Research Finds Antibodies Show Promise for Treatment of Hantavirus

An international team of researchers has discovered the first human antibody that effectively neutralizes two types of hantaviruses in animal models, according to a study published online in the journal Science Translational Medicine. Based on their preliminary results, the antibody appears to be a promising candidate for the development of a "pan-hantavirus" therapy that could prevent outbreaks caused by multiple known or emerging hantaviruses. The title of this paper is “Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses”.

Rodent-borne orthohantaviruses transmitted by rodents are zoonotic viruses with global distribution that cause hantavirus cardiopulmonary syndrome (HCPS) or hemorrhagic fever with renal syndrome (HFRS). Rodent-borne Hantaviruses are divided into two distinct virus families, commonly referred to as "Old World" and "New World" Hantaviruses. HFRS is caused by Old World viruses primarily found in Europe and Asia, while New World viruses cause HCPS, commonly found in North and South America.

The hantavirus causes about 50,000 serious and often fatal infections worldwide each year. While humans are usually infected through contact with rodents, the virus can also be spread through direct human-to-human contact. Currently, there is no FDA-approved vaccine or antiviral therapy to prevent or treat the serious and potentially fatal disease caused by the emerging hantavirus.

In a previous study, Mitler et al. describe the isolation of human monoclonal antibodies (mAbs) directed against the hantavirus Puumala virus (PUUV) spike protein complex from PUUV-experienced donors recovered from HFRS. This set of 135 mAbs exhibited different cross-reactivity and neutralizing activities against viruses from different hantavirus clades and targeted different parts of the viral spike. The mAb ADI-42898 blocked viral entry of seven different hantaviruses and protected Syrian hamsters challenged with HCPS-causing Andes virus or bank voles challenged with HFRS-causing PUUV. These findings suggest that monoclonal antibodies may have utility in the treatment of hantavirus disease.

Now in this new study, the researchers describe the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. They define a dominant class of nAbs recognizing the “capping loop” of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.

The authors of the paper expressed that this is the first monoclonal antibody to demonstrate cross-protective efficacy against distinct Old and New World hantaviruses. According to the authors, hantavirus outbreaks in Sweden, Argentina and the United States over the past two decades highlight the public health risks posed by these viruses. The frequency of these and other emerging disease outbreaks is expected to increase with loss of animal habitat and climate change.

Reference

1.Mittler, Eva, et al. Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses. Science Translational Medicine. 2022. eabl5399.


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