In October 2004, a fifteen-year-old Wisconsin girl named Jeanna Giese became the first known person to survive clinical rabies without receiving the vaccine before or after exposure. Her physicians at Children’s Hospital of Wisconsin placed her in a medically induced coma and administered a combination of antiviral and sedative drugs in what became known as the Milwaukee Protocol. The case made global headlines and ignited a fierce debate in infectious disease medicine that continues two decades later, because the protocol’s record since then has been far less encouraging than the original story suggested.
The Bat Bite That Started Everything
Jeanna Giese was bitten by a bat at her church in Fond du Lac, Wisconsin, in September 2004. Her family cleaned the small wound but did not seek medical treatment or post-exposure prophylaxis, the series of rabies vaccine injections and immunoglobulin that is virtually 100 percent effective when given promptly after a bite. About a month later, she developed tingling in her left hand, then progressive neurological symptoms including double vision, nausea, and difficulty walking. By the time she arrived at the hospital and rabies was confirmed, the virus had reached her brain. At that point, no established treatment existed. Rabies after the onset of symptoms had, with vanishingly rare exceptions, been a death sentence throughout human history.
Rodney Willoughby, a pediatric infectious disease specialist, proposed an untested idea: if the virus could be kept from causing fatal brain damage long enough for the patient’s own immune system to mount a response, she might survive. The plan was radical. No rabies vaccine was given, because Willoughby reasoned the immune system was already responding and adding vaccine at that stage could trigger a harmful inflammatory reaction. Instead, the team focused on buying time.
How Rabies Kills Without Destroying the Brain
Rabies is unusual among fatal infections. When pathologists examine the brains of people who have died from it, they find surprisingly little structural damage. Unlike many other forms of encephalitis, where inflammation shreds tissue, rabies leaves neurons largely intact. Research on both human and canine brains has shown minimal inflammation with preserved neuronal structure, suggesting that neuronal dysfunction rather than neuronal death drives the fatal outcome.1PubMed. Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains The same study found disrupted mitochondrial structure in infected brain cells, pointing to an energy crisis inside neurons as a key mechanism of damage.
The virus travels along peripheral nerves toward the brain at a rate of roughly 50 to 100 millimeters per day, which is why the incubation period between a bite and symptom onset can last weeks to months depending on how far the wound is from the head.2PubMed. Rabies virus infection and transport in human sensory dorsal root ganglia neurons Once it reaches the central nervous system, the virus alters the expression of hundreds of genes within neurons. Gene analysis of infected neurons has found changes in cell-to-cell signaling as well as decreased function in areas related to neurite growth, cytoskeleton organization, and microtubule dynamics.3PLoS Pathogens. Immune Clearance of Attenuated Rabies Virus Results in Neuronal Survival with Altered Gene Expression In plain terms, the virus does not so much kill brain cells as scramble their internal machinery, disrupting how they communicate and maintain themselves. This is what made Willoughby think survival might be possible: if the neurons were still alive, perhaps their function could be restored once the virus was cleared.
What the Protocol Actually Involved
The Milwaukee Protocol’s core strategy was to induce a deep coma using a combination of ketamine and midazolam, a benzodiazepine.4PubMed. Survival after treatment of rabies with induction of coma The reasoning was twofold. First, the coma would protect the brain from the excitotoxic damage that occurs when neurons fire uncontrollably during encephalitis. Second, ketamine has some antiviral properties against rabies in laboratory settings, making it more than just a sedative in this context. Alongside the sedation, Giese was given ribavirin, a broad-spectrum antiviral, and amantadine, a drug originally developed for influenza that also has activity against some neurological viruses.
The team then watched and waited for her immune system to respond. A lumbar puncture after eight days showed rising levels of rabies-neutralizing antibodies in her spinal fluid, a sign that her body was mounting a meaningful defense. Sedation was gradually tapered. Over the following weeks, Giese slowly regained consciousness. She spent months in rehabilitation, relearning how to walk, talk, and perform basic tasks. She eventually returned to school, graduated from college, and went on to have children. Her recovery, while incomplete in some respects, was remarkable by any measure for a disease that had killed essentially every symptomatic patient before her.
Cerebral Vasospasm and a Hidden Complication
One of the less discussed but critical aspects of managing clinical rabies is cerebral vasospasm, a dangerous constriction of blood vessels in the brain that can cause stroke-like damage. Both the Milwaukee Protocol and a Brazilian treatment protocol developed in Recife recognize this as a major complication and recommend daily monitoring with transcranial Doppler ultrasound.5Revista da Sociedade Brasileira de Medicina Tropical. Comparing clinical protocols for the treatment of human rabies: the Milwaukee protocol and the Brazilian protocol (Recife)
The vasospasm appears to be driven by a deficiency of tetrahydrobiopterin, a compound the brain needs to produce nitric oxide, which in turn relaxes blood vessels. Without enough of it, vessels in the brain clamp down. The Milwaukee Protocol addresses this with sapropterin starting around the fifth day of hospitalization, a period when vasospasm risk is highest. The Recife Protocol takes a slightly different approach, beginning biopterin as soon as rabies is suspected. These details matter because even if the virus itself does not kill neurons, a stroke caused by vasospasm certainly can, and managing cerebral blood flow has become a central challenge in any aggressive treatment attempt.
The Replication Record
After Giese’s survival, the Milwaukee Protocol was attempted on rabies patients around the world. The results were devastating. A 2025 review in Clinical Infectious Diseases documented at least 64 reported failures of the protocol.6PubMed Central. Demise of the Milwaukee Protocol for Rabies Patient after patient was placed into an induced coma, given the drug combination, and died anyway. The protocol’s details changed over time as Willoughby and others adjusted the approach, but the fundamental strategy of induced coma plus antivirals failed to produce consistent survival.
The occasional survivors who were treated with the protocol tended to share a revealing characteristic: most had received rabies vaccine before the onset of clinical symptoms, meaning their immune systems already had a head start. That complicates any claim that the protocol itself was responsible for their survival. Even more striking, the same review identified at least 34 rabies survivors who received critical care management without the main components of the Milwaukee Protocol, including many patients from India. These survivors were given intensive supportive care but not the induced coma or the specific drug regimen that defined the Milwaukee approach. Their existence raises an uncomfortable question: was the coma ever the key ingredient, or did survival come down to individual immune responses, viral strain, and aggressive supportive medicine?
The Strain Problem
One of the most persistent criticisms of the Milwaukee Protocol is that its successes, such as they are, cluster around a specific type of rabies virus. Giese was bitten by a bat, and bat rabies strains behave differently from the canine strains responsible for the overwhelming majority of rabies deaths worldwide. Early observations noted that while survivors treated with the protocol had been infected with bat-origin strains, none survived infection with canine strains, suggesting that canine strains are more virulent.7Current Infectious Disease Reports. Rabies: Still a Uniformly Fatal Disease? Historical Occurrence, Epidemiological Trends, and Paradigm Shifts
Laboratory work supports the idea that these are meaningfully different infections. Classic animal experiments showed that canine and bat rabies virus strains produce distinct disease patterns. Canine strains caused a more purely brain-centered encephalitis in mice and overt symptoms in bats, while bat strains produced a wider pattern involving the spinal cord as well and were less likely to cause obvious symptoms in bats themselves.8PubMed Central. Studies on the Pathogenesis of Rabies in Insectivorous Bats: II. Influence of Environmental Temperature More recent research found that in bat-acquired rabies, the initial exposure site is usually limited to the skin, the bite is more often on the face, and the virus may be more adapted for skin entry than dog-transmitted rabies, which could help explain differences in how the two forms progress clinically.9PubMed. Comparative pathogenesis of rabies in bats and carnivores, and implications for spillover to humans
This matters enormously for the protocol’s relevance. Roughly 99 percent of human rabies deaths occur in Africa and Asia and are caused by dog bites, not bat exposure. If the Milwaukee Protocol only works, to the limited extent it works at all, against bat-origin strains, its applicability to the global rabies burden is minimal. The people most likely to die of rabies are those least likely to benefit from this particular approach.
Abortive Rabies and Natural Immunity
Giese’s case was not quite as unprecedented as it first appeared. There is growing evidence that some people are exposed to rabies virus and survive without any medical intervention at all, a phenomenon sometimes called abortive rabies. In a study of communities in the Peruvian Amazon where vampire bat bites are common, rabies-neutralizing antibodies were detected in about 11 percent of people tested. Since the vast majority of those individuals reported bat bites but had never been vaccinated, the finding strongly suggests nonfatal exposure to the virus.10PubMed Central. Evidence of rabies virus exposure among humans in the Peruvian Amazon
Similar patterns appear in animals. A study of livestock in Peru found that about 7.5 percent of apparently healthy, unvaccinated cattle, goats, and sheep had rabies-neutralizing antibodies in their blood, and none of the seropositive animals died from rabies when followed up two years later.11PubMed Central. Abortive vampire bat rabies infections in Peruvian peridomestic livestock A broader review of the evidence concluded that while nonlethal rabies exposure clearly does occur in humans, domestic animals, and wildlife, many serology studies lack appropriate controls and cutoffs, making it difficult to pin down how common it truly is.12PLoS Neglected Tropical Diseases. Rabies virus-neutralising antibodies in healthy, unvaccinated individuals: What do they mean for rabies epidemiology?
The existence of abortive rabies complicates the Milwaukee Protocol story in an important way. If some fraction of exposed individuals naturally mount an immune response strong enough to clear the virus, then the rare survivors of clinical rabies might not owe their lives to any treatment at all. They might simply be the people whose immune systems happened to respond in time. Giese’s case, for all its drama, might reflect her own immune biology more than the drugs she was given.
What Survival Actually Looks Like
The word “survival” can be misleading in the context of rabies. Giese’s recovery, while genuinely impressive, involved extensive neurological rehabilitation and residual deficits. But she was the best-case scenario. A case series of rabies survivors from India found that, with one exception involving mild aftereffects, all survivors had poor functional outcomes.13PubMed Central. Survival from Rabies: Case Series from India Some remained in persistent vegetative states. Others could breathe independently but had severe cognitive impairment.
This pattern is consistent with what is known about the long-term consequences of viral encephalitis more broadly. Even after the viral infection resolves, the local immune response in the brain can remain active, contributing to lasting neurocognitive impairment, psychiatric symptoms, and degenerative changes.14PubMed Central. The Causes and Long-Term Consequences of Viral Encephalitis Rabies antibody levels in spinal fluid tend to rise substantially over the course of illness, with median antibody levels climbing from low values in the first week to much higher levels beyond two weeks of symptoms.15PubMed Central. Utility of rabies neutralizing antibody detection in cerebrospinal fluid and serum for ante-mortem diagnosis of human rabies Even when this immune response eventually clears the virus, the weeks of neuronal dysfunction that precede clearance can leave permanent damage. The brain may survive, but it does not come through unscathed.
For families and physicians facing a rabies diagnosis, the honest conversation involves not just whether a patient can be kept alive, but what kind of life might follow. The gap between biological survival and meaningful recovery is wide, and most patients who survive rabies fall on the wrong side of it.
Where Treatment Stands Now
Despite the attention the Milwaukee Protocol received, the current standard of care for clinical rabies is palliation, meaning comfort-focused end-of-life treatment rather than aggressive attempts at cure.16PubMed Central. Human Rabies Treatment-From Palliation to Promise This is not nihilism on the part of physicians. It reflects two decades of evidence that aggressive interventions, including the Milwaukee Protocol, have not reliably produced survival, and when they have, the functional outcomes are usually devastating. A 2025 review titled “Demise of the Milwaukee Protocol for Rabies” captures the current expert sentiment: the protocol has not lived up to its initial promise, and its continued use is no longer considered justified by the evidence.
Researchers continue to investigate new approaches, including monoclonal antibodies that might neutralize the virus more effectively, novel antivirals, and immunotherapy strategies designed to help the immune system clear virus from the central nervous system without causing collateral inflammatory damage. But these remain experimental. The real public health answer to rabies remains prevention: prompt wound care after animal bites and timely post-exposure prophylaxis, which is extremely effective when administered correctly. A systematic review of fatal breakthrough infections despite post-exposure prophylaxis found that in cases where people still died after receiving treatment, deviations from standard protocols were reported in over half of cases, and severe wounds involving the head or multiple bite sites were common.6PubMed Central. Demise of the Milwaukee Protocol for Rabies The vaccine works. The challenge is getting it to the roughly 59,000 people who die of rabies each year, mostly in low-resource settings where dog vaccination programs are inadequate and post-bite treatment is hard to access.
What Jeanna Giese’s Case Really Showed
Giese’s survival was not meaningless, even if the protocol built around it proved to be a dead end. Her case demonstrated that the rabies virus does not inevitably destroy the brain in a way that forecloses recovery. It showed that some patients, with some strains, under some conditions, can mount an immune response fast enough to clear the infection. And it generated useful data about the pathophysiology of clinical rabies, including the role of vasospasm, the kinetics of antibody production in the central nervous system, and the importance of mitochondrial dysfunction in infected neurons.
But the narrative that took hold in popular culture, that a brilliant doctor found a cure for rabies by putting a teenage girl into a coma, was always an oversimplification. The treatment may have helped, or it may have been incidental to an immune response that would have succeeded regardless. The dozens of patients who died under the same protocol suggest the latter is at least plausible. Giese herself has spoken publicly about her experience and recovery, and her story remains a powerful illustration of both the potential and the limits of experimental medicine when facing a disease that has defied treatment for millennia.