People living in big cities probably aren’t surprised to run into rats on their daily commutes. Some might point to the infamous Pizza Rat, a 2015 internet meme based on a viral video of a rat carrying a slice of pizza down the steps of a New York City Subway station, for making close rat and human contacts seem normal.
Pizza Rat is a symptom of a larger problem. Urbanization leads to deforestation and forces wildlife out of their habitats. Wildlife living in human habitats promote the spread of diseases between animals and people (1). Rats and other rodents in particular can carry hantaviruses that cause a variety of severe and often fatal lung diseases such as hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS).
In a recent Science Translational Medicine study, the Prometheus consortium — a group of scientists from various fields and specialties spanning academia, industry, and government — reported a human monoclonal antibody (mAb), ADI-42898, that counteracts both HFRS and HCPS-causing hantaviruses (2).
We have people on our team who are committed to that because there are doctors in their home countries who face these infections and want to have something to give to patients. —Kartik Chandran, Albert Einstein College of Medicine
“We want to make something that will be used in the clinic,” said Kartik Chandran, a virologist from Albert Einstein College of Medicine, Prometheus’s lead scientist, and an author of this study. “We have people on our team who are committed to that because there are doctors in their home countries who face these infections and want to have something to give to patients.”
Hantaviruses are typically spilt into two groups: New World and Old World. New World viruses are endemic to North and South America and have higher fatality rates than Old World viruses. Old World hantaviruses cause more infections worldwide.
To identify mAbs that neutralize both Old and New World viruses, the researchers focused on a less lethal Old World hantavirus called Puumala virus (PUUV). PUUV is something of a genetic intermediate that shares traits with both virus types. The team reasoned that a patient infected with PUUV would carry antibodies that recognize both Old and New World hantaviruses.
The team collected blood samples from 45 patients diagnosed with PUUV infections from a recent outbreak in Sweden. Because mAbs are not usually present at high levels in the blood, the researchers used a platform that searches for memory B cells, which produce mAbs. These cells are a part of the adaptive immune system that recognizes viruses from past infections and rapidly begins making antibodies to stop new infections in their tracks.
The researchers used a recombinant virus that contained part of the hantavirus spike protein fused to a fluorescent tag as bait for memory B cells that display hantavirus antibodies. The team separated the captured B cells that clung to the bait using single-cell sorting and then isolated the mAb genetic information.
The researchers isolated a total of 135 mAbs that neutralized PUUV and tested the most potent ones for reactivity against other hantaviruses. A single human mAb, ADI-42898, stood out for its ability to protect against seven New and Old World hantaviruses.
ADI-42898 completely protected against PUUV-induced HRFS in a rodent model when administered prior to infection. A single dose of ADI-42898 completely protected rodents even when given three days after viral exposure.
Hantavirus's spike proteins help the virus enter cells in a fashion similar to the SARS-CoV-2 spike protein. To understand how the mAbs they found neutralized the hantavirus spike protein, they used negative stain transmission electron microscopy (EM) to take pictures of a selection of the PUUV mABs bound to the spike protein.
All PUUV mAbs bound to a similar region of the hantavirus spike protein, but not precisely in the same area. The antibodies were split into two groups based on what part of the spike protein they bound. Group one antibodies interacted with the head of the protein while group two antibodies interacted with an opposing tail region.
Gordon Joyce, a virologist at the Walter Reed Army Institute of Research who was not involved in the study, was impressed with the team’s discovery of a human mAb with broad reactivity.
Scientifically, it makes sense that you would be able to find these types of antibodies, but the practical implications of finding one of these is very difficult. — Gordon Joyce, Walter Reed Army Institute of Research
“Scientifically, it makes sense that you would be able to find these types of antibodies, but the practical implications of finding one of these is very difficult,” said Joyce. “By them actually achieving that, that's going to open the doors for a lot of research and next generation vaccines.”
Joyce thinks that the EM images obtained in this study are a good start to understanding how the mAbs bind hantaviruses, but he wants to see higher resolution structures of the mAbs.
“The devil is in those details in terms of exactly what part of the antibody is interacting with the hantavirus protein,” said Joyce. “Those sort of details are what we need for vaccine design.” Chandran and his team are already working on attaining more high resolution structures of the mAbs.
Chandran’s team plans to develop these antibodies for the clinic, but they still have many questions, including learning how the antibody behaves in humans, deciding when to administer the antibody to provide the best patient outcomes, and determining how best to manufacture the antibodies.
“I'm just excited that we have these broadly protective antibodies. The next challenge becomes if we can turn this into a treatment that can actually help people,” said Chandran.
- Tian, H. et al. Urbanization prolongs hantavirus epidemics in cities. Proc Natl Acad Sci U S A 115, 4707-4712 (2018).
- Mittler, E. et al. Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses. Sci Transl Med 14, eabl5399 (2022).