Phenomenon Of Antibody-dependent Enhancement Research Articles

Antibody-Dependent Enhancement with a Focus on SARS-CoV-2 and Anti-Glycan Antibodies.

Antibody-dependent enhancement (ADE) is a phenomenon where virus-specific antibodies paradoxically cause enhanced viral replication and/or excessive immune responses, leading to infection exacerbation, tissue damage, and multiple organ failure. ADE has been observed in many viral infections and is supposed to complicate the course of COVID-19. However, the evidence is insufficient. Since no specific laboratory markers have been described, the prediction and confirmation of ADE are very challenging. The only possible predictor is the presence of already existing (after previous infection) antibodies that can bind to viral epitopes and promote the disease enhancement. At the same time, the virus-specific antibodies are also a part of immune response against a pathogen. These opposite effects of antibodies make ADE research controversial. The assignment of immunoglobulins to ADE-associated or virus neutralizing is based on their affinity, avidity, and content in blood. However, these criteria are not clearly defined. Another debatable issue (rather terminological, but no less important) is that in most publications about ADE, all immunoglobulins produced by the immune system against pathogens are qualified as pre-existing antibodies, thus ignoring the conventional use of this term for natural antibodies produced without any stimulation by pathogens. Anti-glycan antibodies (AGA) make up a significant part of the natural immunoglobulins pool, and there is some evidence of their antiviral effect, particularly in COVID-19. AGA have been shown to be involved in ADE in bacterial infections, but their role in the development of ADE in viral infections has not been studied. This review focuses on pros and cons for AGA as an ADE trigger. We also present the results of our pilot studies, suggesting that AGAs, which bind to complex epitopes (glycan plus something else in tight proximity), may be involved in the development of the ADE phenomenon.

Neurological Complications of Dengue Fever.

Purpose of ReviewTo discuss the neurological complications of dengue virus (DENV) infection and their pathogenesis.Recent FindingsInclude recognition of the four different serotypes of DENV and their epidemiology as well as recognition of the expanded dengue syndrome encompassing multisystem involvement in the severe form of the disease including involvement of the central nervous system (CNS). DENV is a neurotropic virus with the ability to infect the supporting cells of the CNS. Neural injury during the acute stage of the infection results from direct neuro-invasion and/or the phenomenon of antibody-dependent enhancement, resulting in plasma leakage and coagulopathy. Immune mechanisms have been implicated in the development of the delayed neurological sequelae through molecular mimicry. A myriad of neurological syndromes has been described as a result of the involvement of the CNS, the peripheral nervous system (PNS), or both.SummaryNeurological manifestations in DENV infection are increasingly being recognized, some of which are potentially fatal if not treated promptly. DENV encephalopathy and encephalitis should be considered in the differential diagnosis of other acute febrile encephalopathies, autoimmune encephalitides, and in cases of encephalopathy/encephalitis related to SARS-CoV2 infection, especially in dengue-endemic areas. Acute disseminated encephalomyelitis (ADEM) may be occasionally encountered. Clinicians should be knowledgeable of the expanded dengue syndrome characterized by the concurrent compromise of cardiac, neurological, gastrointestinal, renal, and hematopopoietic systems. Isolated cranial nerve palsies occur rather uncommonly and are often steroid responsive. These neuropathies may result from the direct involvement of cranial nerve nuclei or nerve involvement or may be immune-mediated. Even if the diagnosis of dengue is confirmed, it is absolutely imperative to exclude other well-known causes of isolated cranial nerve palsies. Ischemic and hemorrhagic strokes may occur following dengue fever. The pathogenesis may be beyond the commonly observed thrombocytopenia and include cerebral vasculitis. Involvement of ocular blood vessels may cause maculopathy or retinal hemorrhages. Posterior reversible encephalopathy syndrome (PRES) is uncommon and possibly related to dysregulated cytokine release phenomena. Lastly, any patient developing acute neuromuscular weakness during the course or within a fortnight of remission from dengue fever must be screened for acute inflammatory demyelinating polyneuropathy (AIDP), hypokalemic paralysis, or acute myositis. Rarely, a Miller–Fisher-like syndrome with negative anti-GQ1b antibody may develop.

Non-neutralizing antibodies: Deleterious or propitious during SARS-CoV-2 infection?

Antibody-dependent enhancement (ADE) is a complex phenomenon mediated by antibodies, frequently pre-existing non-neutralizing or sub-neutralizing antibodies. In the course of infectious diseases, ADE may be responsible for worsening the clinical course of the disease by increasing the virulence of pathogens (ADE of infection) or enhancing disease severity (ADE of disease). Here we reviewed the mechanisms thought to be behind the ADE phenomenon and its potential relationship with COVID-19 severity. Since the early COVID-19 epidemics, ADE has been mentioned as a possible mechanism involved in severe COVID-19 disease and, later, as a potential risk in the case of infection after vaccination. However, current data do not support its role in disease severity, both after infection and reinfection.

The Role of Antibodies in the Treatment of SARS-CoV-2 Virus Infection, and Evaluating Their Contribution to Antibody-Dependent Enhancement of Infection.

Antibodies play a crucial role in the immune response, in fighting off pathogens as well as helping create strong immunological memory. Antibody-dependent enhancement (ADE) occurs when non-neutralising antibodies recognise and bind to a pathogen, but are unable to prevent infection, and is widely known and is reported as occurring in infection caused by several viruses. This narrative review explores the ADE phenomenon, its occurrence in viral infections and evaluates its role in infection by SARS-CoV-2 virus, which causes coronavirus disease 2019 (COVID-19). As of yet, there is no clear evidence of ADE in SARS-CoV-2, though this area is still subject to further study.

Incidence and severity of SARS-CoV-2 virus post COVID-19 vaccination: A cross-sectional study in India

IntroductionSeveral sociodemographic variables, including ethnic inequality, have been identified as potentially influencing the uptake of COVID-19 vaccinations. To develop herd immunity against COVID-19, at least 70–85% of the population must be vaccinated. As the situation with COVID-19 changes, the public's perception keeps fluctuating. We designed a survey to determine the prevalence of vaccinated individuals and the rate of infectivity post-vaccination. We also aimed to study the clinical manifestations and infectivity of the SARS-CoV-2 virus post-vaccination. Materials and methodsA cross-sectional study was conducted from May 10, 2021 to July 10, 2021 across India through a pre-tested validated semi-structured self-administered electronic questionnaire, to the study subjects with objectives explained and the confidentiality of the data and results had been assured. The questionnaires were prepared using Google forms and the link was sent across social media platforms such as WhatsApp, Facebook, and various social platforms where people are actively engaged following the restrictions and protocols of social distancing. General demographic data, followed by their lifestyle and comorbid conditions, and data on their vaccination, infectivity, and side effects were collected. ResultsWe included 2334 participants in the study, of which the majority of the study participants were in the age group of 25–34 years (38.6%). 1729 were vaccinated individuals of which 80.7% had received Covishield and 17.8% had received Covaxin. Around 61.1% have received both doses among 1729 vaccinated individuals and 38.9% had received only one dose of vaccine. The majority of the fully vaccinated individuals had a gap of 4–5 weeks for the second dose (37.1%) followed by 5–6 weeks (11.2%). Post-vaccination 50.8% had experienced muscle pain, 46% had experienced fatigue, 36.5% weakness, and 12.3% back pain. Among vaccinated 26% turned out to be COVID-19 positive and 44.5% non-vaccinated got infected. The odds of infection among non -vaccinated individuals was 2.27 times higher than vaccinated individuals. Individuals who encountered the viral antigen for the second time experienced either through vaccination or infection demonstrated exaggerated inflammatory response which is explained by the antibody-dependent enhancement phenomenon without life-threatening complications. ConclusionAlthough more than 50% of the vaccinated individuals experienced some form of musculoskeletal side effects, we noted a high acceptance rate (74%) of vaccination among the participants. The vaccinated individuals were two times safer from infection compared to the non-vaccinated individuals.

A fatal case report of antibody-dependent enhancement of dengue virus type 1 following remote Zika virus infection

BackgroundDengue virus (DENV) is endemic in many parts of the world. Antibody dependent enhancement (ADE) in DENV infections occurs when a person with primary immunity is infected by a second, different DENV strain. Antibodies to Zika virus (ZIKV), which emerged in the Western Hemisphere in 2015, are cross reactive with DENV and theoretically could provoke ADE in a DENV naïve individual.Case presentationDENV infection was suspected in a child who had recently returned from a one-month stay in the Dominican Republic. The child presented with fever, vomiting, abdominal pain, and in hypovolemic shock. Volume and pressor resuscitation were unsuccessful, and the child died less than 24 h after hospitalization. Laboratory results suggested an early acute first DENV infection since serum, plasma, and spinal fluid had DENV1 detected by polymerase chain reaction (PCR), yet the serum lacked IgG antibodies to DENV nonstructural protein 1 (NS1) of all four DENV serotypes. This acute DENV infection occurred in the presence of a remote ZIKV infection as determined by antibodies to ZIKV NS1 envelope by multiplex microsphere immunoassay and an exceptionally high plaque reduction neutralization titer to ZIKV. ZIKV IgG avidity index was high, confirming a past infection. DENV1 RNA was detected in all ten organs and tissues examined by PCR. The severe and fatal complications reported here suggest that a remote ZIKV infection may provoke an exaggerated immune response leading to hypovolemic shock when primarily infected by DENV1.ConclusionWe report the first known patient in the United States with a rapidly progressive and fatal case of travel-associated DENV in which prior exposure to ZIKV likely played a role in triggering an ADE phenomenon. This association of prior ZIKV immunity and subsequent new dengue infection is a worrisome phenomenon and an important contribution to the body of knowledge on immunity to flaviviruses.

Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine.

In 2019, the United States Food and Drug Administration accorded restricted approval to Sanofi Pasteur's Dengvaxia, a live attenuated vaccine (LAV) for dengue fever, a mosquito-borne viral disease, caused by four antigenically distinct dengue virus serotypes (DENV 1-4). The reason for this limited approval is the concern that this vaccine sensitized some of the dengue-naïve recipients to severe dengue fever. Recent knowledge about the nature of the immune response elicited by DENV viruses suggests that all LAVs have inherent capacity to predominantly elicit antibodies (Abs) against the pre-membrane (prM) and fusion loop epitope (FLE) of DENV. These antibodies are generally cross-reactive among DENV serotypes carrying a higher risk of promoting Antibody-Dependent Enhancement (ADE). ADE is a phenomenon in which suboptimal neutralizing or non-neutralizing cross-reactive antibodies bind to virus and facilitate Fcγ receptor mediated enhanced entry into host cells, followed by its replication, and thus increasing the cellular viral load. On the other hand, antibody responses directed against the host-cell receptor binding domain of DENV envelope domain-III (EDIII), exhibit a higher degree of type-specificity with lower potential of ADE. The challenges associated with whole DENV-based vaccine strategies necessitate re-focusing our attention toward the designed dengue vaccine candidates, capable of inducing predominantly type-specific immune responses. If the designed vaccines elicited predominantly EDIII-directed serotype specific antibodies in the absence of prM and FLE antibodies, this could avoid the ADE phenomenon largely associated with the prM and FLE antibodies. The generation of type-specific antibodies to each of the four DENV serotypes by the designed vaccines could avoid the immune evasion mechanisms of DENVs. For the enhanced vaccine safety, all dengue vaccine candidates should be assessed for the extent of type-specific (minimal ADE) vs. cross-reactive (ADE promoting) neutralizing antibodies. The type-specific EDIII antibodies may be more directly related to protection from disease in the absence of ADE promoted by the cross-reactive antibodies.

The potential threat of multisystem inflammatory syndrome in children during the COVID-19 pandemic.

Multisystem inflammatory syndrome in children (MIS-C) during the COVID-19 pandemic raised a global alert from the Centers for Disease Control and Prevention's Health Alert Network. The main manifestations of MIS-C (also known as pediatric MIS (PMIS)) in the setting of a severe inflammatory state include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes. In some cases, these symptoms progressed to multi-organ failure. The low percentage of children with asymptomatic cases compared with mild illness and moderate illness could be correlated with the rare cases of MIS-C. One potential explanation for the progression to severe MIS-C disease despite the presence of readily detectable anti-SARS-CoV-2 antibodies could be due to the potential role of antibody-dependent enhancement (ADE). We reason that the incidence of the ADE phenomenon whereby the pathogen-specific antibodies can promote pathology should be considered in vaccine development against SARS-CoV-2.

Intrinsic ADE: The Dark Side of Antibody Dependent Enhancement During Dengue Infection.

Dengue fever is an Aedes mosquito-borne illness caused by any one of the four different dengue virus (DENV) serotypes (1–4) and manifests in the form of symptoms ranging from mild or asymptomatic to severe disease with vascular leakage, leading to shock, and viral hemorrhagic syndrome. Increased risk of severe disease occurs during secondary infection with a virus serotype distinct from that of prior dengue infection. This occurs by antibody dependent enhancement (ADE) of infection, wherein sub-neutralizing antibodies against the virus particles opsonize dengue virus entry via formation of immune complexes that interact with fragment crystallizable gamma receptors (FcγR) on monocytes, dendritic cells, and macrophages. The ADE phenomenon has two components: Extrinsic and Intrinsic ADE. While extrinsic ADE contributes to enhanced virus entry, intrinsic ADE results in heightened virus production by inhibition of type1 interferon and activation of interleukin-10 biosynthesis, thereby favoring a Th2 type immune response. Intrinsic ADE has greater contribution in enhancing Dengue replication as compared to extrinsic ADE. Detailed elucidation of intrinsic ADE during secondary dengue infection can increase our understanding of DENV-pathogenesis and aid in the development of host-targeting antivirals. Here we review literature focusing on intrinsic factors contributing to severe dengue pathology and suggest possible avenues for further research.

Role of antibody-dependent enhancement (ADE) in the virulence of SARS-CoV-2 and its mitigation strategies for the development of vaccines and immunotherapies to counter COVID-19

ABSTRACT Coronavirus disease-2019 (COVID-19) pandemic has become a global threat and death tolls are increasing worldwide. The SARS-CoV-2 though shares similarities with SARS-CoV and MERS-CoV, immunopathology of the novel virus is not understood properly. Previous reports from SARS and MERS-CoV documents that preexisting, non-neutralizing or poorly neutralizing antibodies developed as a result of vaccine or infection enhance subsequent infection, a phenomenon called as antibody-dependent enhancement (ADE). Since immunotherapy has been implicated for COVID-19 treatment and vaccine is under development, due consideration has to be provided on ADE to prevent untoward reactions. ADE mitigation strategies like the development of vaccine or immunotherapeutics targeting receptor binding motif can be designed to minimize ADE of SARS-CoV-2 since full-length protein-based approach can lead to ADE as reported in MERS-CoV. The present mini-review aims to address the phenomenon of ADE of SARS-CoV-2 through the lessons learned from SARS-CoV and MERS-CoV and ways to mitigate them so as to develop better vaccines and immunotherapeutics against SARS-CoV-2.

Antibody Dependent Enhancement Due to Original Antigenic Sin and the Development of SARS.

Human coronavirus (HCoV) is one of the most common causes of respiratory tract infections throughout the world. Two phenomena observed so far in the development of the SARS-CoV-2 pandemic deserve further attention. First, the relative absence of clinical signs of infections in children, second, the early appearance of IgG in certain patients. From the point of view of immune system physiology, such an early rise of specific IgG is expected in secondary immune responses when memory to a cross-reactive antigen is present, usually from an earlier infection with a coronavirus. It is actually typical for the immune system to respond, to what it already knows, a phenomenon that has been observed in many infections with closely related viruses and has been termed “original antigenic sin.” The question then arises whether such cross-reactive antibodies are protective or not against the new virus. The worst scenario would be when such cross-reactive memory antibodies to related coronaviruses would not only be non-protective but even enhance infection and the clinical course. Such a phenomenon of antibody dependent enhancement (ADE) has already been described in several viral infections. Thus, the development of IgG against SARS-CoV-2 in the course of COVID-19 might not be a simple sign of viral clearance and developing protection against the virus. On the contrary, due to cross-reaction to related coronavirus strains from earlier infections, in certain patients IgG might enhance clinical progression due to ADE. The patient's viral history of coronavirus infection might be crucial to the development of the current infection with SARS-CoV-2. Furthermore, it poses a note of caution when treating COVID-19 patients with convalescent sera.

RNA Interference: Antiviral Defense Mechanism and Immune Memory

A review of the mechanisms of the generation of antiviral immunity in bacteria, plants, invertebrates, and vertebrates directly indicates the leading role of innate immunity. Bornovirus infections in mammals have been proven to be inhibited by the RNA interference mechanism. Authors propose a possible role of innate human immunity in combating viral infections, including SARS-Cov2. This hypothesis is based on the notion that antiviral response involves a molecular mechanism of RNA interference stemming from the specific viral patterns incorporated into host cells’ DNA. Innate immunity plays an important role not only at the first encounter with a viral infection, but also fully participates in the formation of specific immune memory. RNA-interference along with interferon system is integral parts of human anti-viral defense system. The joint work of these systems is considered. Caution is warranted in both PCR testing interpretation and in assessing prospective vaccines. False positive result without any clinical presentation of the disease in some people might mean that PCR test was picking up any specific SARS-Cov2 sequences that already had incorporated into asymptomatic person’s cellular DNA due to the possible RNA-interference based anti-viral immunity. Future vaccines aimed at producing specific antibodies can cause the phenomenon of antibody-dependent enhancement (ADE) of the infection. In ADE virus not only infects susceptible cells through appropriate receptor, but is able to highjack virus-specific antibodies to easily traffic virus bodies inside the monocytes/macrophages, granulocytes, platelets, mast and many more host cells through interaction with Fc and/or complement receptors. It is necessary to draw the attention of medical community, especially practitioners to the role of innate immunity, which is especially important in the current COVID-19 pandemic.

Amplificación de la infección dependiente de anticuerpos en la inmunopatogénesis del dengue grave, implicaciones para el desarrollo y uso de las vacunas

Actualmente, la infección por el virus de dengue (DENV) es uno de los problemas más importantes de salud pública en países tropicales y endémicos como Colombia, pues en tanto puede ser producida por cuatro diferentes serotipos virales, durante las infecciones secundarias se presentan frecuentemente cuadros más severos que incluso pueden llevar a desenlaces fatales. El centro de la fisiopatología del dengue grave es el daño producido al endotelio, que se traduce en un aumento en la permeabilidad vascular que se evidencia como fuga plasmática, descontrol en la coagulación y daño de órganos. Aunque hay varias teorías que explican la enfermedad severa, el fenómeno denominado amplificación de la infección dependiente de anticuerpos (antibody dependent enhancement, ADE) es el más conocido. En este, se postula que el virus causante de una infección secundaria es reconocido, pero no neutralizado, por anticuerpos generados en la infección previa e internalizado en las células susceptibles usando receptores Fc-gamma, lo cual aumenta la replicación viral e induce modificaciones en la respuesta inmune celular que contribuyen al desarrollo de dengue grave. En este escrito, se realiza una revisión de los hallazgos sobre los mecanismos involucrados en el fenómeno de ADE y cómo pueden contribuir a la progresión hacia dengue grave, describiendo los conceptos de ADE extrínseco e intrínseco, además de como este fenómeno debe ser tenido en cuenta para el diseño, desarrollo e implementación de una vacuna para dengue, en tanto es capaz de afectar su eficacia y seguridad.

In-depth characterization of congenital Zika syndrome in immunocompetent mice: Antibody-dependent enhancement and an antiviral peptide therapy

BackgroundZika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. MethodsPregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. FindingsZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. InterpretationOur results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection. FundThis work was supported by the Brazilian National Science Council (CNPq, Brazil), Minas Gerais Foundation for Science (FAPEMIG), Funding Authority for Studies and Projects (FINEP), Coordination of Superior Level Staff Improvement (CAPES), National Research Foundation of Singapore and Centre for Precision Biology at Nanyang Technological University.

Protein Disulfide Isomerase Inhibitor Suppresses Viral Replication and Production during Antibody-Dependent Enhancement of Dengue Virus Infection in Human Monocytic Cells.

One of several mechanisms that leads to the development of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) is called antibody-dependent enhancement (ADE). Monocytes can be infected by the ADE phenomenon, which occurs in dengue secondary infection. This study aimed to investigate the proteins involved in ADE of DENV infection in the human monocytic cell line U937. The phosphoproteins were used to perform and analyze for protein expression using mass spectrometry (GeLC-MS/MS). The differential phosphoproteins revealed 1131 altered proteins compared between isotype- and DENV-specific antibody-treated monocytes. The altered proteins revealed 558 upregulated proteins and 573 downregulated proteins. Protein disulfide isomerase (PDI), which is an enzyme that had a high-ranking fold change and that catalyzes the formation, breakage, and rearrangement of disulfide bonds within a protein molecule, was selected for further study. PDI was found to be important for dengue virus infectivity during the ADE model. The effect of PDI inhibition was also shown to be involved in the early stage of life cycle by time-of-drug-addition assay. These results suggest that PDI is important for protein translation and virion assembly of dengue virus during infection in human monocytes, and it may play a significant role as a chaperone to stabilize dengue protein synthesis.

A simple mathematical model to describe antibody-dependent enhancement in heterologous secondary infection in dengue

We develop a mathematical model to describe the role of antibody-dependent enhancement (ADE) in heterologous secondary infections, assuming that antibodies specific to primary dengue virus (DENV) infection are being produced by immunological memory. The model has a virus-free equilibrium (VFE) and a unique virus-presence equilibrium (VPE). VFE is asymptotically stable when VPE is unstable; and unstable, otherwise. Additionally, there is an asymptotic attractor (not a fixed point) due to the fact that the model assumes unbounded increase in memory cells. In the analysis of the model, ADE must be accounted in the initial stage of infection (a window of time of few days), period of time elapsed from the heterologous infection until the immune system mounting an effective response against the secondary infection. We apply the results yielded by model to evaluate ADE phenomonon in heterologous DENV infection. We also associate the possible occurrence of severe dengue with huge viremia mediated by ADE phenomenon.

TBE vaccine and post TBE disease Abs drive antibody dependent enhancement of Zika infection

Abstract Tick-borne encephalitis (TBE) virus belongs to the Flaviviruses, such as Zika, Dengue, Yellow fever viruses (YFV), etc. Antibody dependent enhancement (ADE) was first described between Dengue 1–4 viruses. Recently the ADE phenomenon was extended to include additional Flaviviruses that are phylogenetically close to Dengue: Zika and YFV. All arthropod borne Flaviviruses are antigenically related, however, the existence and extent of ADE between mosquito-borne and tick-borne Flaviviruses were never addressed. In order to explore ADE associated pathogenesis of sera cross-reactivity, we studied human sera from patients with acute TBE (n=30), vaccinated against TBE (n=76) and a control group without antibodies (Abs) to Flaviviruses (n=30). ELISA assays were used to profile the IgG and IgM serological repertoires to TBE and cross-reactivity to Zika antigen (Ag). Viral plaque assays (VPA) were used to test if TBE Abs cause ADE during infection with Zika virus. Flow cytometry (FACS) was used to measure ADE of Zika infection in U937 cells in the presence of the sera with TBE Abs. We found that 25% of TBE vaccinated subjects and 47% of acute TBE subjects had cross-reactive Abs to Zika Ag in ELISA. Furthermore, serum from 37/40 (92%) TBE positive subjects caused ADE in the VPA assay and 58/60 (96%) caused ADE using the FACS assay. The magnitude of Zika ADE correlated with the titer of TBE Abs. Thereby we demonstrate, that previous vaccination or infection with TBE significantly increases the risk of ADE upon a secondary infection with Zika virus. These results highlight that presence of cross-reactive Abs induced by previous exposure even to a very distantly related Flaviviruses by vaccination or infection dictates the risk of ADE upon secondary infection.

Anti-Idiotypic Antibodies Specific to prM Monoantibody Prevent Antibody Dependent Enhancement of Dengue Virus Infection.

Dengue virus (DENV) co-circulates as four serotypes (DENV1-4). Primary infection only leads to self-limited dengue fever. But secondary infection with another serotype carries a higher risk of increased disease severity, causing life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Serotype cross-reactive antibodies facilitate DENV infection in Fc-receptor-bearing cells by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody dependent enhancement (ADE). Most studies suggested that enhancing antibodies were mainly specific to the structural premembrane protein (prM) of DENV. However, there is still no effective drugs or vaccines to prevent ADE. In this study, we firstly confirmed that both DENV-2 infected human sera (anti-DENV-2) and DENV-2 prM monoclonal antibody (prM mAb) could significantly enhance DENV-1 infection in K562 cells. Then we developed anti-idiotypic antibodies (prM-AIDs) specific to prM mAb by immunizing of Balb/c mice. Results showed that these polyclonal antibodies can dramatically reduce ADE phenomenon of DENV-1 infection in K562 cells. To further confirm the anti-ADE effect of prM-AIDs in vivo, interferon-α and γ receptor-deficient mice (AG6) were used as the mouse model for DENV infection. We found that administration of DENV-2 prM mAb indeed caused a higher DENV-1 titer as well as interleukin-10 (IL-10) and alaninea minotransferase (ALT) in mice infected with DENV-1, similar to clinical ADE symptoms. But when we supplemented prM-AIDs to DENV-1 challenged AG6 mice, the viral titer, IL-10 and ALT were obviously decreased to the negative control level. Of note, the number of platelets in peripheral blood of prM-AIDs group were significantly increased at day 3 post infection with DENV-1 compared that of prM-mAb group. These results confirmed that our prM-AIDs could prevent ADE not only in vitro but also in vivo, suggested that anti-idiotypic antibodies might be a new choice to be considered to treat DENV infection.

Relative Contribution of Dengue IgG Antibodies Acquired during Gestation or Breastfeeding in Mediating Dengue Disease Enhancement and Protection in Type I Interferon Receptor-Deficient Mice.

Dengue virus (DENV) causes a spectrum of diseases ranging from self-limiting dengue fever to severe conditions such as haemorrhagic fever and dengue shock syndrome. Antibody-dependent enhancement (ADE) is thought to explain the occurrence of severe dengue whereby pre-existing binding but non-neutralising antibodies enhance DENV infection. The ADE phenomenon is supported by epidemiological findings that infants that born to dengue immune mothers are at greater risk to develop severe dengue upon primary infection. The role of maternally acquired dengue-specific antibodies in disease enhancement was recently recapitulated in a mouse model where mice born to DENV1-immune mothers experienced enhanced disease severity upon DENV2 infection. Here, this study investigates the relative contribution of maternal dengue-specific antibodies acquired during gestation and breastfeeding in dengue disease. Using a surrogate breastfeeding mother experimental approach, we showed that majority of the maternal dengue-specific antibodies were acquired during breastfeeding and conferred an extended enhancement window. On the other hand, in the context of homologous infection, breastfeeding conferred protection. Furthermore, measurement of dengue-specific antibody titres over time in mice born to dengue immune mothers revealed a biphasic pattern of antibody decay as reported in humans. Our work provides evidence of the potential contribution of breast milk-acquired dengue-specific IgG antibodies in enhancement and protection against dengue. Should such contribution be established in humans as well, it may have important implications for the development of guidelines to dengue-immune breastfeeding mothers.

Recent progress in dengue vaccine development.

Dengue virus (DENV) has four distinct serotypes. DENV infection can result in classic dengue fever and life-threatening dengue hemorrhagic fever/dengue shock syndrome. In recent decades, DENV infection has become an important public health concern in epidemic-prone areas. Vaccination is the most effective measure to prevent and control viral infections. However, several challenges impede the development of effective DENV vaccines, such as the lack of suitable animal models and the antibody-dependent enhancement phenomenon. Although no licensed DENV vaccine is available, significant progress has been made. This review summarizes candidate DENV vaccines from recent investigations.