Every year, at the end of August, Travis Livieri drives into the sandy grasslands of South Dakota’s Conata Basin, where, armed with spotlights and syringes, he spends his nights scooping up subjects for a grand experiment they could not hope to understand. His quarry are the region’s black-footed ferrets, considered by many to be North America’s most endangered mammal. His goal is to save the animals from the existential bind that we have put them in.

Black-footed ferrets once dotted the sandy landscapes of a dozen western U.S. states, plus portions of southern Canada and northern Mexico. But decades of habitat destruction and culling of their prairie-dog prey have sent ferret populations plummeting. The greatest threat to their survival now is also one of our own making: plague, a bacterial scourge that Asian trading ships imported into the U.S. more than a century ago. To mitigate that human disturbance, Livieri, a Colorado-based wildlife biologist, has turned to another—a plague vaccine, developed for the military, that protects animals too. Just 200 black-footed ferrets, more than half of the world’s remaining population, are left in Conata Basin and the surrounding Badlands National Park. One by one, Livieri and his team aim to catch and immunize them all. “I’m like an alien-abduction machine,” Livieri told me.

People have been vaccinating domesticated animals for centuries, but only two reasons justify immunizing wildlife, says Tonie Rocke, a research scientist at the U.S. Geological Survey: “to prevent spillover to domestics and humans of a zoonotic disease, and for conservation purposes.” But although human vaccines function primarily as preventives, offering immunity to animals such as black-footed ferrets can be a conservation strategy of last resort. “The fact that we’re looking at vaccines now is almost a sign of desperation,” Jean Tsao, a disease ecologist at Michigan State University, told me. In some cases, it’s even a signal that nearly all other measures have failed.

Just a couple of decades ago, conservation dogma urged minimal interference. “We barely wanted to remove animals from snares,” Sharon Deem, the director of the Saint Louis Zoo Institute for Conservation Medicine, told me. But humans have stamped their footprint onto so many parts of this planet that many species now depend on our ability to undo, or at least mitigate, the damages we’ve done. “The understanding is that humans have had so many negative impacts on these wildlife populations,” Deem said, “that we should also have positive impacts.”

Vaccines can certainly count as one such positive impact. But introducing them into wild species also raises new ethical quandaries about which animals deserve that immunity, against which diseases, and what risks those creatures should have to tolerate. Human interference, even the well-intentioned sort, is “a slippery slope to try to go down,” Livieri told me. Vaccines, however lifesaving, still constitute a form of ecological meddling—one without a clear off-ramp.

The first animals to be vaccinated for their own sake, about a century after the first humans were, were chickens (against cholera), and then cattle and sheep (against anthrax)—for diseases that, when they infiltrated farms, put livelihoods at risk. Nowadays, humans vaccinate all sorts of pets, livestock, zoo animals, and wildlife as a matter of course. How thoroughly depends on how close those creatures are to us.

You can think about this approach as vaccinating in concentric circles, with humans in the center. In the innermost rings are the creatures “with which we are interdependent,” Jen Brown, the president of National Association of State Public Health Veterinarians, told me. Owned dogs and cats receive a core roster of shots that guard against, among other things, canine parvovirus and distemper; the animals we raise on farms generally receive just as many vaccines, if not more. By protecting these animals against disease, vaccines benefit people too. They extend our companions’ lives over those of their free-roaming counterparts; they run necessary interference for farm animals in conditions that are often unsanitary and cramped. Without vaccination, the poultry industry “wouldn’t last for more than a month or so,” says Shayan Sharif, a poultry immunologist at the University of Guelph, in Canada.

At zoos, the calculus is more complicated. By design, the animals are neither domesticated nor fully wild. Still, by sequestering them, Brown said, “we assume responsibility for their care.” Don Neiffer, the chief veterinarian at the Smithsonian’s National Zoo, estimates that “99 percent of the mammals at most zoos, including ours, are vaccinated against something.” (Great apes, for instance, get the same sorts of measles, polio, and tetanus shots that people give to their kids.) The interventions work. A huge part of the reason that the field of geriatric veterinary medicine exists “is because of vaccines,” Neiffer told me.

In the outer rings of the vaccination bull’s-eye are wild animals—“sort of the last frontier for vaccines,” says Jennifer McQuiston, the acting director of the CDC’s Division of High-Consequence Pathogens and Pathology. Here, delivering human-made immunity is much trickier, and harder to justify, for the same reason: These creatures rarely interact with us. A relatively straightforward case can be made for vaccinating wild populations that share some of our diseases, and that do occasionally mingle with us and the domestic creatures we keep. The poster child in that category is rabies, a virus that can infect just about every mammal, and that is almost invariably fatal to us. And so vaccines against this virus permeate every ring, starting with the tightest ones. To prevent human rabies at the population level, “the single most effective intervention,” Brown told me, is making sure that the majority of dogs in a community have gotten their shots. Nationwide campaigns to do exactly that, starting in the 1940s, helped the United States eliminate the canine variant of the virus in 2007. Rabies among dogs, caused by any strain, is now exceedingly rare. Most parts of the country also require owners to vaccinate pet cats, and some loop various livestock into the legislation as well; many zoo mammals also get a version of the vaccine.

To break even more transmission chains, scientists have concocted bespoke rabies vaccines for coyotes, foxes, raccoons, and other wild species that sometimes venture into our realm. Out in nature, “the delivery system has to really match the ecology of the animal,” Tsao, of Michigan State University, told me. In North America, edible forms of the vaccine, flavored with fish or vanilla, fed to land-roving omnivores, have controlled the virus in raccoons, and helped to halt its westward spread; to keep rabies out of super-social bats, researchers are exploring whether immunizing ointments can be slathered onto a few individuals, then groomed off by the rest.

[Read: America has a rabid-raccoon problem]

For every new animal that might need the vaccine, though, scientists must figure out new logistics—maybe even a new recipe. And these sorts of trials are not exactly easy to run in wild settings, which makes it tough to determine how many animals an immunization needs to reach, says Sergio Recuenco, an epidemiologist at the National University of San Marcos, in Peru. Rabies is both an exemplar and an extreme edge case—a disease so widespread and so dangerous to us that the researchers think casting a wide immunity net is worthwhile. Much harder to imagine, experts told me, is pouring the same level of resources into vaccinating animals for a disease that poses them the most risk.

That’s exactly the scenario that avian influenza has presented as a particularly virulent strain has torn across North America. Since the epidemic began in 2021, close to 60 million farmed poultry have died, killed by both the virus and farmers trying to stem its spread; an untold number of wild birds, too, have been felled—geese dropping out of the sky, hawks seizing and spasming as the fallout from the disease reached their muscles and brain. A few outbreaks have been detected in mammals, including mink and seals. And the more the virus spreads, the more chances it has to find a way of more efficiently infecting us. But in the main, the risk to humans remains relatively low: This is, primarily, a tragedy for birds.

To let it play out unrestrained would, on some level, just allow nature to take its course. Viruses are constantly infecting and killing animals; they help keep wild populations in check and ecosystems in balance. But when birds are already battling pollution, habitat destruction, feral-cat predation, and other human-driven perils, the bird-flu epidemic might “be the last nail in the coffin for some species,” Min Huang, who leads the migratory-bird program at Connecticut’s Department of Energy and Environmental Protection, recently told me.

[Read: Eagles are falling, bears are going blind]

Vaccination, to be clear, wouldn’t be enough to halt this outbreak on its own. The virus has already spread to too many regions and too many hosts; reaching all of the susceptible birds would be “an insurmountable task,” Sharif told me. Nor do we have the tools to manage such a feat. Avian vaccines, okayed for use on poultry farms, do exist. But although they can tamp down disease severity, they’re not powerful enough to stop the virus from spreading, even in the species they were designed for. Their performance would probably be spottier still in many of the wild birds suffering the virus’s worst effects.

Some experts have floated the notion of vaccinating a subset of especially vulnerable species: bald eagles, California condors, a whole list of imperiled shoreline birds. When vaccine supply is limited, though, as it so often is, choosing to vaccinate one species can become an implicit decision to not vaccinate another—raising questions about “who gets to say what species should exist in this landscape, and at what level,” Livieri told me. “As humans, we’re already doing that,” directly or indirectly. But wildlife vaccination is especially uncharted conservation territory. There’s no rulebook to follow, and no way to predict the ripple effects of immunizing one species and snubbing the next.

Vaccinating animals just for the sake of vaccinating animals “is not feasible, logical, or even recommended,” says Barbara Wolfe, a veterinarian at Colorado State University. The process isn’t without risk. Simply capturing, containing, and injecting wild creatures can potentially be “more risky than the chance of them actually getting the disease and dying,” Neiffer told me. And though plenty of attempts have been made to make vaccines less invasive—repackaging them into mists, sprays, or even long-range dart guns—that sort of tinkering can yield unacceptable trade-offs with effectiveness or expense. And rare but serious issues with safety can crop up. In 1971, scientists hoping to rescue the dwindling black-footed ferret population—then down to the double digits—captured six of the last animals in the wild and injected them with a distemper vaccine. The shot was known to be safe in other ferret species. But within three weeks, it had killed four of the black-footed ones. In their attempt to save the ferrets, the researchers had inadvertently worsened their plight.

A new vaccine, in a new context—as is the case with any health intervention—always involves at least a small gamble that it will help more than harm. But as the planet’s biodiversity has sustained blow after blow, scientists have had few choices but to step in and take their chances, including with vaccines. “For conservation purposes, we’re being forced into it,” Rocke, of USGS, told me, “or we’re going to lose some species.” In Australia, scientists are now giving endangered koalas chlamydia vaccines; in Chile, researchers such as Ezequiel Hidalgo, a conservation biologist at Chile’s Buin Zoo, are inoculating local dogs against distemper so they won’t spread the virus to, and wipe out, the near-extinct Darwin’s fox. And in Africa, conservations are serving the Ethiopian wolf, the continent’s most endangered carnivore, goat laced with rabies vaccine, while simultaneously immunizing nearby village dogs against the virus to stymie interspecies spread.

Under more natural circumstances, animals might have—over many generations, and repeated rounds of evolution—built up such layers of immunity on their own. Vaccines are a shortcut to a similar end. But they’re also a form of acceptance that outbreaks of foreign disease have become inevitable. Pathogens, too, are leapfrogging intermediate steps: They can hitch rides on people and animals who can now traverse oceans and mountains in just hours or days. Amid all this disturbance, so traceable to our actions, immunity would seem the least we can offer animals—a reparation of sorts. We just have to decide, Wolfe told me, “how invasive we want to be.”

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Still, when the infectious introductions are this sudden, even vaccines, administered after the fact, can only do so much for species already on extinction’s brink. Even for North America’s black-footed ferrets—already probably one of the most highly vaccinated species on Earth—ultra-high shot uptake can’t hold the line on its own. When plague sweeps through their habitat, it doesn’t just kill the ferrets; it’s also highly lethal for prairie dogs, their primary prey and the architects of the underground burrows where the ferrets shelter and breed. The ferrets that escape plague sometimes starve to death instead.

So now some prairie dogs are getting plague vaccines too. In several western states, researchers such as Dan Tripp, with Colorado’s Parks and Wildlife division, have been trialing an edible inoculation that regularly gets scattered around the animals’ underground homes. Uptake is good: The vaccines are peanut-butter flavored, and “everybody likes peanut butter,” Tripp told me. But against transmission, especially, efficacy is imperfect. And the prairie dogs breed so quickly and frequently that it’s tough to pulse enough immunity into the population each year. If the goal is to save the ferrets, the armor around them has to be almost impenetrable. Even a single infected prairie dog can create an opening for the bacterium to once again wriggle through.

The ferret’s immunological armor may also need to be permanent. For humans, vaccines generally stay in use until a disease is eradicated, and plague, swift, insidious, and deadly, is not going anywhere anytime soon. In 2008, the first time plague tore through South Dakota, the outbreak had already taken out 3,000 acres of prairie-dog colony before scientists confirmed the first infected corpse. “Nobody’s come and quite said it, but yes,” Livieri told me, “we’re going to have to keep vaccinating ferrets” effectively indefinitely. Barring a windfall of innovation, on the order of genetically engineering a plague-resistant ferret, the “standard going forward,” he said, will have to keep involving annual rounds of snaring, anesthetizing, and injecting—twice each season, so ferrets can get a priming vaccine dose, and then a boost. Which potentially puts us and the animals into a painful plague stalemate. The goal has always been to grow the ferret population. But the more it balloons, the harder it will be to thoroughly immunize.

Plague vaccines aren’t the only strategy in the ferret-conservation playbook. Frequent application of insecticides has cleared some habitats of plague-carrying fleas; captive breeding programs plus regular infusions of a (new and very safe) distemper vaccine have also helped keep the population afloat. All of these efforts, though, cost money. And when it comes to allocating funds for wild-animal outbreaks, humans will naturally focus on vaccinating against the diseases that most often threaten to spill into us: rabies in raccoons; MERS in camels; Lyme disease in mice. For other creatures, our concern has always scaled more with charisma than need. Black-footed ferrets—compelling, charismatic, and cute—are “pretty lucky,” Livieri told me, and efforts to conserve them have rallied both federal and public support. But most endangered species just “don’t have people paying for them,” Hidalgo told me.

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Commitments to vaccinate can also rapidly wane. At the height of the coronavirus pandemic, researchers scrambled to get veterinary versions of the COVID vaccine into the big cats, great apes, and small carnivores in zoos. Now, though, experts such as Neiffer, of the Smithsonian, worry that the shots aren’t profitable enough to stay in circulation—leaving certain zoo animals vulnerable when and if the virus hits again. A spokesperson from Zoetis, a global animal-health company that has donated more than 26,000 doses of its experimental COVID vaccine to zoos and conservatories since 2021, confirmed that although a limited number of additional doses remain available for further donation, the immunization is “is not available commercially” and “at this time we are not planning to manufacture more doses.”

With COVID-19, at least, black-footed ferrets caught a break: Despite devastating mink, the virus seems to be gentle on their ultra-endangered cousins in the west. But other threats still loom—tick-borne tularemia, a medley of bird- and human-borne flus. “They have a suite of things that can whack ’em, and whack ’em hard,” Livieri told me, and in most cases, the biggest threat remains us. The species’ fate is now lashed to ours—to our compassion, our tolerance, our patience for their plight. Even if all those hold out, Livieri told me, he’s not sure how much more interference the ferrets can handle, even the positive kind. “We’re already giving them two shots at the same time,” he said. “Will we have to add in any more? God, I hope not.”

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