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 Entry may refer to: *Entry, West Virginia, an unincorporated community in the United States *Entry (cards), a term used in trick-taking card-games *Entry (economics), a term in connection with markets *Entry (film), ''Entry'' (film), a 2013 Indian ...

into host

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

s, followed by its replication. The suboptimal antibodies can result from natural infection or from vaccination. ADE may cause enhanced respiratory disease, but is not limited to

respiratory disease Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bro ...

. It has been observed in

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

, RSV virus and Dengue virus and is monitored for in vaccine development.

Technical description

In ADE, antiviral antibodies promote viral infection of target immune cells by exploiting the phagocytic FcγR or complement pathway. After interaction with a virus, the antibodies bind Fc receptors (FcR) expressed on certain immune cells or complement proteins. FcγRs bind antibodies via their fragment crystallizable region (Fc). The process of

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

is accompanied by virus degradation, but if the virus is not neutralized (either due to low affinity binding or targeting to a non-neutralizing

epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...

), antibody binding may result in virus escape and, therefore, more severe infection. Thus, phagocytosis can cause viral replication and the subsequent death of immune cells. Essentially, the virus “deceives” the process of phagocytosis of immune cells and uses the host's antibodies as a

Trojan horse The Trojan Horse was a wooden horse said to have been used by the Greeks during the Trojan War to enter the city of Troy and win the war. The Trojan Horse is not mentioned in Homer's ''Iliad'', with the poem ending before the war is concluded, ...

. ADE may occur because of the non-neutralizing characteristic of an antibody, which binds viral epitopes other than those involved in host-cell attachment and entry. It may also happen when antibodies are present at sub-neutralizing concentrations (yielding occupancies on viral epitopes below the threshold for neutralization), or when the strength of antibody-antigen interaction is below a certain threshold. This phenomenon can lead to increased viral

infectivity In epidemiology, infectivity is the ability of a pathogen to establish an infection. More specifically, infectivity is a pathogen's capacity for horizontal transmission — that is, how frequently it spreads among hosts that are not in a parent ...

and

virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...

. ADE can occur during the development of a primary or secondary viral infection, as well as with a virus challenge after vaccination. It has been observed mainly with

positive-strand RNA virus Positive-strand RNA viruses (+ssRNA viruses) are a group of related viruses that have positive-sense, single-stranded genomes made of ribonucleic acid. The positive-sense genome can act as messenger RNA (mRNA) and can be directly translated int ...

es, including

flavivirus ''Flavivirus'' is a genus of positive-strand RNA viruses in the family ''Flaviviridae''. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other viruses which may cau ...

es such as

dengue Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. Symptoms typically begin three to fourteen days after infection. These may include a high fever, headache, vomiting, muscle and joint pains, and a characteristic ...

yellow fever Yellow fever is a viral disease of typically short duration. In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains – particularly in the back – and headaches. Symptoms typically improve within five days. ...

, and

Zika Zika fever, also known as Zika virus disease or simply Zika, is an infectious disease caused by the Zika virus. Most cases have no symptoms, but when present they are usually mild and can resemble dengue fever. Symptoms may include fever, red ...

; alpha- and

betacoronavirus ''Betacoronavirus'' (β-CoVs or Beta-CoVs) is one of four genera (''Alpha''-, ''Beta-'', '' Gamma-'', and '' Delta-'') of coronaviruses. Member viruses are enveloped, positive-strand RNA viruses that infect mammals (of which humans are part). ...

es; orthomyxoviruses such as influenza; retroviruses such as

; and orthopneumoviruses such as RSV. The viruses that cause it frequently share common features such as antigenic diversity, replication ability, or ability to establish persistence in immune cells. The mechanism that involves phagocytosis of immune complexes via the FcγRII/

CD32 CD32 (cluster of differentiation 32), also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fragm ...

receptor is better understood compared to the complement receptor pathway. Cells that express this receptor are represented by

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

s, macrophages, and some categories of dendritic cells and B-cells. ADE is mainly mediated by IgG antibodies, but

IgM Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...

and

IgA antibodies Immunoglobulin A (Ig A, also referred to as sIgA in its secretory form) is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other typ ...

have also been shown to trigger it.

Coronavirus

COVID-19

Prior to the pandemic, ADE was observed in animal studies of laboratory rodents with vaccines for SARS-CoV, the virus that causes severe acute respiratory syndrome (

SARS Severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by the severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first identified strain of the SARS coronavirus species, ''seve ...

). However, there have been no observed incidents with vaccines for COVID-19 in trials with nonhuman primates, in clinical trials with humans, or following the widespread use of approved vaccines.

Influenza

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. 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. ADE was suspected in infections with

influenza A virus subtype H7N9 Influenza A virus subtype H7N9 (A/H7N9) is a bird flu strain of the species Influenza virus A (avian influenza virus or bird flu virus). Avian influenza A H7 viruses normally circulate amongst avian populations with some variants known to occa ...

, but knowledge is limited.

Dengue

The most widely known ADE example occurs with dengue virus. Dengue is a single-stranded positive-polarity RNA virus of the family ''

Flaviviridae ''Flaviviridae'' is a family of enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vectors (mainly ticks and mosquitoes). The family gets its name from the yellow fever viru ...

''. It causes

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

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. It is estimated that as many as 390 million individuals contract dengue annually. ADE may follow when a person who has previously been infected with one serotype becomes infected months or years later with a different serotype, producing higher

viremia Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to ''bacteremia'', a condition where bacteria enter the bloodstream. The name comes from combining the word "virus" wit ...

than in first-time infections. Accordingly, while primary (first) infections cause mostly minor disease (dengue fever) in children, re-infection is more likely to be associated with dengue hemorrhagic fever and/or dengue shock syndrome in both children and adults. Dengue encompasses four

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...

ically different serotypes (dengue virus 1–4). In 2013 a fifth serotype was reported. Infection induces the production of neutralizing homotypic immunoglobulin G (IgG) antibodies that provide lifelong immunity against the infecting serotype. Infection with dengue virus also produces some degree of cross-protective immunity against the other three serotypes. Neutralizing heterotypic ( cross-reactive) IgG antibodies are responsible for this cross-protective immunity, which typically persists for a period of months to a few years. These heterotypic

titer Titer (American English) or titre (British English) is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positiv ...

s decrease over long time periods (4 to 20 years). While heterotypic titers decrease, homotypic IgG antibody titers increase over long time periods. This could be due to the preferential survival of long-lived

memory B cell In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiesc ...

s producing homotypic antibodies. In addition to neutralizing heterotypic antibodies, an infection can also induce heterotypic antibodies that neutralize the virus only partially or not at all. The production of such cross-reactive, but non-neutralizing antibodies could enable severe secondary infections. By binding to but not neutralizing the virus, these antibodies cause it to behave as a "

trojan horse The Trojan Horse was a wooden horse said to have been used by the Greeks during the Trojan War to enter the city of Troy and win the war. The Trojan Horse is not mentioned in Homer's ''Iliad'', with the poem ending before the war is concluded, ...

", where it is delivered into the wrong compartment of dendritic cells that have ingested the virus for destruction. Once inside the white blood cell, the virus replicates undetected, eventually generating high virus titers and severe disease. A study conducted by Modhiran et al. attempted to explain how non-neutralizing antibodies down-regulate the immune response in the host cell through the

Toll-like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize ...

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 the one hand, an unknown protein induced by the stimulated Fc receptor reduces 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 TRAF6 is a TRAF human protein. Function The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF recep ...

, TRAM,

TIRAP TIRAP is an adapter molecule associated with toll-like receptors. The innate immune system recognizes microbial pathogens through Toll-like receptors (TLRs), which identify pathogen-associated molecular patterns. Different TLRs recognize different ...

, IKKα,

TAB1 Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the ''TAB1'' gene. Function The protein encoded by this gene was identified as a regulator of the MAP kinase kinase kinase MAP3K7 ...

, TAB2,

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

complex) involved in the Toll-like receptor signaling pathway are down-regulated, which led to a decrease in 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. One example occurred in

Cuba Cuba ( , ), officially the Republic of Cuba ( es, República de Cuba, links=no ), is an island country comprising the island of Cuba, as well as Isla de la Juventud and several minor archipelagos. Cuba is located where the northern Caribbea ...

, lasting from 1977 to 1979. The infecting serotype was dengue virus-1. This epidemic was followed by outbreaks in 1981 and 1997. In those outbreaks; dengue virus-2 was the infecting serotype. 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 dengue virus-1 during the first outbreak. Furthermore, people with secondary infections with dengue virus-2 in 1997 had a 3-4 fold increased probability of developing severe disease than those with secondary infections with dengue virus-2 in 1981. This scenario can be explained by the presence of sufficient neutralizing heterotypic IgG antibodies in 1981, whose titers had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.

HIV-1

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. The increase in infection has been reported to be over 350 fold which is comparable to ADE in other viruses like dengue virus. 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 the 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. Complement component receptors CR2, CR3 and CR4 have been found to mediate this Complement-mediated enhancement of infection. 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. 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. 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. 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 the virus alone. 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. 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. 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 to have accelerated release of reverse transcriptase and viral progeny. 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 the more efficient delivery of viruses to the immune-compromised organs. 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 the rgp120 vaccine in phase 1 and 2 trials. 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

Interaction of a virus with antibodies must prevent the virus from attaching to the host cell entry receptors. However, instead of preventing infection of the host cell, this process can facilitate viral infection of immune cells, causing ADE. After binding the virus, the antibody interacts with Fc or complement receptors expressed on certain immune cells. These receptors promote virus-antibody internalization by the immune cells, which should be followed by the virus destruction. However, the virus might escape the antibody complex and start its replication cycle inside the immune cell avoiding the degradation. This happens if the virus is bound to a low-affinity antibody.

Different virus serotypes

There are several possibilities to explain the phenomenon of enhancing intracellular virus survival: 1) Antibodies against a virus of one serotype binds to a virus of a different serotype. The binding is meant to neutralize the virus from attaching to the host cell, but the virus-antibody complex also binds to the Fc-region antibody receptor ( FcγR) on the immune cell. The cell internalizes the virus for programmed destruction but the virus avoids it and starts its replication cycle instead. 2) Antibodies against a virus of one serotype binds to a virus of a different serotype, activating the classical pathway of the complement system. The complement cascade system 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. This mechanism has been shown for Ebola virus ''in vitro'' and some

es ''in vivo''.

Conclusion

When an antibody to a virus is unable to neutralize the virus, it forms sub-neutralizing virus-antibody complexes. Upon phagocytosis by macrophages or other immune cells, the complex may release the virus due to poor binding with the antibody. This happens during acidification and eventual fusion of the

phagosome In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs). A phagosome is formed by the fusion of the cell ...

with

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...

s. The escaped virus begins its replication cycle within the cell, triggering ADE.

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