similar to COVID-19 immunopathological effects that include aggressive inflammation through poorly understood mechanisms. The authors of the study[29] draw parallel between vaccinated SARS-CoV/macaque models and severely ill patients who eventually died of SARS. They concluded that IgG antibodies targeting S-protein cause acute lung injury in macaques after the virus challenge. The presence of these antibodies prior to a viral clearance promotes the production of MCP1 and IL-8, which triggers the recruitment and accumulation of pro-inflammatory monocytes / macrophages. The serum of severely sick patients has similar characteristics. However, blocking of FcγR reduces these immunopathological effects. These data reveal some characteristic features of mechanisms responsible for immune-mediated acute lung injuries in severely ill SARS patients and vaccinated SARS-CoV/macaques challenged with the virus. Most likely IgG antibodies targeting viral S-protein represent a common trigger for the immunopathology development in humans and in animals.[29]

Infection of immune cells mediated or not by antibodies[edit]

MERS-CoV. Active replication along with productive viral infection has been observed in human macrophages ex vivo. In the cells from different healthy blood donors a 2–4-log increase in viral RNA level was consistently detected. The productive virus infection was confirmed with TCID50 assays.[100]

SARS-CoV-1. There is some limited evidence that SARS-CoV-1 can replicate ex vivo in primary monocytes and macrophages, triggering abortive infection[101][100] or producing low infectious virus titers.[66] Also some evidence exist that antibodies targeting S-protein can promote non-productive abortive viral infection ex vivo of monocytes, B-cells, and macrophages. Established cell lines[25][44][68] and primary human macrophages[30][11] can be vulnerable to antibody mediated abortive virus infection.

SARS-CoV-2. There is some limited evidence that SARS-CoV-2 ex vivo can promote abortive infection of primary CD4+ T cells isolated from peripheral blood mononuclear cells (PBMC) of healthy donors.[102] This viral replication happens without antibodies being present. Some preliminary data indicate that SARS-CoV-2 virus antigens and replication double stranded RNA intermediates can be detected in monocytes, B-cells, and less frequently in CD4+ T-cells from PBMCs of COVID-19 patients. In addition, the study states that the virus can replicate to low titers ex vivo in PBMC cells of healthy donors. Some evidence has been obtained that antibodies level against RBD of S-protein correlates with severity of multisystem inflammatory syndrome (MIS-C) in children, however, causative relationship was not established.[103][104] All children with MIS-C also had IgM antibodies targeted RBD, indicating recent SARS-CoV-2 infection. IgG titers correlated with erythrocyte sedimentation rate, with hospital and ICU lengths of stay.[103]

Table below summarizes evidence of immune cells infection by SARS-CoV-1 and SARS-CoV-2.

SARS-CoV-1

               Evidence of viral replication in immune cells without antibodies Reference.
PBMCs of SARS patients Genomic RNA (+RNA) and replicative intermediates (-RNA) were detected by RT-PCR. [65]
               Evidence of viral infection of immune cells without antibodies
PBMCs of healthy donors (ex vivo) Primary monocytes/macrophages Primary cells from some donors were virus resistant and from others were capable of being infected and produce infectious virions. [66]
Abortive infection [101]
Immature and mature monocyte-derived dendritic cells [105]
Monocyte-derived dendritic cells Low infectious titer of produced virions [106]
Evidence of antibodies mediated non-productive infection of immune cells
PBMCs of healthy donors (ex vivo) Primary monocytes/macrophages Antibodies targeting S-protein can promote non-productive viral infection. [30][11]
Cell line Monocyte/macrophage cell line (THP-1) [25]
B-cell lines (Raji, Daudi) [25][44][68]

SARS-CoV-2

               Evidence of viral replication in immune cells without antibodies
PBMCs of COVID-19 patients (ex vivo) Some traces of viral RNA are present in PBMCs [107]
               Evidence of viral infection of immune cells without antibodies
PBMCs of healthy donors (ex vivo) Primary CD4+ T-cells Non-productive infection [102]
Evidence of viral infection of immune cells in vivo
PBMCs of COVID-19 patients (in vivo) B-cells, monocytes, CD4+ T-cells Positive staining for SARS-CoV-2 antigens and double stranded viral RNA
Secondary infection[edit]

Rabbits intranasally infected with MERS-CoV developed a lung infection with viremia and perivascular inflammation.[77] The rabbits produced neutralizing antibodies after the initial virus challenge, however re-exposure to MERS-CoV triggered more severe lung disease.[77] ADE is likely to be triggered in cats by re-infection with the same serotype of FIPS virus.[73]

Antigenic imprinting or original antigenic sin[edit]

An ongoing question in the COVID-19 pandemic is whether—and if so, to what extent—COVID-19 receives ADE from prior infection with seasonal coronaviruses through a mechanism of antigenic imprinting also known as original antigenic sin.[108] The phenomenon of antigenic imprinting is based on the body's ability to form long-lived immunological memory cells during a primary infection, which remain in the body and provide protection against subsequent infections. Immune memory cells respond to specific antigenic epitopes on the surface of viral proteins to produce antigen-specific antibodies. Memory B cells respond to infection faster than naive B cells that produce antibodies to new antigens. Antigenic imprinting reduces the time required to clear subsequent infections. This is its positive role in the fight against infection. However, there is also a negative role. Between primary and secondary infections, or after vaccination, the virus can undergo antigenic drift, in which its surface antigenic epitopes are altered by mutations, which allows the virus to escape immune surveillance. When this happens, the new variant of the virus preferentially reactivates memory B cells and stimulates the production of appropriate antibodies. However, the antibodies produced by these B cells tend to bind inefficiently to the altered antigens. They often experience loss of affinity and avidity. In addition, these antibodies inhibit the activation of naive B cells, which could produce more effective neutralizing antibodies to the second variant of the virus. This leads to a less efficient immune response, antibody-dependent enhancement of infection, and / or recurrent infections. As a result, the body may take longer to fight infection. The hypothesis put forward in a few research groups[108][109][110] is associated with this phenomenon and is based on the possible immunological cross-reactivity between seasonal low pathogenic coronaviruses and SARS-CoV-2. According to the hypothesis, due to the rapid response of the immune system to the pathogen, antigenic imprinting developed for seasonal coronaviruses can either prevent or alleviate the course of COVID-19. Most likely, the development of the disease in one form or another depends both on the individual characteristics of all systems of the human body and on the repertoire of pathogens with which the immune system has already encountered. Regardless of preexisting infections, aged mice are developing more severe SARS disease compared to young. The difference in this severity models human SARS.[111]

IgG antibodies targeting SARS-CoV-1[edit]

The following observations made on a small group of six patients, three of whom recovered and three died, also support the idea that antibodies to the S-protein can harm patients by causing ADE.[112] A comparative analysis of the specific humoral response showed that in patients who died from SARS-CoV-1 infection, neutralizing antibodies to the S-protein were produced much faster than in recovered people. So, it was revealed that on the 15th day of illness in patients who subsequently died, the titer of antibodies to the S-protein was significantly higher than in those who subsequently recovered. At the same time, although the titer of neutralizing antibodies during the course of the disease in patients who subsequently died grew faster than the titer in subsequently recovered patients, it also decreased faster. At the same time, in patients who subsequently recovered, the antibody titer increased more slowly, but rose to a higher level and stayed at this level longer. This dynamics of changes in antibody titers was characteristic of both IgM and IgG antibodies. It can be assumed that patients who subsequently died developed an antibody-dependent increase in viral infection in severe form and the rapid production of antibodies to the S-protein, which could not neutralize the virus, contributed to this. It is possible that the slower titer rise contributed to the production of antibodies with a higher binding constant corresponding to stronger antigen-antibody complexes, with higher affinity and avidity.[112] A significant excess of the level of antibodies in severe patients compared with non-severe patients was also observed in a sample of 325 patients in another study.[113] Other researchers received similar data on a sample of 347 SARS patients. Moreover, it was found that in patients who subsequently died, antibodies appeared first.[114]

IgG antibodies targeting SARS-CoV-2[edit]

In critically sick patients IgG antibodies can be found in higher levels at certain disease stage. A positive relationship between high IgG antibody titers and COVID-19 severity[115][116][117][118][119][120] supports hypothesis that connects the disease pathogenesis and antibodies production in a causative way. It is not clear, however, if this connection is a result of enhanced immune-cell infection, or direct production of pathogenic and auto-reactive antibodies. Further, It is now understood that mature B cells may have pathological effects independently of antibody production through the direct secretion of cytokines.[121] Antibodies also can harm without promoting infection of immune cells if they are auto-antibodies against type I IFNs. Thus, it has been found that 10% of patients with life-threatening COVID-19 have such antibodies, while some of these antibodies target IFN-α, some IFN-ω, or both.[122]

Perhaps harming potential of some clones of IgG antibodies is higher versus potential of any other antibodies belonging to other classes. Disease severity was linked to high IgG antibody levels targeting S and N proteins in a study that involved 35 hospitalized and 105 convalescent subjects. A faster appearance of IgG antibodies in patients with severe illness compared with those in whom it was mild was observed in a sample of 285 people.[115] Interestingly, with respect to IgM antibodies, a different dynamic was observed, they were found either in the same or in lower titer in patients with a more severe form of the disease.[115][123] Similar results were obtained with 723 patients, severe patients had higher levels of IgG, but not IgM antibodies levels.[117] In both samples of 173[116] and 153[118] of COVID-19 patients, a significant excess of antibody levels in critically ill patients compared with non-severe patients occurred two / three weeks after the symptoms onset. In addition, a positive and significant correlation was found between the S1 sub-unit targeting IgG antibodies titer and the concentration of some inflammatory markers such as lactate dehydrogenase (LDH).[124] The data [124] was obtained from 29 patients. In a same study a significant inverse correlation was found between the S1 sub-unit targeting IgG antibody titer and the number of lymphocytes.[124] The correlation between COVID19 disease severity and levels of antibodies was not, however, found in other two studies, which include of 76[125] or 2529[126] patients. The table below summarizes antibody measurement results. It also should be noted that the virus-specific IgG level in asymptomatic SARS-CoV-2+ patients is lower than in the symptomatic group.[127]

Antibodies production in COVID-19 patients
Number of patients IgG level difference in severe and mild cases Days after symptoms onset IgM level difference in severe and mild cases Days after symptoms onset Antibody targeting Detection ref
285 Significant increase in severe patients 8-14 No significant difference 8-14 S-protein peptide and N-protein MCLIA kits supplied by Bioscience, China [115]
285 Not reported Significant increase in severe patients 3-21 S-protein, N-protein SARS-CoV-2 IgM GICA kit (Shanghai Outdo Biotech Co., China) [123]
723 Significant increase in severe patients Active stage of disease No significant difference Active stage of disease Not reported Axceed 260 magnetic particle-based chemiluminescence immunoanalyzer

(Bioscience, Tianjin, China)

[117]
No significant difference Early stage Early stage
Late convalescent Late convalescent
173 Significant increase in severe patients of total Ab from

10–22 days after symptoms onset

RBD ELISA kits by Beijing Wantai Biological Pharmacy Enterprise Co.,Ltd, China [116]
149 Significantly higher in severe and hospitalized patients non reported No significant difference non reported RBD, S-protein and other ELISA kits [128]
153 Significant increase in severe patients 10-40 Significant increase in severe patients 10-40 RBD and N-protein Pylon 3D automated immunoassay system (ET Healthcare, Palo Alto, CA) [118]
338 Small but significant decrease in severe patients 1-35 Small but significant increase in severe patients 1-35 S-protein and N-protein anti‐SARS‐CoV‐2 CLIA‐YHLO kit (YHLO Biotech Co. Ltd Shenzhen, China) [129]
38 Lower in severe patients 14-21 Higher in severe patients 7-14 S-protein ELISA [130]
38 Significantly higher in severe patients 1-21 Significantly higher in severe patients 1-21 N-protein
22 Lower IgG in diseased patient 1-20 Lower in individuals who died 1-20 S-protein, RBD Customized multiplexed Luminex assay [131]
22 Higher IgG in diseased patient Higher in individuals who died N-protein
76 No significant difference between severe and mild cases in IgG and IgM antibody levels N-protein Abbott Architect SARS-CoV-2 497 platform [125]
2529 No significant difference between severe and mild cases 20-40 No significant difference between severe and mild cases 20-40 not reported IgM/IgG chemiluminescence test kit (Shenzhen Yahuilong Biotechnology Co., Ltd., China) [126]

In influenza infection[edit]

Prior receipt of 2008–09 TIV (Trivalent Inactivated Influenza Vaccine) was associated with an increased risk of medically attended pH1N1 illness during the spring-summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.[132]

Natural infection and the attenuated vaccine induce antibodies that enhance the update of the homologous virus and H1N1 virus isolated several years later, demonstrating that a primary influenza A virus infection results in the induction of infection enhancing antibodies.[133]

ADE was suspected in infections with influenza A virus subtype H7N9, but knowledge is limited.

In dengue virus infection[edit]

The most widely known example of ADE occurs in the setting of infection with dengue virus, a single-stranded positive-polarity RNA virus of the family Flaviviridae. It causes a disease of varying severity in humans, from dengue fever (DF), which is usually self-limited, to dengue hemorrhagic fever and dengue shock syndrome, either of which may be life-threatening.[134] It is estimated that as many as 390 million individuals are infected with dengue virus annually.[135]

The phenomenon of ADE may be observed when a person who has previously been infected with one serotype of the dengue virus becomes infected months or years later with a different serotype. In such cases, the clinical course of the disease is more severe, and these people have higher viremia compared with those in whom ADE has not occurred. This explains the observation that while primary (first) infections cause mostly minor disease (dengue fever) in children, secondary infection (re-infection at a later date) is more likely to be associated with dengue hemorrhagic fever and/or dengue shock syndrome in both children and adults.[136]

There are four antigenically different serotypes of dengue virus (dengue virus 1–4).[137] In 2013 a fifth serotype was reported.[138] Infection with dengue virus induces the production of neutralizing homotypic immunoglobulin G (IgG) antibodies which provide lifelong immunity against the infecting serotype. Infection with dengue virus also produces some degree of cross-protective immunity against the other three serotypes.[139] Neutralizing heterotypic (cross-reactive) IgG antibodies are responsible for this cross-protective immunity, which typically persists for a period of several months to a few years. These heterotypic antibody titers decrease over long time periods (4 to 20 years).[140] While heterotypic IgG antibody titers decrease, homotypic IgG antibody titers increase over long time periods. This could be due to the preferential survival of long-lived memory B cells producing homotypic antibodies.[140]

In addition to inducing neutralizing heterotypic antibodies, infection with the dengue virus can also induce heterotypic antibodies that neutralize the virus only partially or not at all.[141] The production of such cross-reactive but non-neutralizing antibodies could be the reason for more severe secondary infections. It is thought that by binding to but not neutralizing the virus, these antibodies cause it to behave as a "trojan horse",[142][143][144] where it is delivered into the wrong compartment of dendritic cells that have ingested the virus for destruction.[145][146] Once inside the white blood cell, the virus replicates undetected, eventually generating very high virus titers which cause severe disease.[147]

A study conducted by Modhiran et al.[148] attempted to explain how non-neutralizing antibodies down-regulate the immune response in the host cell through the Toll-like receptor signaling pathway. Toll-like receptors are known to recognize extra- and intracellular viral particles and to be a major basis of the cytokines production. In vitro experiments showed that the inflammatory cytokines and type 1 interferon production were reduced when the ADE-dengue virus complex bound to the Fc receptor of THP-1 cells. This can be explained by both a decrease of Toll-like receptor production and a modification of its signaling pathway. On one hand, an unknown protein induced by the stimulated Fc receptor reduces the Toll-like receptor transcription and translation, which reduces the capacity of the cell to detect viral proteins. On the other hand, many proteins (TRIF, TRAF6, TRAM, TIRAP, IKKα, TAB1, TAB2, NF-κB complex) involved in the Toll-like receptor signaling pathway are down-regulated, which led to a decrease of the cytokine production. Two of them, TRIF and TRAF6, are respectively down-regulated by 2 proteins SARM and TANK up-regulated by the stimulated Fc receptors.

To illustrate the phenomenon of ADE, consider the following example: an epidemic of dengue fever occurred in Cuba, lasting from 1977 to 1979. The infecting serotype was dengue virus-1. This epidemic was followed by two more outbreaks of dengue fever—one in 1981 and one in 1997; dengue virus-2 was the infecting serotype in both of these later epidemics. 205 cases of dengue hemorrhagic fever and dengue shock syndrome occurred during the 1997 outbreak, all in people older than 15 years. All but three of these cases were demonstrated to have been previously infected by the dengue virus-1 serotype during the epidemic of 1977–1979.[149] Furthermore, people who had been infected with dengue virus-1 during the 1977-79 outbreak and secondarily infected with dengue virus-2 in 1997 had a 3-4 fold increased probability of developing severe disease than those secondarily infected with dengue virus-2 in 1981.[140] This scenario can be explained by the presence of neutralizing heterotypic IgG antibodies in sufficient titers in 1981, the titers of which had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.

In HIV-1 virus infection[edit]

ADE of infection has also been reported in HIV. Like dengue virus, non-neutralizing level of antibodies have been found to enhance the viral infection through interactions of the complement system and receptors.[150] The increase in infection has been reported to be over 350 fold which is comparable to ADE in other viruses like dengue virus.[150] ADE in HIV can be complement-mediated or Fc receptor-mediated. Complements in the presence of HIV-1 positive sera have been found to enhance the infection of MT-2 T-cell line. The Fc-receptor mediated enhancement was reported when HIV infection was enhanced by sera from HIV-1 positive guinea pig enhanced the infection of peripheral blood mononuclear cells without the presence of any complements.[151] Complement component receptors CR2, CR3 and CR4 have been found to mediate this Complement-mediated enhancement of infection.[150][152] The infection of HIV-1 leads to activation of complements. Fragments of these complements can assist viruses with infection by facilitating viral interactions with host cells that express complement receptors.[153] The deposition of complement on the virus brings the gp120 protein close to CD4 molecules on the surface of the cells, thus leading to facilitated viral entry.[153] Viruses pre-exposed to non-neutralizing complement system have also been found to enhance infections in interdigitating dendritic cells. Opsonized viruses have not only shown enhanced entry but also favorable signaling cascades for HIV replication in interdigitating dendritic cells.[154]

HIV-1 has also shown enhancement of infection in HT-29 cells when the viruses were pre-opsonized with complements C3 and C9 in seminal fluid. This enhanced rate of infection was almost 2 times greater than infection of HT-29 cells with virus alone.[155] Subramanian et al., reported that almost 72% of serum samples out of 39 HIV positive individuals contained complements that were known to enhance the infection. They also suggested that the presence of neutralizing antibody or antibody-dependent cellular cytotoxicity-mediating antibodies in the serum contains infection-enhancing antibodies.[156] The balance between the neutralizing antibodies and infection-enhancing antibodies changes as the disease progresses. During advanced stages of the disease the proportion of infection-enhancing antibodies are generally higher than neutralizing antibodies.[157] Increase in viral protein synthesis and RNA production have been reported to occur during the complement-mediated enhancement of infection. Cells that are challenged with non-neutralizing levels of complements have been found have accelerated release of reverse transcriptase and the viral progeny.[158] The interaction of anti-HIV antibodies with non-neutralizing complement exposed viruses also aid in binding of the virus and the erythrocytes which can lead to more efficient delivery of viruses to the immune-compromised organs.[152]

ADE in HIV has raised questions about the risk of infections to volunteers who have taken sub-neutralizing levels of vaccine just like any other viruses that exhibit ADE. Gilbert et al., in 2005 reported that there was no ADE of infection when they used rgp120 vaccine in phase 1 and 2 trials.[159] It has been emphasized that much research needs to be done in the field of the immune response to HIV-1, information from these studies can be used to produce a more effective vaccine.

Mechanism[edit]

There are several possibilities to explain the phenomenon:

  1. A viral surface protein studded with antibodies against a virus of one serotype binds to a similar virus with a different serotype. The binding is meant to neutralize the virus surface protein from attaching to the cell, but the virus-antibody complex also binds to the Fc-region antibody receptor (FcγR) on the cell membrane. This brings the virus into close proximity to the virus-specific receptor, and the cell internalizes the virus through the normal infection route.[160]
  2. A virus surface protein may be attached to antibodies of a different serotype, activating the classical pathway of the complement system. The complement cascade system instead binds C1Q complex attached to the virus surface protein via the antibodies, which in turn bind C1q receptor found on cells, bringing the virus and the cell close enough for a specific virus receptor to bind the virus, beginning infection.[citation needed] This mechanism has not been shown specifically for dengue virus infection, but may occur with Ebola virus infection in vitro.[161]
  3. When an antibody to a virus is present for a different serotype, it is unable to neutralize the virus, which is then ingested into the cell as a sub-neutralized virus particle. These viruses are phagocytosed as antigen-antibody complexes, and degraded by macrophages. Upon ingestion the antibodies no longer even sub-neutralize the body due to the denaturing condition at the step for acidification of phagosome before fusion with lysosome.[clarification needed] The virus becomes active and begins its proliferation within the cell.[citation needed]

See also[edit]

  • Original antigenic sin
  • Other ways in which antibodies can (unusually) make an infection worse instead of better
    • Blocking antibody, which can be either good or bad, depending on circumstances
    • Hook effect, most relevant to in vitro tests but known to have some in vivo relevances

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