Antibody protects mice against Zika infection

Researchers have reported that an antibody protected Zika-infected mice against the virus, in a small trial of ten mice. The antibody has previously been effective in animal models against viruses related to Zika, such as dengue and West Nile virus. The authors, publishing in Cell Host & Microbe, say a humanized version of the antibody could be a potential therapy for Zika infection.
 

Dr. Amelia Pinto, Assistant Professor, Department of Molecular Microbiology & Immunology, Saint Louis University (webpage):

Expertise: Understanding the immune response to arboviruses including West Nile, chikungunya, Zika, and dengue.

“Monoclonal antibody therapies, which have been effective against some cancers and autoimmune diseases, are one of the newest technologies being developed against emerging pathogens. One of the most notable examples of this new therapy is ZMab, which is composed of three monoclonal antibodies against Ebola. In this study the flavivirus-specific monoclonal antibody 2A10G6 is proposed as a possible therapeutic for Zika virus. If effective, this antibody provides a way to diversify the tools available to treat emerging pathogens.

“This study, along with two other recently published studies provides researchers with a high-resolution picture of the surface of Zika virus. The authors begin this study with a very impressive crystal structure of the envelope protein of Zika virus and demonstrate with a high degree of detail where the 2A10G6 antibody binds to Zika. By showing where the 2A10G6 antibody binds to the envelope protein of Zika virus the authors are able to explain how 2A10G6 functions to neutralize flaviviruses. The strength of this study is in the detail published in the structure.

“However, the studies with their flavivirus monoclonal antibody as a therapeutic are far less remarkable. The structural studies demonstrated that the monoclonal antibody 2A10G6 was able to bind to Zika virus and a prior study with this antibody and Dengue suggested that 2A10G6 could neutralize Dengue infection in mice. While 2A10G6 is reported to be protective against a lethal challenge of Zika in mice, the numbers of mice used in the study are too small to conclusively determine the antibody’s effectiveness. There are very few neutralizing antibodies approved by the FDA for use against viral infections and more studies will need to be completed to determine how practical it is for a therapy against Zika virus in humans.”

 

Dr. James D Brien and Mariah Hassert, Saint Louis University School of Medicine (webpage):

Dr. James D Brien is an Assistant Professor of Microbiology and Immunology. Mariah Hassert is a graduate student in J. Brien’s laboratory.

Expertise: immune responses to arthropod borne viruses, antibody mediated protection against flaviviruses like Zika

“This study improves our understanding of Zika virus structure; significantly advancing the fields of diagnostics and vaccine design. Flaviviruses, including Zika virus have an outer envelope that surrounds genetic material. Dai et al used x-ray crystollagraphy to determine the structure of the Zika virus envelope protein. This work acts synergistically with two recent publications that determined the structure of Zika virus (1, 2) allowing us to compare and contrast Zika virus with closely related family members such as West Nile virus and Dengue virus.

‘The authors highlight structural features found in Zika virus that are conserved in other flaviviruses, including West Nile and Dengue viruses. One domain they focus on is the fusion loop, which is responsible for viral entry into cells, and is a common target for antibody recognition. Due to the observed similarities in the fusion loop, the authors reasoned that antibody 2A10G6, which they identified previously, may neutralize Zika virus in the same manner as other flaviviruses. The authors use a mouse model to provide limited information on a proposed therapeutic antibody (2A10G6) (3, 4). Unfortunately, the antibody 2A10G6 targets an epitope on the surface of the virus that has minimal therapeutic potential because the quantity of antibody required for complete virus neutralization is very high.

“The significance of this work rests on the structural biology aspects. By developing an understanding of how Zika virus differs from closely related flaviviruses, diagnostics and vaccines can be driven to target those unique characteristics, allowing the control of the Zika virus epidemic.”

  1. Kostyuchenko VA et al., Structure of the thermally stable Zika virus. Nature. 2016. Apr 19
  2. Sirohi D et al., The 3.8 A resolution cryo-EM structure of Zika virus. Science. 2016;352(6284):467-70
  3. Aliota MT et al., Characterization of Lethal Zika Virus Infection in AG129 Mice. PLoS Negl Trop Dis. 2016;10(4):e0004682.
  4. Rossi SL et al., Characterization of a Novel Murine Model to Study Zika Virus. Am J Trop Med Hyg. 2016.

 

Dr. Vincent Racaniello, Higgins Professor of Microbiology & Immunology, Columbia University (webpage):

Expertise: Molecular biology of picornavirus replication and pathogenesis

“In this paper the authors determine the high resolution structure of a monoclonal antibody bound with the envelope protein of Zika virus. The envelope glycoprotein is on the surface of the virus particle and is the way the virus attaches to cells. Thus blocking this molecule is a good way to inhibit infection. This monoclonal antibody is very unusual because it can block infection of multiple flaviviruses, including Zika virus, dengue virus, West Nile virus, and yellow fever virus. The methods are well established and the results are fully supported by the data.

“The finding that the antibody protects mice against Zika virus is important. Therefore it is likely that this antibody would have therapeutic potential in humans. However, additional pre-clinical data would be needed before this monoclonal antibody went into human trials. For example, it would be important to show protection in a nonhuman primate model, at least in the US. Having a monoclonal antibody for human treatment would be an important therapeutic, although it is several years away from licensing. Because the antibody can block infection with multiple flaviviruses, it could also be used to treat other flavivirus disease.

“The novel aspect of this work is that it shows exactly how the antibody binds to the viral glycoprotein. In looking at the molecular interaction of the antibody with the viral glycoprotein, one can see exactly which parts of the protein are involved. From this we can say that the antibody binds to parts of the glycoprotein that are conserved in most flaviviruses. Thus the work explains why the antibody can block infection with many flaviviruses.”

 

Declared interests (see GENeS register of interests policy):

No interests declared.

 

Reference

Structures of the Zika virus envelope protein and its complex with a flavivirus broadly-protective antibody‘ by Lianpan Dai et. al., published in Cell Host and Microbe on Monday, 2 May 2016.

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