Why do we have no treatments for hantaviruses?

The 100-plus passengers who disembarked the MV Hondius cruise ship this past week might understandably wonder why no FDA-approved vaccine or treatment exists to treat the disease caused by the hantavirus they were just exposed to. Hantavirus researchers say the crucial issue is funding.

There are more than 28 hantaviruses that infect rodents and can cause illness in humans. The specific virus that has infected the Hondius passengers is the Andes virus, usually found in South America. In people, the virus incubates for 2 to 8 weeks and can cause hantavirus pulmonary syndrome (HPS), which is fatal about a third of the time. Currently, doctors can only treat the symptoms, not the underlying virus.

Although dangerous, HPS is a rare orphan disease, which means it is underfunded and inherently difficult to study. Despite the lack of funding for human testing, hantavirus virologists do have a pipeline of possible candidate vaccines and drug leads.

Potential treatments in the works

In 2019, Kartik Chandran, professor of microbiology and immunology at Albert Einstein College of Medicine, led a coalition of research groups that got 5-year funding from NIH to discover and develop therapeutic antibodies against highly lethal viruses with no treatments, including the Andes hantavirus. Part of the strategy of the project, called Prometheus, was to follow the same game plan that worked for getting therapies for Ebola disease.

After an Ebola virus outbreak in West Africa in 2014–16 killed 28,000, researchers worked together to screen survivors for protective antibodies and develop engineered ones that could slow down the disease. It worked. In 2020, the FDA approved two monoclonal antibody therapies for Ebola disease.

For hantavirus, Chandran and his colleagues first screened antibodies from survivors of the disease. One survivor of a less lethal strain, the Puumala virus, carried an antibody that binds to the two hantavirus glycoproteins that dot the viral surface in the shape of four-petal flowers. Those flower glycoproteins play an important role in host cell infection because they change shape dramatically just as the virus fuses membranes with its host, Chandran says.

But if an antibody binds the glycoproteins before the virus infects cells, it prevents the shape change and the infection. The scientists engineered that natural survivor antibody to bind tighter and longer to the glycoproteins and “staple it together so it can’t rearrange,” which stops the infection and kills the virus.

Chandran’s group tested this antibody (ADI-65534) in the Syrian hamster model, which is the best animal model researchers have for studying Andes hantavirus in an organism. It works well there. But a Syrian hamster is not a human, so the next steps are preclinical and clinical testing for safety and efficacy in humans. And that is where the similarity with Ebola virus ends because those steps have not happened.

“We have been trying for the last 3 or 4 years to get funding to develop our antivirus monoclonal antibody,” Chandran says, “and so far, we have not been very successful.”

“Hantaviruses have just not been high on anybody’s priority list,” he says.

Chandran’s group and many others are pursuing other antibodies as well: some bind to the glycoproteins that flag infected cells, telling immune cells to come and kill them; some bind to the hantavirus nuclear capsid protein—which usually sits well inside the virus and might be a powerful therapy because the capsid protein is well conserved. Yet none have gone through the paces of human testing.

“The various government agencies and nonprofits have, not unreasonably, considered hantavirus to be a lower public health priority. . . . Maybe with the current situation and seeing the potential for Andes virus to cause a larger public health emergency, there might be more interest,” Chandran says.

Even once there is funding, however, clinical testing for a hantavirus therapy or vaccine is not a trivial undertaking.

Difficulties getting trials going

Hantaviruses are a “chronically understudied family of viruses,” says Alison Kell, a virologist at the University of New Mexico. Much is still unknown about the virus’s biology, partly because, as zoonotic viruses, they spend most of their time benignly infecting small mammals, and only occasionally infect humans, where they cause disease.

Kell calls hantaviruses “wild,” with sporadic outbreaks. Doing a clinical trial on a possible therapy or vaccine for such a rare, dangerous disease is no easy task. “We don’t have a big cohort of people that we know are likely to be exposed and likely to be infected,” Kell says.

Much could still be done, however, Chandran says. “Part of the goal here is to get some treatments at least through to the point where you can have a GMP batch and you’ve established safety, so that if there’s an emergency, they could be given under compassionate use guidelines. For the folks on the cruise ship, having something—an antibody that could have been given as a prophylactic—would have been a nice option.”

Future work to be prepared

Having a vaccine may not have been as useful in this type of outbreak, Kell says. Yet a vaccine would be useful for certain populations who are likely to come in contact with animal droppings. And if hantavirus mutated to become more transmissible, a ready vaccine would be welcome.

The US military has been working toward a vaccine for hantavirus since the 1980s, and has taken a DNA vaccine through phase 1 clinical trials. And other groups are working on vaccines against hantaviruses.

Currently, Chandran is heading another large consortium of 13 research groups funded by NIH called PROVIDENT that is tasked with staging all the prevaccine research and design that needs to be done for hantaviruses and two other emerging viral threats. The idea is that when one of the viruses suddenly becomes a threat, all the pieces will be in place to quickly produce a vaccine. Their eventual goal is to be able to put together a vaccine ready for animal testing in 10 days.

The consortium is simultaneously developing multiple types of vaccines against hantavirus: subunit vaccines, self-amplifying RNA vaccines, and a vesicular stomatitis vaccine. Chandran is particularly excited about their RNA vaccine candidate.

And if none of those ready-to-test treatments or vaccines pan out, scientists are also working on finding new targets for hantavirus treatments.

Kell is at the end of what she calls an interactome study to identify all the host proteins that interact in any way with the four viral proteins of a hantavirus called the Seoul virus. Her lab created new antibodies for the four hantavirus proteins and sent them into infected rat, human, and mouse cells. “We used those antibodies to essentially pull out all of the viral proteins. And when we pull out the viral proteins, we also pull out all of the host proteins that the virus protein is interacting with at that moment,” she says.

By comparing host proteins between rat, mouse, and human, they may be able to identify those critical for causing severe disease in humans and target those for creating new therapies and vaccines.