RESUMEN

Advances in antibody technologies have resulted in the development of potent antibody-based therapeutics with proven clinical efficacy against infectious diseases. Several monoclonal antibodies (mAbs), mainly against viruses such as SARS-CoV-2, HIV-1, Ebola virus, influenza virus, and hepatitis B virus, are currently undergoing clinical testing or are already in use. Although these mAbs exhibit potent neutralizing activity that effectively blocks host cell infection, their antiviral activity results not only from Fab-mediated virus neutralization, but also from the protective effector functions mediated through the interaction of their Fc domains with Fcγ receptors (FcγRs) on effector leukocytes. Fc-FcγR interactions confer pleiotropic protective activities, including the clearance of opsonized virions and infected cells, as well as the induction of antiviral T-cell responses. However, excessive or inappropriate activation of specific FcγR pathways can lead to disease enhancement and exacerbated pathology, as seen in the context of dengue virus infections. A comprehensive understanding of the diversity of Fc effector functions during infection has guided the development of engineered antiviral antibodies optimized for maximal effector activity, as well as the design of targeted therapeutic approaches to prevent antibody-dependent enhancement of disease.

RESUMEN

The four serotypes of the dengue virus (DENV) cause a range of diseases ranging from mild fever to severe conditions. Understanding the immunological interactions among the four serotypes is crucial in comprehending the dynamics of serotype shifting during outbreaks in areas where all four serotypes co-circulate. Hence, we evaluated the neutralizing antibody and antibody-dependent enhancement responses against the four DENV serotypes using acute-phase plasma samples collected from 48 laboratory-confirmed dengue patients during a dengue outbreak in Bali, Indonesia in 2022. Employing single-round infectious particles to exclusively investigate immunogenicity to the structural surface proteins of DENV, which are the targets of antibodies, we found that individuals with a probable prior history of DENV-1 infection exhibited increased susceptibility to secondary DENV-3 infection, attributed to cross-reactive antibodies with limited neutralizing activity against DENV-3 (geometric mean 50 % neutralization titer (GMNT50) = 47.6 ± 11.5). This susceptibility was evident in vitro, with a mean fold enhancement of 28.4 ± 33.9. Neutralization titers against DENV-3 were significantly lower compared to other serotypes (DENV-1 GMNT50 = 678.1 ± 9.0; DENV-2 GMNT50 = 210.5 ± 8.7; DENV-4 GMNT50 = 95.14 ± 7.0). We demonstrate that prior immunity to one serotype provides limited cross-protection against the other serotypes, influencing the dominant serotype in subsequent outbreaks. These findings underscore the complexity of dengue immunity and its implications for vaccine design and transmission dynamics in hyperendemic regions.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , Reacciones Cruzadas , Virus del Dengue , Dengue , Brotes de Enfermedades , Serogrupo , Humanos , Indonesia/epidemiología , Dengue/epidemiología , Dengue/inmunología , Dengue/virología , Virus del Dengue/inmunología , Virus del Dengue/clasificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Masculino , Femenino , Adulto , Acrecentamiento Dependiente de Anticuerpo/inmunología , Adulto Joven , Persona de Mediana Edad , Adolescente , Pruebas de Neutralización , Enfermedades Endémicas

RESUMEN

Antibody dependant enhancement refers that viral infectivity was unexpectedly enhanced at low antibody concentration compared to when antibodies were absent, such as Dengue, Zika and influenza virus. To mathematically describe switch from enhancement to neutralisation with increase of antibody concentration, one hyperbolic tangent variant is used as switching function in existed models. However, switching function with hyperbolic tangent contains four parameters, and does not always increase with antibody concentration. To address this problem, we proposed a monotonically increasing Logistical function variant as switching function, which only contains position parameter and magnitude parameter. Analysing influenza viral titre estimated from 21 focus reduction assay (FRA) datasets from neutralisation group (viral titre lower than negative control on all serial dilutions) and 20 FRA dataset from enhancement group (viral titre higher than negative control on high serial dilution), switching function with Logistic function performs better than existed model independent of both groups and exhibited different behaviour/character; specifically, magnitude parameter estimated from enhancement group is lower, but position parameter estimated from enhancement group is higher. A lower magnitude parameter refers that enhancement group more rapidly switches from enhancement to neutralisation with increase of antibody concentration, and a higher position parameter indicates that enhancement group provides a larger antibody concentration interval corresponding to enhancement. Integrating estimated neutralisation kinetics with viral replication, we demonstrated that antibody-induced bistable influenza kinetics exist independent of both groups. However, comparing with neutralisation group, enhancement group provides higher threshold value of antibody concentration corresponding to influenza infectivity. This explains the observed phenomenon that antibody dependent enhancement enhances susceptibility, severity, and mortality to influenza infection. On population level, antibody dependant enhancement can promote H1N1 and H3N2 influenza virus cooperate to sustain long-term circulation on human populations according to antigenic seniority theory.

RESUMEN

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a highly contagious disease that can kill up to 100% of domestic pigs and wild boars. It has been shown that the pigs inoculated with some ASF vaccine candidates display more severe clinical signs and die earlier than do pigs not immunized. We hypothesize that antibody-dependent enhancement (ADE) of ASFV infection may be caused by the presence of some unidentified antibodies. In this study, we found that the ASFV-encoded structural protein A137R (pA137R) can be recognized by the anti-ASFV positive sera, indicating that the anti-pA137R antibodies are induced in the ASFV-infected pigs. Interestingly, our results demonstrated that the anti-pA137R antibodies produced in rabbits or pigs enhanced viral replication of different ASFV strains in primary porcine alveolar macrophages (PAMs), the target cells of ASFV. Mechanistic investigations revealed that anti-pA137R antibodies were able to promote the attachment of ASFV to PAMs and two types of Fc gamma receptors (FcγRs), FcγRII and FcγRIII, mediated the ADE of ASFV infection. Taken together, anti-pA137R antibodies are able to drive ASFV ADE in PAMs. These findings shed new light on the roles of anti-ASFV antibodies and have implications for the pathophysiology of the disease and the development of ASF vaccines.

Asunto(s)

Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Anticuerpos Antivirales , Acrecentamiento Dependiente de Anticuerpo , Macrófagos Alveolares , Receptores de IgG , Animales , Virus de la Fiebre Porcina Africana/inmunología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/virología , Porcinos , Fiebre Porcina Africana/virología , Fiebre Porcina Africana/inmunología , Anticuerpos Antivirales/inmunología , Receptores de IgG/inmunología , Replicación Viral , Conejos

RESUMEN

Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is one of the mechanisms contributing to increased severity during heterotypic, secondary infection. The complement protein C1q has been shown to reduce the magnitude of ADE in vitro. Therefore, we investigated the mechanisms of C1q modulation of ADE, focusing on processes of viral entry. Using a model of ADE of DENV-1 infection in human myeloid cell lines in the presence of monoclonal antibodies, 4G2 and 2H2, we found that C1q produced nearly a 40-fold reduction of ADE of DENV-1 in K562 cells, but had no effect in U937 cells. In K562 cells, C1q reduced adsorption of DENV-1/4G2 and exerted a dual inhibitory effect on adsorption and internalization of DENV-1/2H2. Distinct endocytic pathways in the presence of antibody corresponded to conditions where C1q produced a differential action. Also, C1q did not affect the intrinsic cell response mediated by FcγR in human myeloid cells. The modulation of ADE of DENV-1 by C1q is dependent on the FcγR expressed on immune cells and the specificity of the antibody comprising the immune complex. Understanding protective and pathogenic mechanisms in the humoral response to DENV infections is crucial for the successful design of antivirals and vaccines.

RESUMEN

Dengue virus (DENV), transmitted by mosquitoes, is classified into four serotypes (DENV1-4) and typically causes mild, self-limiting symptoms upon initial infection. However, secondary infection can lead to severe symptoms due to antibody-dependent enhancement (ADE). To address this, anti-DENV antibodies are being developed with the goal of neutralizing infection without ADE activity. Previous attempts using a 54_hG1 antibody from CHO-K1 mammalian cells resulted in ADE induction, increasing viral infection. This study aimed to express the D54 monoclonal antibody in Nicotiana benthamiana. The plant-produced antibody had a similar neutralizing profile to the previous 54_hG1 antibody. Notably, the ADE activities of the plant-derived antibody were successfully eliminated, with no sign of viral induction. These findings suggest that N. benthamiana could be a source of therapeutic DENV antibodies. The method offers several advantages, including lower ADE, cost-effectiveness, simple facility requirements, scalability, and potential industrial-scale production in GMP facilities.

RESUMEN

Understanding the antibody response to SARS-CoV-2, the virus responsible for COVID-19, is crucial to comprehending disease progression and the significance of vaccine and therapeutic development. The emergence of highly contagious variants poses a significant challenge to humoral immunity, underscoring the necessity of grasping the intricacies of specific antibodies. This review emphasizes the pivotal role of antibodies in shaping immune responses and their implications for diagnosing, preventing, and treating SARS-CoV-2 infection. It delves into the kinetics and characteristics of the antibody response to SARS-CoV-2 and explores current antibody-based diagnostics, discussing their strengths, clinical utility, and limitations. Furthermore, we underscore the therapeutic potential of SARS-CoV-2-specific antibodies, discussing various antibody-based therapies such as monoclonal antibodies, polyclonal antibodies, anti-cytokines, convalescent plasma, and hyperimmunoglobulin-based therapies. Moreover, we offer insights into antibody responses to SARS-CoV-2 vaccines, emphasizing the significance of neutralizing antibodies in order to confer immunity to SARS-CoV-2, along with emerging variants of concern (VOCs) and circulating Omicron subvariants. We also highlight challenges in the field, such as the risks of antibody-dependent enhancement (ADE) for SARS-CoV-2 antibodies, and shed light on the challenges associated with the original antigenic sin (OAS) effect and long COVID. Overall, this review intends to provide valuable insights, which are crucial to advancing sensitive diagnostic tools, identifying efficient antibody-based therapeutics, and developing effective vaccines to combat the evolving threat of SARS-CoV-2 variants on a global scale.

RESUMEN

Human immunoglobulin preparations contain a diverse range of polyclonal antibodies that reflect past immune responses against pathogens encountered by the blood donor population. In this study, we examined a panel of intravenous immunoglobulins (IGIVs) manufactured over the past two decades (1998-2020) for their capacity to neutralize or enhance Zika virus (ZIKV) infection in vitro. These IGIVs were selected specifically based on their production dates in relation to the occurrences of two flavivirus outbreaks in the U.S.: the West Nile virus (WNV) outbreak in 1999 and the ZIKV outbreak in 2015. As demonstrated by enzyme-linked immunosorbent assay (ELISA) experiments, IGIVs made before the ZIKV outbreak already harbored antibodies that bind to various peptides across the envelope protein of ZIKV because of the WNV outbreak. Using phage display, the most dominant binding site was mapped precisely to the P2 peptide between residues 211 and 230 within domain II, where BF1176-56, an anti-ZIKV monoclonal antibody, also binds. When tested in permissive Vero E6 cells for ZIKV neutralization, the IGIVs, even after undergoing rigorous enrichment for P2 binding specificity, failed, as did BF1176-56. Meanwhile, BF1176-56 enhanced ZIKV infection in both FcγRII-expressing K562 cells and human peripheral blood mononuclear cells. However, for enhancement by the IGIVs to be detected in these cells, a substantial increase in their P2 binding specificity was required, thus linking the P2 site with ZIKV enhancement in vitro. Our findings warrant further study of the significance of elevated levels of anti-WNV antibodies in IGIVs, considering that various mechanisms operating in vivo may modulate ZIKV infection outcomes.IMPORTANCEWe investigated the capacity of intravenous immunoglobulins manufactured previously over two decades (1998-2020) to neutralize or enhance Zika virus infection in vitro. West Nile virus antibodies in IGIVs could not neutralize Zika virus initially; however, once the IGIVs were concentrated further, they enhanced its infection. These findings lay the groundwork for exploring how preexisting WNV antibodies in IGIVs could impact Zika infection, both in vitro and in vivo. Our observations are historically significant, since we tested a panel of IGIV lots that were carefully selected based on their production dates which covered two major flavivirus outbreaks in the U.S.: the WNV outbreak in 1999 and the ZIKV outbreak in 2015. These findings will facilitate our understanding of the interplay among closely related viral pathogens, particularly from a historical perspective regarding large blood donor populations. They should remain relevant for future outbreaks of emerging flaviviruses that may potentially affect vulnerable populations.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , Fiebre del Nilo Occidental , Virus del Nilo Occidental , Infección por el Virus Zika , Virus Zika , Humanos , Virus Zika/inmunología , Virus del Nilo Occidental/inmunología , Anticuerpos Antivirales/inmunología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/virología , Animales , Chlorocebus aethiops , Células Vero , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/virología , Anticuerpos Neutralizantes/inmunología , Sitios de Unión , Inmunoglobulinas Intravenosas/inmunología , Proteínas del Envoltorio Viral/inmunología , Ensayo de Inmunoadsorción Enzimática

Asunto(s)

Fiebre Chikungunya , Vacunas contra el Dengue , Dengue , Medicina del Viajero , Humanos , Dengue/prevención & control , Fiebre Chikungunya/prevención & control , Medicina del Viajero/métodos , Vacunas contra el Dengue/administración & dosificación , Virus Chikungunya/inmunología , Viaje , Virus del Dengue/inmunología , Vacunas Virales/administración & dosificación

RESUMEN

This study evaluated the potential for antibody-dependent enhancement (ADE) in serum samples from patients exposed to Middle East respiratory syndrome coronavirus (MERS-CoV). Furthermore, we evaluated the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on ADE in individuals with a MERS infection history. We performed ADE assay in sera from MERS recovered and SARS-CoV-2-vaccinated individuals using BHK cells expressing FcgRIIa, SARS-CoV-2, and MERS-CoV pseudoviruses (PVs). Further, we analyzed the association of ADE to serum IgG levels and neutralization. Out of 16 MERS patients, nine demonstrated ADE against SARS-CoV-2 PV, however, none of the samples demonstrated ADE against MERS-CoV PV. Furthermore, out of the seven patients exposed to SARS-CoV-2 vaccination after MERS-CoV infection, only one patient (acutely infected with MERS-CoV) showed ADE for SARS-CoV-2 PV. Further analysis indicated that IgG1, IgG2, and IgG3 against SARS-CoV-2 S1 and RBD subunits, IgG1 and IgG2 against the MERS-CoV S1 subunit, and serum neutralizing activity were low in ADE-positive samples. In summary, samples from MERS-CoV-infected patients exhibited ADE against SARS-CoV-2 and was significantly associated with low levels of neutralizing antibodies. Subsequent exposure to SARS-CoV-2 vaccination resulted in diminished ADE activity while the PV neutralization assay demonstrated a broadly reactive antibody response in some patient samples.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , Acrecentamiento Dependiente de Anticuerpo , COVID-19 , Inmunoglobulina G , Coronavirus del Síndrome Respiratorio de Oriente Medio , SARS-CoV-2 , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Anticuerpos Antivirales/sangre , SARS-CoV-2/inmunología , Inmunoglobulina G/sangre , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Persona de Mediana Edad , Masculino , Femenino , Pruebas de Neutralización , Adulto , Vacunas contra la COVID-19/inmunología , Antígenos Virales/inmunología , Animales , Anciano , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunación

RESUMEN

Before the emergence of SARS-CoV-1, MERS-CoV, and most recently, SARS-CoV-2, four other coronaviruses (the alpha coronaviruses NL63 and 229E and the beta coronaviruses OC43 and HKU1) had already been circulating in the human population. These circulating coronaviruses all cause mild respiratory illness during the winter seasons, and most people are already infected in early life. Could antibodies and/or T cells, especially against the beta coronaviruses, have offered some form of protection against (severe) COVID-19 caused by infection with SARS-CoV-2? Related is the question of whether survivors of SARS-CoV-1 or MERS-CoV would be relatively protected against SARS-CoV-2. More importantly, would humoral and cellular immunological memory generated during the SARS-CoV-2 pandemic, either by infection or vaccination, offer protection against future coronaviruses? Or rather than protection, could antibody-dependent enhancement have taken place, a mechanism by which circulating corona antibodies enhance the severity of COVID-19? Another related phenomenon, the original antigenic sin, would also predict that the effectiveness of the immune response to future coronaviruses would be impaired because of the reactivation of memory against irrelevant epitopes. The currently available evidence indicates that latter scenarios are highly unlikely and that especially cytotoxic memory T cells directed against conserved epitopes of human coronaviruses could at least offer partial protection against future coronaviruses.

RESUMEN

Infectious diseases, such as Dengue fever, pose a significant public health threat. Developing a reliable mathematical model plays a crucial role in quantitatively elucidating the kinetic characteristics of antibody-virus interactions. By integrating previous models and incorporating the antibody dynamic theory, we have constructed a novel and robust model that can accurately simulate the dynamics of antibodies and viruses based on a comprehensive understanding of immunology principles. It explicitly formulates the viral clearance effect of antibodies, along with the positive feedback stimulation of virus-antibody complexes on antibody regeneration. In addition to providing quantitative insights into the dynamics of antibodies and viruses, the model exhibits a high degree of accuracy in capturing the kinetics of viruses and antibodies in Dengue fever patients. This model offers a valuable solution to modeling the differences between primary and secondary Dengue infections concerning IgM/IgG antibodies. Furthermore, it demonstrates that a faster removal rate of antibody-virus complexes might lead to a higher peak viral loading and worse clinical symptom. Moreover, it provides a reasonable explanation for the antibody-dependent enhancement of heterogeneous Dengue infections. Ultimately, this model serves as a foundation for constructing an optimal mathematical model to combat various infectious diseases in the future.

Asunto(s)

Enfermedades Transmisibles , Virus del Dengue , Dengue , Virus , Humanos , Anticuerpos Antivirales , Interacciones Microbiota-Huesped , Modelos Teóricos

RESUMEN

Serological studies of COVID-19 convalescent patients have identified polyclonal lineage-specific and cross-reactive antibodies (Abs), with varying effector functions against virus variants. Individual specificities of anti-SARS-CoV-2 Abs and their impact on infectivity by other variants have been little investigated to date. Here, we dissected at a monoclonal level neutralizing and enhancing Abs elicited by early variants and how they affect infectivity of emerging variants. B cells from 13 convalescent patients originally infected by D614G or Alpha variants were immortalized to isolate 445 naturally-produced anti-SARS-CoV-2 Abs. Monoclonal antibodies (mAbs) were tested for their abilities to impact the cytopathic effect of D614G, Delta, and Omicron (BA.1) variants. Ninety-eight exhibited robust neutralization against at least one of the three variant types, while 309 showed minimal or no impact on infectivity. Thirty-eight mAbs enhanced infectivity of SARS-CoV-2. Infection with D614G/Alpha variants generated variant-specific (65 neutralizing Abs, 35 enhancing Abs) and cross-reactive (18 neutralizing Abs, 3 enhancing Abs) mAbs. Interestingly, among the neutralizing mAbs with cross-reactivity restricted to two of the three variants tested, none demonstrated specific neutralization of the Delta and Omicron variants. In contrast, cross-reactive mAbs enhancing infectivity (n = 3) were found exclusively specific to Delta and Omicron variants. Notably, two mAbs that amplified in vitro the cytopathic effect of the Delta variant also exhibited neutralization against Omicron. These findings shed light on functional diversity of cross-reactive Abs generated during SARS-CoV-2 infection and illustrate how the balance between neutralizing and enhancing Abs facilitate variant emergence.

Asunto(s)

COVID-19 , SARS-CoV-2 , Humanos , Anticuerpos Bloqueadores , Anticuerpos Neutralizantes , Anticuerpos Monoclonales , Anticuerpos Antivirales , Glicoproteína de la Espiga del Coronavirus

RESUMEN

The infection with coxsackievirus B4 (CVB4) can be enhanced in vitro by antibodies directed against the viral capsid protein VP4. In peripheral blood mononuclear cells, antibody-dependent enhancement (ADE) of CVB4 infection leads to the production of interferon alpha (IFN-α). To investigate ADE of CVB4-induced production of IFN-α, an agent-based model was constructed with enhancing and neutralizing antibodies. The model recapitulates viral neutralization and ADE in silico. The enhancing and neutralizing activities of serum samples were evaluated in vitro to confront the model predictions with experimental results. Increasing the incubation time of CVB4 with serum samples improves virus neutralization in silico as well as in vitro. It also results in ADE at lower antibody numbers in silico, which is confirmed in vitro with IFN-α production at lower serum concentrations. Furthermore, incubation of CVB4 with serum at a low temperature does not induce IFN-α production in vitro. Thus, taken together our results suggest that enhancing antibodies bind cryptic epitopes, more accessible with longer incubation time and at higher temperature due to changes in capsid conformation, consistent with previous results indicating that enhancing antibodies are anti-VP4 antibodies.

Asunto(s)

Enterovirus Humano B , Leucocitos Mononucleares , Humanos , Acrecentamiento Dependiente de Anticuerpo , Anticuerpos Bloqueadores , Anticuerpos Antivirales , Interferón-alfa

RESUMEN

OBJECTIVE: The invasion of dengue virus (DENV)-2 Cosmopolitan genotype into the Philippines, where the Asian II genotype previously circulated challenges the principle of dengue serotype-specific immunity. Assessment of antibodies in this population may provide a mechanistic basis for how new genotypes emerge in dengue-endemic areas. METHODS: We evaluated the neutralizing antibody (nAb) and antibody-dependent enhancement (ADE) responses against the two genotypes using archived serum samples collected from 333 patients with confirmed dengue in Metro Manila, Philippines, before, during, and after the introduction of the Cosmopolitan genotype. We quantified nAb titers in baby hamster kidney (BHK-21) cells with or without the Fcγ receptor IIA (FcγRIIA) to detect the capacity of virus-antibody complexes to neutralize or enhance DENV. RESULTS: The nAb potency of the archived serum samples against the two genotypes was greatly affected by the presence of FcγRIIA. We found significant differences in nAb titers between the two genotypes in BHK-21 cells with FcγRIIA (P <0.0001). The archived serum samples were incapable of fully neutralizing the Cosmopolitan genotype, but instead strongly promoted its ADE compared to the Asian II genotype (P <0.0001). CONCLUSION: These results reinforce the role of pre-existing immunity in driving genotype shifts. Our finding that specific genotypes exhibit differing susceptibilities to ADE by cross-reactive antibodies may have implications for dengue vaccine development.

Asunto(s)

Virus del Dengue , Dengue , Animales , Cricetinae , Humanos , Anticuerpos Antivirales , Serogrupo , Filipinas , Estudios Retrospectivos , Anticuerpos Neutralizantes , Genotipo

RESUMEN

Objective:To establish an antibody expression system to reduce the antibody-dependent enhancement (ADE) effect of target antibody.Methods:Site-directed mutagenesis was used to mutate the 234 and 235 sites of the Fc region of the mammalian cell antibody expression vector-L234A and L235A to establish the antibody expression vector pFRT-IgG1κ-FcM. An antibody Wt-WNV with significant ADE effect obtained in previous work was selected and expressed by the pFRT-IgG1κ-FcM system to obtain mutant antibody FcM-WNV. The binding ability of FcM-WNV to target antigen West Nile virus envelope protein-DⅢ (WNV E-DⅢ) was detected by ELISA, and the its binding ability to human high-affinity IgG Fc receptor hFcγRⅠ (hCD64 ) was analyzed by flow cytometry. The neutralizing activity of FcM-WNV in vitro was detected by pseudovirus infection of host cells (BHK21 and K562). Results:The expression levels of FcM-WNV and Wt-WNV were comparable, and FcM-WNV could recognize and bind to WNVE-DIII in a concentration-dependent manner. Compared with Wt-WNV, the binding ability of FcM-WNV to hCD64 was significantly weakened, showing a significant decrease in fluorescence intensity. Consistent with the previous experimental results, Wt-WNV at a concentration of 5 μg/ml significantly enhanced the infection of K562 by WNV pseudovirus, while FcM-WNV at a concentration of 5 μg/ml could effectively block pseudovirus infection in both K562 and BHK21 cells.Conclusions:The established antibody expression system can effectively reduce the ADE effect of the target antibody.

RESUMEN

As part of the non-clinical safety package characterizing bamlanivimab (SARS-CoV-2 neutralizing monoclonal antibody), the risk profile for antibody-dependent enhancement of infection (ADE) was evaluated in vitro and in an African green monkey (AGM) model of COVID-19. In vitro ADE assays in primary human macrophage, Raji, or THP-1 cells were used to evaluate enhancement of viral infection. Bamlanivimab binding to C1q, FcR, and cell-based effector activity was also assessed. In AGMs, the impact of bamlanivimab pretreatment on viral loads and clinical and histological pathology was assessed to evaluate enhanced SARS-CoV-2 replication or pathology. Bamlanivimab did not increase viral replication in vitro, despite a demonstrated effector function. In vivo, no significant differences were found among the AGM groups for weight, temperature, or food intake. Treatment with bamlanivimab reduced viral loads in nasal and oral swabs and BAL fluid relative to control groups. Viral antigen was not detected in lung tissue from animals treated with the highest dose of bamlanivimab. Bamlanivimab did not induce ADE of SARS-CoV-2 infection in vitro or in an AGM model of infection at any dose evaluated. The findings suggest that high-affinity monoclonal antibodies pose a low risk of mediating ADE in patients and support their safety profile as a treatment of COVID-19 disease.

RESUMEN

Dengue is an infectious disease caused by dengue virus (DENV) and is a serious global burden. Antibody-dependent enhancement and the ability of DENV to infect immune cells, along with other factors, lead to fatal Dengue Haemorrhagic Fever and Dengue Shock Syndrome. This necessitates the development of a robust and efficient vaccine but vaccine development faces a number of hurdles. In this review, we look at the epidemiology, genome structure and cellular targets of DENV and elaborate upon the immune responses generated by human immune system against DENV infection. The review further sheds light on various challenges in development of a potent vaccine against DENV which is followed by presenting a current account of different vaccines which are being developed or have been licensed.

Asunto(s)

Vacunas contra el Dengue , Virus del Dengue , Dengue , Humanos , Dengue/epidemiología , Dengue/prevención & control , Virus del Dengue/genética , Vacunas contra el Dengue/genética , Acrecentamiento Dependiente de Anticuerpo , Vacunación , Anticuerpos Antivirales

RESUMEN

Flaviviruses are a genus within the Flaviviridae family of positive-strand RNA viruses and are transmitted principally through mosquito and tick vectors. These viruses are responsible for hundreds of millions of human infections worldwide per year that result in a range of illnesses from self-limiting febrile syndromes to severe neurotropic and viscerotropic diseases and, in some cases, death. A vaccine against the prototype flavivirus, yellow fever virus, has been deployed for 85 years and is highly effective. While vaccines against some medically important flaviviruses are available, others have proven challenging to develop. The emergence and spread of flaviviruses, including dengue virus and Zika virus, demonstrate their pandemic potential. This review highlights the gaps in knowledge that need to be addressed to allow for the rapid development of vaccines against emerging flaviviruses in the future.

Asunto(s)

Infecciones por Flavivirus , Flavivirus , Vacunas , Infección por el Virus Zika , Virus Zika , Animales , Humanos , Infecciones por Flavivirus/prevención & control , Mosquitos Vectores , Infección por el Virus Zika/prevención & control

RESUMEN

BACKGROUND: Dengue fever (DF), caused by the dengue virus (DENV), is the most common arboviral disease in travellers worldwide. It is hypothesized that compared with primary DF, secondary DF may result in antibody-dependent enhancement of the immune response, resulting in more severe disease. We aimed to compare clinical and laboratory parameters in travellers with primary and secondary DF to determine whether secondary DF is associated with markers of severe disease. METHODS: We conducted a retrospective cohort study, which included all patients diagnosed with DF at the Central Virology Laboratory of the Israeli Ministry of Health during 2008-19. Clinical, laboratory and virological data were extracted from laboratory and patient records. A diagnosis of DENV infection was based on a positive nonstructural protein 1 (NS1) test, polymerase chain reaction or serology testing for immunoglobulin M (IgM) and immunoglobulin G (IgG). Primary and secondary infections were classified based on travel history, NS1 result and IgM/IgG ratio. Severe DF was defined according to WHO classification. RESULTS: We identified 245 DF cases: 210 (86%) primary and 35 (14%) secondary. Whilst fever duration was significantly longer in secondary compared with primary infections (6.4 vs 5.3 days, P = 0.027), mean Aspartate aminotransferase levels were significantly higher in primary compared with secondary cases (146 vs 65 U/L, P < 0.001), and no other clinical or laboratory parameter differed significantly between the groups. Of note, only four patients had severe DF, all had primary infections and none died. CONCLUSIONS: In a cohort of returning travellers with DF, secondary infection, compared with primary infection, was not associated with a consistent trend towards greater severity of the clinical and laboratory markers examined in this study.

Asunto(s)

Coinfección , Dengue , Humanos , Estudios Retrospectivos , Inmunoglobulina G , Inmunoglobulina M , Dengue/diagnóstico