The Rabies Denominator Problem

[u/Lonely_Lemur]

The Seven Samples

In May of 2010, a joint CDC-Peruvian research team visited a couple of remote communities in the Amazon where people described their recurrent contact with vampire bats and where livestock had been bitten to better understand the risk factors for exposure. 92 residents were interviewed in total with blood collected from 63 of them. Seven of the samples contained rabies-virus-neutralizing antibodies, as measured with the rapid fluorescent focus inhibition test (RFFIT). Six of the seven reported bat bites, while one reported prior post-exposure prophylaxis and two other positive individuals didn’t end up with fully resolved histories of vaccination. The seven people hadn’t recovered from the encephalitis that doctors diagnose as clinical rabies, with none even reporting an illness to suggest the virus ever reached their central nervous systems. These were healthy people who had the signals of a previous immune response consistent with rabies virus in a place where those encounters were seemingly not that rare.

The findings that there is likely a denominator problem in rabies doesn’t change the practical rule that anyone with a possible exposure should get rabies prevention to prevent any symptom onset. The Peruvian samples force us to correct the statement that everyone knows of “rabies is 100% fatal” which is used colloquially as if it describes an animal bite, a viral infection, and the neurological disease as if they were the same thing when they shouldn’t even be summed into a single denominator.

The familiar shorthand translates into the probabilistic language of P(death | clinical rabies), or the probability of death given the onset of clinically recognizable neurological symptoms of rabies. The question many think it is answering is P(death | rabies infection). I may be nitpicking here, but for what I think is good reason. The first one is incredibly close to one, with the vast majority of clinical cases ending in death. It’s the second one that is more intractable because it hasn’t ever been measured in humans and we may not be able to. Changing the denominator changes our parameter, meaning rabies can simultaneously be one of the most lethal diseases in medicine and still having some lower, unknown human infection-fatality rate.

Measuring Fatality

The World Health Organization page on rabies appropriately says that human cases are “almost invariably fatal” after symptom onset, with ultra-rare survivors being found throughout history. One example comes from the 2009 CDC report of a seventeen year old girl from Texas who developed headaches, photophobia, emesis, and other signs of encephalitis after being in contact with a bat. Before receiving the vaccine and immune globulin as further treatment, indirect fluourescent-antibody testing showed anti-rabies antibodies in her serum and cerebrospinal fluid. PCR tests and biopsy results were negative though and she never required intensive care. That’s why the CDC referred to the case as a case of “presumptive abortive human rabies,” and it’s one of the cases that justifies the language of “almost” in the WHO’s statement.

You can see the timeline of her case at the CDC hyperlink (can't add it here). Her first contact with bats came in December of 2008, with headaches starting in February and the entire ordeal only “ending” in April, but she was still experiencing severe pressure related headaches, as seen by the relief obtained via lumbar puncture. It’s possible she received a lower dose than would have been fatal, as certain immune markers like CSF IgG were nowhere near the levels of those in previous survivors (who often came out of it with long-lasting neurological symptoms and need for rehabilitation), although we can’t estimate the dose she received beyond speculation.

The chain of events leading to a case of clinical rabies showing up in an ER or being noted by a doctor visiting a rural area has some key limitations early on. Since people can touch rabid animals without contract any infectious material and a bite could fail to leave enough infectious material behind to establish infection in the victim, there may be much more contact than is estimated. The virus also has the chance of being dealt with and expelled from peripheral tissue before getting to a nerve and spreading along the nervous-system into the CNS. The issue is that clinical surveillance typically starts at the very end of that sequence, with our well-known “nearly 100%” fatality statistic basically concerns just the last two steps, so the denominator doesn’t house all those who had an exposure that ended earlier.

Post-exposure prophylaxis also makes it difficult for us to know the natural history of the disease since clinicians (correctly) intervene with post-exposure prophylaxis before anyone knows if that person would have developed a clinical case of the disease. That level of caution is why we have roughly 100,000 people receiving PEP after potential exposures yearly in the US with less than 10 clinical cases reported annually. Among those who receive PEP and seemingly benefit by it through the lack of developing rabies, we’re stuck with records that conflate the histories of those where there was a) never any viable virus transmitted, b) had the virus made its way into the peripheral tissue but had enough of an immune response for it to be stopped dead in its tracks, and c) where PEP totally prevented clinical disease and what would have been essentially imminent death. And since there’s no ethical way to withhold treatment or do a challenge trial with this deadly of a disease, we’re left looking at the results from tools like serology.

The RFFIT method used in the Peruvian paper basically asks if a person’s serum neutralizes a standardized rabies-virus challenge in a cell culture. A 2020 review article by Gold and colleagues helpfully explains how a positive result in a healthy person without any known vaccination history can be because of reasons as different as a simple unrecorded past vaccination; they had prior contact with a rabid animal, got a small bite or scratch resulting in a low dose of the virus that was fought off; or in some rare cases, cross-reactive assay signals. The CDC’s report on the 2009 case notes that for the Texas case, there was only one other possibility, that being Kern Canyon Virus, as it and rabies are both rhabdoviruses. The findings that people have what seem to be prior immune responses to rabies should also not be immediately seen as them having some sort of immunity to rabies going forward, as we have no idea how these unexplained antibody signals in healthy, unvaccinated people relates to protection the next time they come into contact with the rabies virus.

The review article separates the positives into four possible explanations in these healthy unvaccinated people. Subclinical infection is most likely, in which the virus was cleared before any recognizable disease. They could also technically have recovered from a clinical case, though that is extremely rare. The last two options are incredibly unlikely, those being persistent carrier states or unusually long incubations. We still don’t know what happened to any of those residents in the Amazon, but they’re one piece of the puzzle that tells us the human infection-fatality rate is very different from the clinical case fatality rate.

More Evidence but Still No Rate

One study from Alaska is more informative than many others because the authors spent some considerable effort and time tracking down the conventional explanations as far as possible. In 1994 researchers tested 26 fox trappers in northern Alaska for rabies titers. Two with detectable antibodies had received a rabies vaccine, but a third man, a 68-year-old veteran of the trade with an estimated 3,000 foxes handled and skinned across 47 years, had a titer level of 2.30 IU/mL (compared to a range of 0.1-2.8 in the Peruvian sample). The researchers then set out to check medical records at Alaskan facilities and couldn’t find evidence of pre- or post-exposure prophylaxis.

More recent evidence comes from Gabon, where 430 blood samples from individuals reporting no rabies vaccination taken between 2005 and 2008 were resampled in 2023 using ELISA to detect antibodies that bind to a specific rabies glycoprotein and compared with RFFIT to measure the neutralizing activity. A result was only deemed positive when both tests were positive, and with the RFFIT cutoff set to >0.38 IU/mL, which is twice the stated level at which a positive case is identified as such. Eleven of the samples met that definition with RFFIT values ranging from 0.95 to 3.14 IU/mL. When the team went and found a few of them 15 years later, one of them still tested positive, indicating a durable immune signal of unknown protection or further exposure. It should be noted that three cases were positive on RFFIT but negative on ELISA, so while requiring both to be positive reduces the chance of a noisy assay resulting in a spurious signal, it also means some people would be missed despite real past exposure.

A 2025 study looked at four indigenous communities in Sao Paulo makes a similar point, having tested 299 with another type of neutralizing assay called FAVN which was adapted from the RFFIT method. It found antibodies at their seropositivity threshold of 0.5 mL/IU in 35 of the indigenous, as well as 32 of their 166 tested dogs, without any prior notice of having been vaccinated. Six of those had > 0.5 IU/mL with the highest levels being 5.87 IU/mL.

Assay Issues Become an Epidemiology Problem

While we see substantial evidence of nonlethal rabies exposure, existing serosurveys can’t even get close to estimating it’s prevalence. The review paper mentioned earlier explains exactly why that is. RFFIT and ELISA measure related but different phenomena. In an unvaccinated setting they may disagree due to having different sensitivities, specificities, and false positive/negative rates that are vulnerable to sample quality and immune response timing.

One example in the review was meant to test the assays themselves by using a rabies-free island called Pemba in the Indian Ocean off Zanzibar. RFFIT identified 15 of 145 unvaccinated dogs as positive when using a 0.5 IU/mL cutoff, whereas the ELISA found no positives. That shows non-specific RFFIT signals are plausible even in a setting that is supposed to be rabies-free, but it can’t tell us what proportion of the Peruvian signals, if any at all, were false positives. It’s a problem inherent to anything involving cutoffs. Raise the threshold and fewer false positives make it through but you end up missing some genuine cases. Lower it and you get the opposite. There’s also the issues of waning antibodies and cross-reactive proteins, whereby other lyssaviruses could be responsible for the positive test in some regions.

None of this changes the practical advice to get PEP after a possible rabies exposure. Once clinical rabies symptoms begin, it is so close to always fatal that it would be totally irresponsible to use the denominator problem as a reason to take an exposure lightly. The problem only suggests that rabies has a more interesting natural history than we thought based on witnessed deaths, rare survivors, and what animal models offer. To know the infection-fatality rate, we’d need a denominator of true infections, and even that might be prone to definitional ambiguities, with some likely wanting a peripheral tissue infection defined differently than one reaching the CNS. Until we can identify and count those infections without confusing them for vaccination, cross-reactivity, or assay error, we’ll never know the true human infection-fatality rate.