Novel virulence factor Cba induces antibody-dependent enhancement (ADE) of Streptococcus suis Serotype 9 infection in a mouse model.

Streptococcus suis (SS) is a zoonotic pathogen that affects the health of humans and the development of the pig industry. The SS Cba protein is a collagen adhesin, and a few of its homologs are related to the enhancement of bacterial adhesion. We compared the phenotypes of SS9-P10, SS9-P10 cba knockout strains and its complementary strains in vitro and in vivo and found that knocking out the cba gene did not affect the growth characteristics of the strain, but it significantly reduced the ability of SS to form biofilms, adhesion to host cells, phagocytic resistance to macrophages and attenuated virulence in a mouse infection model. These results indicated that Cba was a virulence related factor of SS9. In addition, Mice immunized with the Cba protein had higher mortality and more serious organ lesions after challenge, and the same was observed in passive immunization experiments. This phenomenon is similar to the antibody-dependent enhancement of infection by bacteria such as Acinetobacter baumannii and Streptococcus pneumoniae. To our knowledge, this is the first demonstration of antibody-dependent enhancement of SS, and these observations highlight the complexity of antibody-based therapy for SS infection.

Development of a rapid assay system for detecting antibody-dependent enhancement of dengue virus infection.

Antibody-dependent enhancement (ADE) is one of the pathogenic mechanisms related to disease severity in dengue virus infection. Conventional assays for detecting ADE activity usually require several days. In this study, we established a rapid assay system to evaluate ADE activity in dengue-seropositive samples using single round infectious particles (SRIPs). Human Fc-gamma receptor-bearing cells (K562 and Mylc cells) were infected with SRIP antigen in the presence of human serum samples to measure ADE activity. Two assay protocols were introduced: (i) rapid assay with 5 h of incubation, and (ii) semi-rapid assay with 24 h of incubation. The rapid assay requires a large quantity of SRIP antigen and gives results in half a day. Although the semi-rapid assay requires slightly more than a day, it can be performed using only a small amount of SRIP. Interestingly, the range of the number of Mylc cells required for the semi-rapid assay was wider than that of K562 cells. Significant correlations were observed between the rapid and semi-rapid assays for both cell types. Although it is difficult to judge which protocol best reflects the current immune status in vivo, both assays could rapidly provide valuable information regarding the risk assessment for severe diseases.

Antibody Dependent Enhancement of SARS-CoV-2 Infection in the Era of Rapid Vaccine Development.

Background: Antibody dependent enhancement (ADE) is a unique immunopathological phenomenon in which pre-existing immunity to a viral agent accentuate disease severity upon secondary exposure. Multiple viruses have been shown to demsotrate ADE with no clear understanding of the underlying mechansims. Recently, with the emeregence of Sever acute respiratory syndrome-2 (SARS-CoV2) and the need for rapid vaccine prodcution, ADE have emerged as an important issue that need to be assessed. Objective: The aim of this study was to review ADE, proposed mechanisms and impact of ADE in the era of rapid SARS-CoV2 vaccine production. Methods: Review of existing published literature on ADE and SARS-CoV2 and identify facts that support or otherwise contradict the impact of ADE on SARS-CoV2 vaccination. Results: SARS-CoV2 demonstrate high genetic homology to other members of the Coronaviridae viral family and animal studies and studies on SARS-CoV, another member of the Coronaviridae have been shown to induce ADE. In addition sever SARS-CoV2 infection have been associated with high antibody titer. Yet vaccine efficacy studies and studies on breakthrough infection showed reduced severity in individual with preexisting immunity. Conclusion: Although evidence exist to support ADE in SARS-CoV2, multiple studies do not support its occurrence, indicating the need for more case control studies to understand the role of high antibody titer and disease severity and compare disease severity in patient with preexisting immunity vs naïve individuals.

Comparative Analysis of In Vitro Models to Study Antibody-Dependent Enhancement of Zika Virus Infection.

During the 2015-2016 outbreak of Zika virus (ZIKV) in the Americas, a previously unknown severe complication of ZIKV infection during pregnancy resulting in birth defects was reported. Since the ZIKV outbreak occurred in regions that were highly endemic for the related dengue virus (DENV), it was speculated that antibody-dependent enhancement (ADE) of a ZIKV infection, caused by the presence of cross-reactive DENV antibodies, could contribute to ZIKV disease severity. Emerging evidence indicates that, while in vitro models can show ADE of ZIKV infection, ADE does not seem to contribute to congenital ZIKV disease severity in humans. However, the role of ADE of ZIKV infection during pregnancy and in vertical ZIKV transmission is not well studied. In this study, we hypothesized that pregnancy may affect the ability of myeloid cells to become infected with ZIKV, potentially through ADE. We first systematically assessed which cell lines and primary cells can be used to study ZIKV ADE in vitro, and we compared the difference in outcomes of (ADE) infection experiments between these cells. Subsequently, we tested the hypothesis that pregnancy may affect the ability of myeloid cells to become infected through ADE, by performing ZIKV ADE assays with primary cells isolated from blood of pregnant women from different trimesters and from age-matched non-pregnant women. We found that ADE of ZIKV infection can be induced in myeloid cell lines U937, THP-1, and K562 as well as in monocyte-derived macrophages from healthy donors. There was no difference in permissiveness for ZIKV infection or ADE potential of ZIKV infection in primary cells of pregnant women compared to non-pregnant women. In conclusion, no increased permissiveness for ZIKV infection and ADE of ZIKV infection was found using in vitro models of primary myeloid cells from pregnant women compared to age-matched non-pregnant women.

Antibody-Dependent Enhancement (ADE) and the role of complement system in disease pathogenesis.

Antibody-dependent enhancement (ADE) has been associated with severe disease outcomes in several viral infections, including respiratory infections. In vitro and in vivo studies showed that antibody-response to SARS-CoV and MERS-CoV could exacerbate infection via ADE. Recently in SARS CoV-2, the in vitro studies and structural analysis shows a risk of disease severity via ADE. This phenomenon is partially attributed to non-neutralizing antibodies or antibodies at sub-neutralizing levels. These antibodies result in antigen-antibody complexes' deposition and propagation of a chronic inflammatory process that destroys affected tissues. Further, antigen-antibody complexes may enhance the internalization of the virus into cells through the Fc gamma receptor (FcγR) and lead to further virus replication. Thus, ADE occur via two mechanisms; 1. Antibody mediated replication and 2. Enhanced immune activation. Antibody-mediated effector functions are mainly driven by complement activation, and the first complement in the cascade is complement 1q (C1q) which binds to the virus-antibody complex. Reports say that deficiency in circulating plasma levels of C1q, an independent predictor of mortality in high-risk patients, including diabetes, is associated with severe viral infections. Complement mediated ADE is reported in several viral infections such as dengue, West Nile virus, measles, RSV, Human immunodeficiency virus (HIV), and Ebola virus. This review discusses ADE in viral infections and the in vitro evidence of ADE in coronaviruses. We outline the mechanisms of ADE, emphasizing the role of complements, especially C1q in the outcome of the enhanced disease.

Evolving understanding of antibody-dependent enhancement (ADE) of SARS-CoV-2.

Since immune system and internal environment in vivo are large and complex, the interpretation of the observed immune effect from the perspective of a single immune cell or antibody seems a little feeble. Many studies have shown that specific antibodies against " former" viruses have a reduced ability to neutralize "new" mutant strains. However, there is no comprehensive and clear view of whether there will be Antibody-dependent enhancement (ADE). We review the latest relevant studies, hoping to explain the ADE of SARS-CoV-2 infection sometimes observed in some patients.

The resurgence risk of COVID-19 in China in the presence of immunity waning and ADE: A mathematical modelling study.

The mass vaccination program has been actively promoted since the end of 2020. However, waning immunity, antibody-dependent enhancement (ADE), and increased transmissibility of variants make the herd immunity untenable and the implementation of dynamic zero-COVID policy challenging in China. To explore how long the vaccination program can prevent China at low resurgence risk, and how these factors affect the long-term trajectory of the COVID-19 epidemics, we developed a dynamic transmission model of COVID-19 incorporating vaccination and waning immunity, calibrated using the data of accumulative vaccine doses administered and the COVID-19 epidemic in 2020 in mainland China. The prediction suggests that the vaccination coverage with at least one dose reach 95.87%, and two doses reach 77.92% on 31 August 2021. However, despite the mass vaccination, randomly introducing infected cases in the post-vaccination period causes large outbreaks quickly with waning immunity, particularly for SARS-CoV-2 variants with higher transmissibility. The results showed that with the current vaccination program and 50% of the population wearing masks, mainland China can be protected at low resurgence risk until 8 January 2023. However, ADE and higher transmissibility for variants would significantly shorten the low-risk period by over 1 year. Furthermore, intermittent outbreaks can occur while the peak values of the subsequent outbreaks decrease, indicating that subsequent outbreaks boosted immunity in the population level, further indicating that follow-up vaccination programs can help mitigate or avoid the possible outbreaks. The findings revealed that the integrated effects of multiple factors: waning immunity, ADE, relaxed interventions, and higher variant transmissibility, make controlling COVID-19 challenging. We should prepare for a long struggle with COVID-19, and not entirely rely on the COVID-19 vaccine.

Zika Virus Vaccine: The Current State of Affairs and Challenges Posed by Antibody-Dependent Enhancement Reaction.

Infection caused by the Zika virus (ZIKV) can lead to serious neurological complications such as microcephaly in neonates. At present, no approved ZIKV vaccine is available, but few vaccine candidates are undergoing clinical trial. One major challenge faced is antibody-dependent enhancement (ADE) reaction that may provoke severe outcome in subsequent infection by ZIKV or other flaviviruses. Thus, more efforts should be dedicated to understanding ADE in designing a safe and effective vaccine to minimize the consequence of the potentially fatal infection's complications and to tackle potential ZIKV reemergence. This review discusses different types of ZIKV vaccine candidates that are currently underway in various stages of preclinical and clinical evaluations.

Theoretical Explanation for the Rarity of Antibody-Dependent Enhancement of Infection (ADE) in COVID-19.

Global vaccination against the SARS-CoV-2 virus has proved to be highly effective. However, the possibility of antibody-dependent enhancement of infection (ADE) upon vaccination remains underinvestigated. Here, we aimed to theoretically determine conditions for the occurrence of ADE in COVID-19. We developed a series of mathematical models of antibody response: model Ab-a model of antibody formation; model Cv-a model of infection spread in the body; and a complete model, which combines the two others. The models describe experimental data on SARS-CoV and SARS-CoV-2 infections in humans and cell cultures, including viral load dynamics, seroconversion times and antibody concentration kinetics. The modelling revealed that a significant proportion of macrophages can become infected only if they bind antibodies with high probability. Thus, a high probability of macrophage infection and a sufficient amount of pre-existing antibodies are necessary for the development of ADE in SARS-CoV-2 infection. However, from the point of view of the dynamics of pneumocyte infection, the two cases where the body has a high concentration of preexisting antibodies and a high probability of macrophage infection and where there is a low concentration of antibodies in the body and no macrophage infection are indistinguishable. This conclusion could explain the lack of confirmed ADE cases for COVID-19.

Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells.

Many therapeutic antibodies (Abs) and mRNA vaccines, both targeting SARS-CoV-2 spike protein (S-protein), have been developed and approved in order to combat the ongoing COVID-19 pandemic. In consideration of these developments, a common concern has been the potential for Ab-dependent enhancement (ADE) of infection caused by inoculated or induced Abs. Although the preventive and therapeutic effects of these Abs are obvious, little attention has been paid to the influence of the remaining and dwindling anti-S-protein Abs in vivo. Here, we demonstrate that certain monoclonal Abs (mAbs) approved as therapeutic neutralizing anti-S-protein mAbs for human usage have the potential to cause ADE in a narrow range of Ab concentrations. Although sera collected from mRNA-vaccinated individuals exhibited neutralizing activity, some sera gradually exhibited dominance of ADE activity in a time-dependent manner. None of the sera examined exhibited neutralizing activity against infection with the Omicron strain. Rather, some ADE of Omicron infection was observed in some sera. These results suggest the possible emergence of adverse effects caused by these Abs in addition to the therapeutic or preventive effect.

Does potential antibody-dependent enhancement occur during SARS-CoV-2 infection after natural infection or vaccination? A meta-analysis.

Coronavirus disease 2019 (COVID-19) continues to constitute an international public health emergency. Vaccination is a prospective approach to control this pandemic. However, apprehension about the safety of vaccines is a major obstacle to vaccination. Amongst health professionals, one evident concern is the risk of antibody-dependent enhancement (ADE), which may increase the severity of COVID-19. To explore whether ADE occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and increase confidence in the safety of vaccination, we conducted a meta-analysis to investigate the relationship between post-immune infection and disease severity from a population perspective. Databases, including PubMed, EMBASE, Chinese National Knowledge Infrastructure, SinoMed, Scopus, Science Direct, and Cochrane Library, were searched for articles on SARS-CoV-2 reinfection published until 25 October 2021. The papers were reviewed for methodological quality, and a random effects model was used to analyse the results. Heterogeneity was assessed using the I2 statistic. Publication bias was evaluated using a funnel plot and Egger's test. Eleven studies were included in the final meta-analysis. The pooled results indicated that initial infection and vaccination were protective factors against severe COVID-19 during post-immune infection (OR = 0.55, 95%CI = 0.31-0.98). A subgroup (post-immune infection after natural infection or vaccination) analysis showed similar results. Primary SARS-CoV-2 infection and vaccination provide adequate protection against severe clinical symptoms after post-immune infection. This finding demonstrates that SARS-CoV-2 may not trigger ADE at the population level.

Antibody-Dependent Enhancement: ″Evil″ Antibodies Favorable for Viral Infections.

The pandemics caused by emerging viruses such as severe acute respiratory syndrome coronavirus 2 result in severe disruptions to public health. Vaccines and antibody drugs play essential roles in the control and prevention of emerging infectious diseases. However, in contrast with the neutralizing antibodies (NAbs), sub- or non-NAbs may facilitate the virus to enter the cells and enhance viral infection, which is termed antibody-dependent enhancement (ADE). The ADE of most virus infections is mediated by the Fc receptors (FcRs) expressed on the myeloid cells, while others are developed by other mechanisms, such as complement receptor-mediated ADE. In this review, we comprehensively analyzed the characteristics of the viruses inducing FcRs-mediated ADE and the new molecular mechanisms of ADE involved in the virus entry, immune response, and transcription modulation, which will provide insights into viral pathogenicity and the development of safer vaccines and effective antibody drugs against the emerging viruses inducing ADE.

Functional analysis of differentially expressed long non-coding RNAs in DENV-3 infection and antibody-dependent enhancement of viral infection.

Dengue fever, as a mosquito-borne viral disease widely spread in tropical and subtropical regions, remarkably threatens public health, while the mechanism involved in host-DENV interaction has not been fully elucidated. Firstly, we analyzed the expression levels of long non-coding RNAs (lncRNAs) in THP-1 cells after DENV-3 infection and Antibody- Dependent Enhancement of viral infection (ADE-VI) by RNA-Seq. Secondly, through the RT-qPCR to confirm those differentially expressed (DE) lncRNAs. Then, we also analyzed the competitive endogenous RNA (CeRNA) regulatory network of DE lncRNAs. Finally, we predicted the encode ability of DE lncRNAs. It was found that on the X and Y chromosomes, the expression levels of lncRNAs in THP-1 cells after ADE-VI were significantly different from those in the negative control and the DENV-3 infection groups. There were 71 DE lncRNAs after DENV-3 infection, including 42 up-regulated and 29 down-regulated lncRNAs. A total of 70 DE lncRNAs after ADE-VI were detected, including 38 up-regulated and 32 down- regulated lncRNAs. After ADE-VI and DENV-3 infection, there were 35 DE lncRNAs, including 11 up-regulated and 24 down-regulated lncRNAs. The analysis of the CeRNA regulatory network of DE lncRNAs revealed that, TRIM29, STC2, and IGFBP5 were correlated with the ADE-VI. Additionally, it was found that lncRNAs not only participated in the CeRNA regulatory network, but also maybe encoded small peptides. Our findings provided clues for further investigation into the lncRNAs associated antiviral mechanism of ADE-VI and DENV-3 infection.

Zika Virus Replication in a Mast Cell Model is Augmented by Dengue Virus Antibody-Dependent Enhancement and Features a Selective Immune Mediator Secretory Profile.

Zika virus and dengue virus are evolutionarily related and structurally similar mosquito-borne Flaviviruses. These congruencies can lead to cross-reactive antibody binding, whereby antibodies generated from previous dengue virus immunity can augment Zika virus replication in vitro. This phenomenon, termed antibody-dependent enhancement, may participate in the clinical manifestations detected in areas with Flavivirus cocirculations where Zika virus is endemic; however, a causal relationship has yet to be determined. The KU812 mast cell/basophil line was integral in identifying the first Flavivirus infection in mast cells and serves as an effective in vitro model to study dengue virus antibody-dependent enhancement. Mast cells, sentinel white blood cells intrinsic in coordinating early immune defenses, are characteristically situated in the intradermal space and are therefore among the first immune cells interfaced with blood-feeding mosquitoes. Here, we tested whether KU812 cells were permissive to Zika virus, how previous dengue virus immunity might augment Zika virus infection, and whether either condition induces an immunological response. We report an antibody-dependent enhancement effect of Zika virus infection in KU812 cells across multiple time points (48, 72, and 96 hours postinfection [hpi]) and a range of multiplicities of infection (4.0 × 10-3 to 4) using various concentrations of cross-reactive dengue virus monoclonal antibodies (D11C and 1.6D). This antigen-specific antibody-mediated infection was selectively coupled to chemokine ligand 5 (CCL5), interleukin 1ß (IL-1ß), and C-X-C motif chemokine ligand 10 (CXCL10) secretion and a reduction in granzyme B (GrB) release. Therefore, mast cells and/or basophils may significantly augment Zika virus infection in the context of preexisting dengue virus immunity. IMPORTANCE Antibodies generated against one dengue serotype can enhance infection of another by a phenomenon called antibody-dependent enhancement (ADE). Additionally, antigenic similarities between Zika and dengue viruses can promote Zika virus infection by way of ADE in vitro using these very same anti-dengue antibodies. We used the KU812 cell line to demonstrate for the first time that anti-dengue antibodies enhanced infectious Zika virus replication in a mast cell model and specifically increased CCL5, CXCL10, and IL-1ß, while also impairing granzyme B secretion. Furthermore, enhanced Zika virus infection and selective mediator release were mechanistically dependent on fragment crystallizable gamma receptor II (FcγRII). These findings establish a new model for Zika virus research and a new subcategory of immune cells previously unexplored in the context of Zika virus enhancement while being some of the very first immune cells likely to meet a blood-feeding infected mosquito.

Dengue Infection - Recent Advances in Disease Pathogenesis in the Era of COVID-19.

The dynamics of host-virus interactions, and impairment of the host's immune surveillance by dengue virus (DENV) serotypes largely remain ambiguous. Several experimental and preclinical studies have demonstrated how the virus brings about severe disease by activating immune cells and other key elements of the inflammatory cascade. Plasmablasts are activated during primary and secondary infections, and play a determinative role in severe dengue. The cross-reactivity of DENV immune responses with other flaviviruses can have implications both for cross-protection and severity of disease. The consequences of a cross-reactivity between DENV and anti-SARS-CoV-2 responses are highly relevant in endemic areas. Here, we review the latest progress in the understanding of dengue immunopathogenesis and provide suggestions to the development of target strategies against dengue.

Mice immunized with trimethyl chitosan nanoparticles containing DENV-2 envelope domain III elicit neutralizing antibodies with undetectable antibody-dependent enhancement activity.

Dengue is a disease that poses a significant global public health concern. Although a tetravalent live-attenuated dengue vaccine has been licensed, its efficacy is still debated due to evidence of vaccine breakthrough infection. To avoid this issue, dengue vaccines should stimulate a high degree of serotype-specific response. Thus, envelope domain III (EDIII), which contains serotype-specific neutralizing epitopes, is an attractive target for dengue vaccine development. In this study, we investigated how EDIII encapsidated in N, N, N-trimethyl chitosan chloride nanoparticles (TMC NPs) stimulates a serotype-specific response and whether this response exerts a potential in vitro breakthrough infection. The immune response to DENV-2 elicited by EDIII TMC NP-immunized mice was monitored. We demonstrated that immunization with EDIII TMC NPs resulted in a high level of anti-EDIII antibody production. These antibodies included IgG, IgG1, and IgG2a subtypes. Importantly, antibodies from the immunized mice exerted efficient neutralizing activity with undetectable antibody dependent enhancement (ADE) activity. We also found that EDIII TMC NPs activated functional EDIII-specific CD4+ and CD8+ T cell responses. In conclusion, EDIII TMC NPs stimulated humoral immunity with a strong neutralizing antibody response, as well as a cellular immune response against DENV-2.

Zika virus infects human osteoclasts and blocks differentiation and bone resorption.

Bone-related complications are commonly reported following arbovirus infection. These arboviruses are known to disturb bone-remodeling and induce inflammatory bone loss via increased activity of bone resorbing osteoclasts (OCs). We previously showed that Zika virus (ZIKV) could disturb the function of bone forming osteoblasts, but the susceptibility of OCs to ZIKV infection is not known. Here, we investigated the effect of ZIKV infection on osteoclastogenesis and report that infection of pre- and early OCs with ZIKV significantly reduced the osteoclast formation and bone resorption. Interestingly, infection of pre-OCs with a low dose ZIKV infection in the presence of flavivirus cross-reacting antibodies recapitulated the phenotype observed with a high viral dose, suggesting a role for antibody-dependent enhancement in ZIKV-associated bone pathology. In conclusion, we have characterized a primary in vitro model to study the role of osteoclastogenesis in ZIKV pathogenesis, which will help to identify possible new targets for developing therapeutic and preventive measures.

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.

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.

Self-Assembling Nanovaccine Confers Complete Protection Against Zika Virus Without Causing Antibody-Dependent Enhancement.

The Zika virus (ZIKV) epidemic poses a substantial threat to the public, and the development of safe and effective vaccines is a demanding challenge. In this study, we constructed a kind of self-assembling nanovaccine which confers complete protection against ZIKV infection. The ZIKV envelop protein domain III (zEDIII) was presented on recombinant human heavy chain ferritin (rHF) to form the zEDIII-rHF nanoparticle. Immunization of mice with zEDIII-rHF nanoparticle in the absence of an adjuvant induced robust humoral and cellular immune responses. zEDIII-rHF vaccination conferred complete protection against lethal infection with ZIKV and eliminated pathological symptoms in the brain. Importantly, the zEDIII-rHF nanovaccine induced immune response did not cross-react with dengue virus-2, overcoming the antibody-dependent enhancement (ADE) problem that is a safety concern for ZIKV vaccine development. Our constructed zEDIII-rHF nanovaccine, with superior protective performance and avoidance of ADE, provides an effective and safe vaccine candidate against ZIKV.