How do we know that mild forms of rabies are nonexistent?

Question

Wikipedia's rabies article says: "Death usually occurs 2 to 10 days after first symptoms. Survival is almost unknown once symptoms have presented, even with the administration of proper and intensive care."

I am wondering why we exclude the possibility of bite victims developing a mild form of rabies, in the same way that influenza can be mild or asymptomatic depending on the individual and the season. I noticed that rabies vaccines use an inactivated (killed) virus, while influenza vaccines can be attenuated, for example cold-adapted, so that a live virus may be used causing minimal symptoms. Clearly, for these vaccines to work, influenza infection must be able to proceed without symptoms. Similarly, the bubonic plague bacillus Yersinia pestis is endemic in many regions and presumably spread through asymptomatic carriers. Rabies vaccines are made from viruses whose infectivity upon intracranial injection is titrated according to a method of serial dilutions, suggesting that a harmless live vaccine would also be feasible at some level of dilution (barring, perhaps, the infeasibility of intracranial administration of such a vaccine).

What evidence do we have to suggest that rabies is different from influenza or plague, i.e. that it is not possible to have an infectious case of rabies with no or with mild symptoms?

Answer 1

There are many people worldwide who are exposed to rabies and don't die (they get treatment), but there are very few of these cases where people don't die after rabies has entered the central nervous system, and even fewer who didn't receive post exposure prophylaxis before the virus reached the central nervous system. Rabies isn't as rare as many would like to believe, unfortunately, with approximately 15 million exposures and 59,000 deaths a year, so data is available.

"Once symptoms have presented" in the Wikipedia article should probably be edited to "once central nervous system symptoms have presented". As discussed in this review rabies entry to the central nervous system is typically the "point of no return". One of the main challenges of rabies is that the virus hides from the immune system inside cells, making its way from muscle to peripheral nerves to the central nervous system before the immune system can mount a response. Once in the central nervous system, it has special protection from immune surveillance. The goal of post exposure prophylaxis is to allow the body to generate an immune response clear the virus before it gets to the central nervous system.

Generally, we say that central nervous system rabies is almost uniformly fatal without treatment because that is what has been observed and reported. *I'm not aware of any published epidemiologic survey looking for anti rabies antibody in healthy non-immunized adults. I know it's not very satisfying, but I would strongly suspect that someone has done a seroepidemiologic study and not published these results, since they're exactly what physicians have been taught since before Hippocrates: a dog bite followed by the characteristic illness leads (almost inevitably) to death. Other illnesses, on the other hand are observed to produce an antibody response in individuals' with mild disease. It is possible that there are unknown cases of mild non-encephalitic rabies that are self limited, but given the 150 years of intense study, I don't think it is likely there is a major aspect of the disease's natural history that hasn't been observed and reported.

Re: your idea about dilution of the vaccine suggesting you could dilute the virus, I think you may have a misconception about what that method actually involves. A killed virus vaccine cannot replicate, and so cannot cause rabies (though some forms of rabies vaccines used in the developing world have fairly high rates of nasty side effects).

Pasteur's risky rabies vaccine trial in 1885 may have involved a live vaccine, but he was notorious for incomplete documentation on his methods. It was essentially, a specimen of air dried rabbit spinal cord that didn't cause rabies in dogs. Here, his method was reported as drying spinal cord segments for longer and longer periods of time until the specimen did not produce rabies in dogs. This isn't a method that "dilutes the virus", but rather a method that attenuates the virus, making it less virulent. Pasteur didn't have methods for detecting what exactly that meant, other than that it didn't cause rabies, but did prevent the animal (or human child) from developing rabies after exposure to a virulent sample.

You can read more about rabies in Murray Medical Microbiology, Ch. 60

*Please see the link in @iayork's comment for a very interesting example of rabies serology in members of two communities in the Peruvian Amazon.

Answer 2

Exposure events are very clear in the case of rabies. Unlike the flu, that one may catch without even knowing how or when, individuals at risk of developing rabies are usually clearly identified (for instance, people bitten by wild animals) and as a consequence they are carefully monitored. If they were to occasionally develop mild symptoms like fever, these would not go unnoticed.

In addition, it is very easy to take biological samples from these patients and check for the presence of virus using sensitive detection techniques; it turns out that no case of asymptomatic infection was ever documented, and at this stage it is reasonable to assume that if it had a signifiant risk of happening, we would have seen it by now.