Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human

Zika virus (ZIKV) specific neutralizing antibodies hold a great promise for antibody-based interventions and vaccine design against ZIKV infection. However, their development in infected patients remain unknown. Here, we report on the dynamic development of a potent and protective ZIKV-specific human antibody ZK2B10 initially isolated from a ZIKV convalescent individual using next-generation sequencing (NGS). The unbiased repertoire analysis showed dramatic changes in many families of heavy and light chain variable regions. However, lineage tracing of ZK2B10 revealed limited somatic hypermutation throughout the 12 months since the onset of symptom. In particular, NGS-derived germline-like somatic variants neutralized and protected mice from lethal challenge of ZIKV without detectable cross-reactivity with Dengue virus (DENV). Site-directed mutagenesis identified two residues within λ chain, N31 and S91 that are essential to the functional maturation. The dynamic features unveiled here will assist us to better understand the pathogenesis of ZIKV infection and inform rational design of vaccines. Author summary Recently emerged ZIKV is associated with severe neurological complications such as Guillain–Barré syndrome in adults and congenital microcephaly in newborns. No ZIKV-specific therapeutics or vaccines are currently available. We and others have identified a number of neutralizing antibodies capable of protecting experimental animals from ZIKV infection. However, the development of these potent antibodies during ZIKV natural infection remains unknown. Here, we report on the longitudinal analysis of one such antibody ZK2B10 using next-generation sequencing (NGS), bioinformatics and functional analysis. We found that the ZK2B10 germline-like antibodies possess strong neutralizing activity in vitro and impressive protectivity against lethal ZIKV infection in vivo. These findings suggest that the potent and protective antibody response against ZIKV can be generated within relative short term with high germline identity which provide great hope and promise for successful vaccine development against ZIKV.

[1]  Fuchun Zhang,et al.  Structural Basis for Neutralization and Protection by a Zika Virus-Specific Human Antibody. , 2019, Cell reports.

[2]  Jonathan R. McDaniel,et al.  Longitudinal Analysis Reveals Early Development of Three MPER‐Directed Neutralizing Antibody Lineages from an HIV‐1‐Infected Individual , 2019, Immunity.

[3]  J. Bukh,et al.  Genetic and structural insights into broad neutralization of hepatitis C virus by human VH1-69 antibodies , 2019, Science Advances.

[4]  T. Pierson,et al.  The emergence of Zika virus and its new clinical syndromes , 2018, Nature.

[5]  D. Barouch,et al.  Zika virus vaccines , 2018, Nature Reviews Microbiology.

[6]  Fuchun Zhang,et al.  A Single Injection of Human Neutralizing Antibody Protects against Zika Virus Infection and Microcephaly in Developing Mouse Embryos , 2018, Cell Reports.

[7]  G. Screaton,et al.  Therapeutic and Protective Efficacy of a Dengue Antibody Against Zika Infection in Rhesus Monkeys , 2018, Nature Medicine.

[8]  F. Bai,et al.  A plant-produced vaccine protects mice against lethal West Nile virus infection without enhancing Zika or dengue virus infectivity. , 2018, Vaccine.

[9]  D. Burton,et al.  Neutralizing human monoclonal antibodies prevent Zika virus infection in macaques , 2017, Science Translational Medicine.

[10]  M. Diamond,et al.  Anti-Dengue E-dimer epitope human antibodies have therapeutic activity against Zika virus infection , 2017, Nature Immunology.

[11]  D. Burton,et al.  Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer , 2017, Front. Immunol..

[12]  Bryan Briney,et al.  Zika virus activates de novo and cross-reactive memory B cell responses in dengue-experienced donors , 2017, Science Immunology.

[13]  Jian Wang,et al.  Delineating antibody recognition against Zika virus during natural infection. , 2017, JCI insight.

[14]  D. Burton,et al.  A human inferred germline antibody binds to an immunodominant epitope and neutralizes Zika virus , 2017, PLoS neglected tropical diseases.

[15]  C. Rice,et al.  Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico , 2017, Cell.

[16]  Andrew S. Miller,et al.  A human antibody against Zika virus crosslinks the E protein to prevent infection , 2017, Nature Communications.

[17]  M. Diamond,et al.  Zika Virus Pathogenesis and Tissue Tropism. , 2017, Cell host & microbe.

[18]  K. Stiasny,et al.  The Antigenic Structure of Zika Virus and Its Relation to Other Flaviviruses: Implications for Infection and Immunoprophylaxis , 2017, Microbiology and Molecular Biology Reviews.

[19]  Lu Lu,et al.  Neutralization of Zika virus by germline-like human monoclonal antibodies targeting cryptic epitopes on envelope domain III , 2017, Emerging microbes & infections.

[20]  Jennifer Abbasí.  First Inactivated Zika Vaccine Trial. , 2016, JAMA.

[21]  G. Gao,et al.  Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus , 2016, Science Translational Medicine.

[22]  James E. Crowe,et al.  Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice , 2016, Nature.

[23]  T. Pierson,et al.  Zika Virus: Immunity and Vaccine Development , 2016, Cell.

[24]  M. Castro,et al.  Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation , 2016, The Lancet.

[25]  M. Beltramello,et al.  Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection , 2016, Science.

[26]  C. Jessica E. Metcalf,et al.  Assessing the global threat from Zika virus , 2016, Science.

[27]  C. Nelson,et al.  Structural Basis of Zika Virus-Specific Antibody Protection , 2016, Cell.

[28]  Anavaj Sakuntabhai,et al.  Structural basis of potent Zika–dengue virus antibody cross-neutralization , 2016, Nature.

[29]  D. Burton,et al.  A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans. , 2016, Immunity.

[30]  Duncan R. Smith,et al.  Zika virus: history of a newly emerging arbovirus. , 2016, The Lancet. Infectious diseases.

[31]  Y. Tong,et al.  Excretion of infectious Zika virus in urine. , 2016, The Lancet. Infectious diseases.

[32]  G. Saade,et al.  Zika virus: History, emergence, biology, and prospects for control. , 2016, Antiviral research.

[33]  Yi Shi,et al.  Structures of the Zika Virus Envelope Protein and Its Complex with a Flavivirus Broadly Protective Antibody. , 2016, Cell host & microbe.

[34]  Penghua Wang,et al.  Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes , 2016, Nature Microbiology.

[35]  J. Mascola,et al.  Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor. , 2016, Immunity.

[36]  S. Rasmussen,et al.  Zika Virus and Birth Defects--Reviewing the Evidence for Causality. , 2016, The New England journal of medicine.

[37]  T. Pierson,et al.  The 3.8 Å resolution cryo-EM structure of Zika virus , 2016, Science.

[38]  Michael G. Rossmann,et al.  The 3.8 angstrom resolution cryo-EM structure of Zika virus. , 2016 .

[39]  A. Act,et al.  Zika Virus Infection in Pregnant Women in Rio de Janeiro - Preliminary Report. , 2016 .

[40]  I. López-Martínez,et al.  Lower IgG somatic hypermutation rates during acute dengue virus infection is compatible with a germinal center-independent B cell response , 2016, Genome Medicine.

[41]  J. Mascola,et al.  Rhesus Macaque B-Cell Responses to an HIV-1 Trimer Vaccine Revealed by Unbiased Longitudinal Repertoire Analysis , 2015, mBio.

[42]  Young Do Kwon,et al.  Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection , 2015, Cell.

[43]  P. Desprès,et al.  Recognition determinants of broadly neutralizing human antibodies against dengue viruses , 2015, Nature.

[44]  Cameron P Simmons,et al.  A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus , 2014, Nature Immunology.

[45]  Dennis R. Burton,et al.  Toward a more accurate view of human B-cell repertoire by next-generation sequencing, unbiased repertoire capture and single-molecule barcoding , 2014, Scientific Reports.

[46]  W. Koff,et al.  Toward a Human Vaccines Project , 2014, Nature Immunology.

[47]  K. Yuen,et al.  Potent Neutralization of MERS-CoV by Human Neutralizing Monoclonal Antibodies to the Viral Spike Glycoprotein , 2014, Science Translational Medicine.

[48]  D. Musso,et al.  Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013. , 2014, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[49]  S. Quake,et al.  The promise and challenge of high-throughput sequencing of the antibody repertoire , 2014, Nature Biotechnology.

[50]  Tongqing Zhou,et al.  De novo identification of VRC01 class HIV-1–neutralizing antibodies by next-generation sequencing of B-cell transcripts , 2013, Proceedings of the National Academy of Sciences.

[51]  Philip R. Johnson,et al.  Accelerating Next-Generation Vaccine Development for Global Disease Prevention , 2013, Science.

[52]  Baoshan Zhang,et al.  Mining the antibodyome for HIV-1–neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains , 2013, Proceedings of the National Academy of Sciences.

[53]  J. Mullikin,et al.  Somatic Populations of PGT135–137 HIV-1-Neutralizing Antibodies Identified by 454 Pyrosequencing and Bioinformatics , 2012, Front. Microbio..

[54]  J. Mullikin,et al.  Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing , 2011, Science.

[55]  T. Pierson,et al.  Antibody-mediated neutralization of flaviviruses: a reductionist view. , 2011, Virology.

[56]  T. Pierson,et al.  Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection , 2008, Expert Reviews in Molecular Medicine.

[57]  G. Dick,et al.  Zika virus. I. Isolations and serological specificity. , 1952, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[58]  M. Diamond,et al.  Anti-Dengue E-dimer epitope human antibodies have therapeutic activity against Zika virus infection , 2017 .

[59]  L. R. Petersen,et al.  Zika Virus. , 2016, The New England journal of medicine.

[60]  D. Horovitz,et al.  Zika Virus Infection in Pregnant Women in Rio de Janeiro. , 2016, The New England journal of medicine.

[61]  P. Parameswaran,et al.  Short Communication Characterization of a model of lethal dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor , 2012 .

[62]  M. Levine,et al.  Immunity and Vaccine Development , 1992 .