It’s hard to imagine anything more despised than mosquitos. They menacingly buzz about, swoop in to feast on your blood, and often leave behind an annoying, itchy lump. But by far the worst bit is that they spread throngs of pathogens—dengue, Zika, chikungunya, yellow fever, West Nile, malaria… the list goes on. Their bites cause hundreds of millions of infections each year. Dengue alone infects around 390 million people a year globally. Malaria strikes around 214 million.

What if there was a vaccine that could, in one fell swoop, prevent all of those infections? As a bonus, what if it could also prevent itchy responses to mosquito bites and even knock back the bug’s populations? It sounds like a dream. But SEEK, a UK-based biotech company, and the US National Institutes of Health are hoping it could be a reality some day.

This week, the NIH announced the start of a Phase I clinical trial for a vaccine that’s designed to do all of that. It’s called AGS-v, and it has been in the works for nearly a decade. It takes an approach to disease blocking that scientists have danced around for decades but never pulled off—it targets the saliva of mosquitos instead of any individual germ.

The disease-specific vaccines have “proven to be very difficult,” Gregory Stoloff, CEO of SEEK, told Ars. Germs are complex, always changing, and new ones—like Zika—will continue to pop up. Instead, SEEK created a vaccine composed of four synthetic mosquito saliva proteins.

“What this approach does is it makes your immune system be on alert for recognizing the saliva of the mosquito,” he said. When it detects it, an immune response ensues that’s different from the one normally incited by a bite. This different response keeps the few, invading microbes from establishing an infection. “They die at the site,” Stoloff explained.

That’s the idea, at least. There are bits and pieces of data in the scientific literature to back it up. But so far, SEEK hasn’t published its data showing safety and efficacy of this particular vaccine—let alone more detailed molecular data to prove what’s going on. (With the boom of Zika outbreaks recently, the company fast-tracked the development.) They’ve tested it in mice, rats, and dogs, Stoloff says, and have seen promising results. But, however convincing that data may be, humans are different. And even if there is success in the Phase I trial—which is mostly focused on assessing safety—it would take years and years to make it through the next phases and show up in clinics.

Still, the idea is enticing. “A single vaccine capable of protecting against the scourge of mosquito-borne diseases is a novel concept that, if proven successful, would be a monumental public health advance,” said Dr. Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases, which is conducting the clinical trial.

The ticket to infection-ville

The idea of targeting mosquito saliva has been around for a while—here’s just one review from 2006 in Parasite Immunology in which researchers toss around the idea. There are dozens of proteins in mosquito saliva and a tiny cocktail of them—in less than a microliter of fluids—can get delivered into humans when a bug bites. We don’t know much about what they all do individually, as researchers discussed in a 2016 article in Current Opinion in Virology. But, it’s well established that our immune responses get manipulated by whatever’s in the saliva of mosquitos—as well as other biting insects, such as sand flies that transmit the parasite that causes leishmaniasis.

Generally, we know that saliva proteins stifle pain responses and prevent blood clotting—which helps a mosquito feed. We also know that saliva proteins tend to trigger an allergy-like response—that pink, itchy welt after a bite. And in many cases, researchers have found that saliva components can make germs more infectious.

For instance, in a study published in Immunity last June, researchers found that mosquito saliva helped Semliki Forest virus, SFV, (a relative of chikungunya) invade cells and establish infections in mice. The saliva stimulated a specific type of immune response that had immune cells, called macrophages, rushing to the site of the bite. Macrophages are normally like Pac-Men—they gobble pathogens and vacuum up cellular debris. But, in this case, the arriving macrophages were duped into showing up and becoming infected by the virus. The compromised macrophages then went on their way, carrying the virus off to other sites of the body where they could establish infection.

When mice were injected with SFV and mosquito saliva, they got sick and four of 11 died. Without the saliva, SFV-injected mice hardly got sick and none died. The same was true when researchers injected both SFV and saliva into mice without macrophages.

Missing the bus

Stoloff is convinced that with the right-sized cocktail of saliva proteins, we could train our immune systems to mount a different type of response to a biting mosquito. In this scenario, first-responder immune cells would come prepared to fight against microbes that want to invade them, plus kill off any virus or parasites that are freely floating around at the site of the bite.

“The microbes wouldn’t be able to hop a ride on the bus around the body and go to where they want to,” he said. And, “if they don’t jump into these immune cells, they die at the site… it’s quite a hostile environment.”

As a bonus, Stoloff says that the immune response won’t result in an itchy bump. And if the feeding mosquito sucks up some of the chemical warfare used in the new immune response, it could harm or even kill them.

Finding the right cocktail of saliva proteins might seem like a sticking point, since we don’t know what most of them do. But, Stoloff isn’t concerned. “You don’t need to necessarily know the function of each protein,” he explained. All that matters is if they trigger the right type of immune response.

So, he and his colleagues at SEEK fished through the proteins, testing them in groups based on the proteins’ weights. They focused in on a group of 15 proteins that weighed 20 to 40 kilodaltons. From there, they picked out four, which are commonly found in different types of mosquitos, Stoloff said.

Because harvesting spit from mosquitos isn’t a viable long-term strategy for vaccine production, the researchers created synthetic versions of the four proteins to create AGS-v. In animal tests, the vaccine candidate protected animals from malaria, dengue, and yellow fever. Usually, about 60 percent of control animals would get sick with a mosquite-borne infection while only 10 percent of vaccinated animals got sick—an 83 percent reduction—Stoloff said.

There is some precedent for such a vaccine to work. In 2009, researchers reported in PLOS Pathogens that an anti-saliva vaccine could help protect dogs from Leishmania parasites spread by sand fly bites. But, there’s also research showing that such a strategy could fail. In 2010, researchers reported in Infection and Immunity that mice immunized with whole mosquito saliva didn’t fare any better at warding off malaria than non-immunized mice.

Now, it’s up to the clinical trial to determine if AGS-v will pan out. The NIH is currently recruiting 60 healthy adults to get the vaccine and then suffer through some mosquito bites. Those mosquitos won’t be carrying any pathogens. Instead, researchers will draw the participants’ blood and see if it displays a modified immune response to the mosquitos’ saliva. The trial is expected to wrap up during the summer of 2018.