#Reciprocal immune #enhancement of #dengue and #Zika virus #infection in #human #skin (JCI Insight, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

JCI Insight. 2020 Jan 7. pii: 133653. doi: 10.1172/jci.insight.133653. [Epub ahead of print]

Reciprocal immune enhancement of dengue and Zika virus infection in human skin.

Castanha PM, Erdos G, Watkins SC, Falo LD Jr, Marques ET, Barratt-Boyes SM.



Dengue (DENV) and Zika viruses (ZIKV) are closely related mosquito-borne flaviviruses that co-circulate in tropical regions and constitute major threats to global human health. Whether preexisting immunity to one virus affects disease caused by the other during primary or secondary infections is unknown but is critical in preparing for future outbreaks and predicting vaccine safety. Using a human skin explant model, we show that DENV-3 immune sera increased recruitment and infection of Langerhans cells, macrophages and dermal dendritic cells following inoculation with DENV-2 or ZIKV. Similarly, ZIKV immune sera enhanced infection with DENV-2. Immune sera increased migration of infected Langerhans cells to dermis and emigration of infected cells out of skin. Heterotypic immune sera increased viral RNA in dermis almost tenfold and reduced the amount of virus required to infect a majority of myeloid cells by 100 to 1,000 fold. Enhancement was associated with cross-reactive IgG and induction of IL-10 expression and was mediated by both CD32 and CD64 Fcγ receptors. These findings reveal that preexisting heterotypic immunity greatly enhances DENV and ZIKV infection, replication and spread in human skin. This relevant tissue model will be valuable in assessing the efficacy and risk of dengue and Zika vaccines in humans.

KEYWORDS: Dendritic cells; Immunoglobulins; Immunology; Infectious disease; Macrophages

PMID: 31910161 DOI: 10.1172/jci.insight.133653

Keywords: Dengue fever; Zika Virus; ADE.


Molecular #mechanism for #ADE of #coronavirus entry (J Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Virol. 2019 Dec 11. pii: JVI.02015-19. doi: 10.1128/JVI.02015-19. [Epub ahead of print]

Molecular mechanism for antibody-dependent enhancement of coronavirus entry.

Wan Y1, Shang J1, Sun S, Tai W2, Chen J3, Geng Q1, He L4, Chen Y4, Wu J1, Shi Z3, Zhou Y, Du L5, Li F6.

Author information: 1 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA. 2 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA. 3 Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China. 4 Laboratory of infection and immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. 5 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA lifang@umn.edu LDu@nybc.org. 6 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA lifang@umn.edu LDu@nybc.org.



Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on host cell surface and then fusing viral and host membranes. Here we investigated how a neutralizing monoclonal antibody (mAb), which targets the receptor-binding domain (RBD) of MERS coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that mAb binds to the virus-surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, mAb binds to cell-surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized mAb dosages in viral-receptor-dependent, antibody-dependent, and both-receptors-dependent entry pathways, delineating guidelines on mAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.



Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only sub-neutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the virus-surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG-Fc-receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.

Copyright © 2019 American Society for Microbiology.

PMID: 31826992 DOI: 10.1128/JVI.02015-19

Keywords: Coronavirus; MERS-CoV; Monoclonal antibodies; ADE.


A protective #Zika virus E-dimer-based subunit #vaccine engineered to abrogate #ADE of #dengue #infection (Nat Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Nat Immunol. 2019 Sep 2. doi: 10.1038/s41590-019-0477-z. [Epub ahead of print]

A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection.

Slon-Campos JL1, Dejnirattisai W1, Jagger BW2,3, López-Camacho C4, Wongwiwat W1, Durnell LA2, Winkler ES2, Chen RE2, Reyes-Sandoval A4, Rey FA5,6, Diamond MS2,7,8,9, Mongkolsapaya J10,11, Screaton GR12.

Author information: 1 Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 2 Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA. 3 Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA. 4 Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 5 Unité de Virologie Structurale, Département de Virologie, Institut Pasteur, Paris, France. 6 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3569, Paris, France. 7 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA. 8 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA. 9 Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA. 10 Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. jmongkol@well.ox.ac.uk. 11 Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. jmongkol@well.ox.ac.uk. 12 Division of Medical Sciences, University of Oxford, Oxford, UK. gavin.screaton@medsci.ox.ac.uk.



Infections with dengue virus (DENV) and Zika virus (ZIKV) can induce cross-reactive antibody responses. Two immunodominant epitopes-one to precursor membrane protein and one to the fusion loop epitope on envelope (E) protein-are recognized by cross-reactive antibodies1-3that are not only poorly neutralizing, but can also promote increased viral replication and disease severity via Fcγ receptor-mediated infection of myeloid cells-a process termed antibody-dependent enhancement (ADE)1,4,5. ADE is a significant concern for both ZIKV and DENV vaccines as the induction of poorly neutralizing cross-reactive antibodies may prime an individual for ADE on natural infection. In this report, we describe the design and production of covalently stabilized ZIKV E dimers, which lack precursor membrane protein and do not expose the immunodominant fusion loop epitope. Immunization of mice with ZIKV E dimers induces dimer-specific antibodies, which protect against ZIKV challenge during pregnancy. Importantly, the ZIKV E-dimer-induced response does not cross-react with DENV or induce ADE of DENV infection.

PMID: 31477918 DOI: 10.1038/s41590-019-0477-z

Keywords: Zika Virus; Vaccines; A.D.E.; Dengue fever; Animal models.


Previous #dengue or #Zika virus #exposure can drive to #infection #enhancement or neutralisation of other #flaviviruses (Mem Inst Oswaldo Cruz, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Mem Inst Oswaldo Cruz. 2019;114:e190098. doi: 10.1590/0074-02760190098. Epub 2019 Aug 12.

Previous dengue or Zika virus exposure can drive to infection enhancement or neutralisation of other flaviviruses.

Oliveira RA1,2, de Oliveira-Filho EF1,3, Fernandes AI4,5, Brito CA6, Marques ET1,7, Tenório MC1, Gil LH1.

Author information: 1 Fundação Oswaldo Cruz, Instituto Aggeu Magalhães, Departamento de Virologia, Recife, PE, Brasil. 2 Universidade Federal da Paraíba, Departamento de Fisiologia e Patologia, João Pessoa, PB, Brasil. 3 Charité-Universitätsmedizin Berlin, Berlin, Germany. 4 Universidade Federal da Paraíba, Hospital Universitário Lauro Wanderley, Serviço de Doenças Infecciosas e Parasitárias, João Pessoa, PB, Brasil. 5 Universidade Federal da Paraíba, Escola Técnica de Saúde, Grupo de Estudos e Pesquisas em Imunologia Humana, João Pessoa, PB, Brasil. 6 Universidade Federal de Pernambuco, Departamento de Medicina Clínica, Recife, PE, Brasil. 7 University of Pittsburgh, Center for Vaccine Research, Department of Infectious Diseases and Microbiology, Pittsburgh, PA, USA.




Dengue virus (DENV) has circulated in Brazil for over 30 years. During this time, one serotype has cyclically replaced the other, until recently, when all four distinct serotypes began to circulate together. Persistent circulation of DENV for long time periods makes sequential infections throughout a person’s life possible. After primary DENV infection, life-long immunity is developed for the infecting serotype. Since DENV and Zika virus (ZIKV) are antigenically similar, the possibility of cross-reactions has attracted attention and has been demonstrated in vitro.


The aim of this study was to investigate whether immune-sera from DENV and ZIKV infected patients would cross-react in vitro with other Flaviviridae family members.


Cross-reaction of the studied samples with yellow fever virus (YFV), West Nile virus (WNV), Rocio virus (ROCV), Saint Louis virus (SLEV) and Ilheus virus (ILHV) has been investigated by plaque reduction neutralisation test (PRNT) and the antibody-dependent enhancement (ADE) by flow-cytometry.


Antibodies against ZIKV and DENV virus cross-reacted with other flaviviruses either neutralising or enhancing the infection. Thus, viral entrance into FcRFcɣRII-expressing cells were influenced by the cross-reactive antibodies. ZIKV or DENV immune sera enhanced cellular infection by WNV, ILHV, ROCV and SLEV. Finally, DENV immune sera presented higher neutralising activity for YFV and SLEV. While ZIKV immune sera neutralised WNV, ILHV and ROCV with high frequencies of positivity.


The co-circulation of those viruses in the same area represents a risk for the development of severe infections if they spread throughout the country. Successive flavivirus infections may have an impact on disease pathogenesis, as well as on the development of safe vaccine strategies.

PMID: 31411310 DOI: 10.1590/0074-02760190098

Keywords: Flavivirus; Dengue fever; Zika Virus; WNV; Rocio Virus; St Louis Virus; Ilheus virus; Yellow Fever; Serology; ADE; Brazil.


#ADE of #influenza #disease promoted by increase in #hemagglutinin stem flexibility and virus #fusion kinetics (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics

Katie L. Winarski, Juanjie Tang, Laura Klenow, Jeehyun Lee, Elizabeth M. Coyle, Jody Manischewitz, Hannah L. Turner, Kazuyo Takeda, Andrew B. Ward, Hana Golding, and Surender Khurana

PNAS first published July 11, 2019 / DOI: https://doi.org/10.1073/pnas.1821317116

Edited by Robert G. Webster, St. Jude Children’s Research Hospital, Memphis, TN, and approved June 19, 2019 (received for review December 14, 2018)



Next-generation influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these do not block virus–receptor interactions and thus are predicted to provide protection via alternative mechanisms at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of respiratory disease (ERD). Our study describes ADE with two different functional MAbs that destabilized HA stem domain, increased influenza virus fusion kinetics, and led to enhanced lung pathology and ERD in a dose-dependent manner in a mice model. This study underlines careful preclinical evaluation of next-generation influenza vaccines or antibody-based therapeutics that do not block influenza virus receptor binding.



Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral infection or disease. In the current study, two monoclonal antibodies (MAbs) 72/8 and 69/1, enhanced respiratory disease (ERD) in mice following H3N2 virus challenge by demonstrating increased lung pathology and changes in lung cytokine/chemokine levels. MAb 78/2 caused changes in the lung viral loads in a dose-dependent manner. Both MAbs increased HA sensitivity to trypsin cleavage at a higher pH range, suggesting MAb-induced conformational changes. pHrodo-labeled virus particles’ entry and residence time in the endocytic compartment were tracked during infection of Madin-Darby canine kidney (MDCK) cells. Both MAbs reduced H3N2 virus residence time in the endocytic pathway, suggesting faster virus fusion kinetics. Structurally, 78/2 and 69/1 Fabs bound the globular head or base of the head domain of influenza hemagglutinin (HA), respectively, and induced destabilization of the HA stem domain. Together, this study describes Mab-induced destabilization of the influenza HA stem domain, faster kinetics of influenza virus fusion, and ERD in vivo. The in vivo animal model and in vitro assays described could augment preclinical safety evaluation of antibodies and next-generation influenza vaccines that generate antibodies which do not block influenza virus–receptor interaction.

universal – stem – influenza – antibody-dependent enhancement (ADE) – vaccine



1 K.L.W., J.T., and L.K. contributed equally to this work.

2 To whom correspondence may be addressed. Email: Surender.Khurana@fda.hhs.gov.

Author contributions: S.K. designed research; K.L.W., J.T., L.K., J.L., E.M.C., J.M., H.L.T., K.T., A.B.W., and S.K. performed research; K.L.W., J.T., L.K., H.L.T., K.T., A.B.W., and S.K. analyzed data; and A.B.W., H.G., and S.K. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1821317116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Influenza A; Monoclonal antibodies; Vaccines; Antibody Dependent Enhancement.


#Zika Virus-Immune #Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika #Pathogenesis in #Adult and #Pregnant Mice (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Zika Virus-Immune Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika Pathogenesis in Adult and Pregnant Mice

Byoung-Shik Shim, Young-Chan Kwon, Michael J. Ricciardi, Mars Stone, Yuka Otsuka, Fatma Berri, Jaclyn M. Kwal, Diogo M. Magnani, Cody B. Jackson, Audrey S. Richard, Philip Norris,Michael Busch, Christine L. Curry, Michael Farzan, David Watkins, Hyeryun Choe

Mark R. Denison, Editor

DOI: 10.1128/mBio.00758-19



Preexisting immunity against dengue virus or West Nile virus was previously reported to mediate antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection in a mouse model. We show here that ZIKV-immune plasma samples from both symptomatic and asymptomatic individuals mediated ZIKV ADE of infection in vitro and in mice. In a lethal infection model with a viral inoculum 10 times higher, both ADE and protection were observed, depending on the amount of infused immune plasma. In a vertical-transmission model, ZIKV-immune plasma infused to timed pregnant mice increased fetal demise and decreased the body weight of surviving fetuses. Depletion of IgG from an immune plasma abolished ADE of infection, and the presence of purified IgG alone mediated ADE of infection. Higher viral loads and proinflammatory cytokines were detected in mice treated with ZIKV-immune plasma samples compared to those receiving control plasma. Together, these data show that passive immunization with homotypic ZIKV antibodies, depending on the concentration, could either worsen or limit a subsequent ZIKV infection.



Antibody-dependent enhancement (ADE) of virus infection is common to many viruses and is problematic when plasma antibody levels decline to subneutralizing concentrations. ADE of infection is especially important among flaviviruses, many of which are the cause of global health problems. Recently, human plasma samples immune to heterologous flaviviruses were shown to promote Zika virus (ZIKV) infection. Here we showed in immunocompromised mouse models that homologous immune plasma samples protect mice from subsequent infection at high antibody concentrations but that they mediate ADE of infection and increase ZIKV pathogenesis in adult mice and fetal demise during pregnancy at low concentrations.

Keywords: Zika Virus; ADE; Pregnancy; Immunopathology; Animal models.


#WNV #infection in individuals with pre-existing #Usutu virus #immunity, northern #Italy, 2018 (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

West Nile virus infection in individuals with pre-existing Usutu virus immunity, northern Italy, 2018

Alessandro Sinigaglia1, Monia Pacenti2, Thomas Martello1, Silvana Pagni1,2, Elisa Franchin1,2, Luisa Barzon1,2

Affiliations: 1 Department of Molecular Medicine, University of Padova, Padova, Italy; 2 Microbiology and Virology Unit, Padova University Hospital, Padova, Italy

Correspondence:  Luisa Barzon

Citation style for this article: Sinigaglia Alessandro, Pacenti Monia, Martello Thomas, Pagni Silvana, Franchin Elisa, Barzon Luisa. West Nile virus infection in individuals with pre-existing Usutu virus immunity, northern Italy, 2018. Euro Surveill. 2019;24(21):pii=1900261. https://doi.org/10.2807/1560-7917.ES.2019.24.21.1900261

Received: 27 Apr 2019;   Accepted: 22 May 2019



In 2018, there was a large West Nile virus (WNV) outbreak in northern Italy. We observed five atypical cases of WNV infection that were characterised by the presence of WNV RNA and WNV IgG at the time of diagnosis, but no IgM response during follow-up. Neutralisation assays demonstrated pre-existing Usutu virus immunity in all patients. Besides challenging diagnosis, the immunological crosstalk between the two viruses warrants further investigation on possible cross-protection or infection enhancement effects.

©  This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: WNV; Usutu virus; ADE; Italy.