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Brad Immel
C7 Research Paper
Dr. LeFebvre and Master Dockter
27 July 2015
Rabies: Clinical and Experimental Treatments 1885-2005
Rabies is a globally spread zoonotic infectious disease that is most commonly spread
through saliva from animals to humans. Any suspected exposure, such as an animal bite
from a common vector, warrants immediate treatment of the infected area. The most
common treatments for the rabies virus include a weakened strain rabies vaccine and
human rabies immunoglobulin, while some modern treatments have required more
drastic measures, such as chemically induced coma. The most important part of any
rabies treatment is that it is administered early to stop the progression of the virus and
prevent dangerous procedures such as induced coma.
Rabies – caused by the lyssaviruses rabies and Australian bat lyssavirus – is a deadly
virus spread through saliva. Common vectors of transmission include dogs, bats, and other wild
animals such as raccoons and skunks, which spread the disease through bites and scratches.
Rabies is zoonotic, so it can be spread from animals to humans, posing an especially large threat
in third-world countries where rabid dogs run wild. The Rabies virus can cause inflammation of
the Central Nervous System (CNS), damaging the brain and almost certainly resulting in death.
Rabies symptoms can take two forms: paralytic, in which muscle paralysis and coma kill the
carrier, and furious, which alter the behavior of its subject, leading to the classic signs of
aggression and foaming along with other symptoms such as hydrophobia. Because of its
variation and its tendency towards poor countries, rabies is hard to diagnose and its deaths are
extremely underreported. However, in countries such as the United States, very specific
procedures are laid out following any animal bite, ranging from washing with soap and water to
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direct antibody injection. Furthermore, wealthy countries provide preventative measures such as
vaccines. Unfortunately, by the time symptoms appear, the patient is often on the border of
death, calling for more drastic measures such as the Milwaukee Protocol. Many treatments for
rabies have been attempted; many worked and some failed. This paper serves to explain the
origin and nature of each of these “cures,” including how they worked and when they were
intended to be used, ranging from the first vaccine ever created to the one of the most drastic and
experimental procedures ever attempted.
1. Pre-Exposure
The first step in the prevention of any disease is vaccination; rabies vaccines are
administered to most pets to stop the spread of the disease. The first vaccine was developed in
1885 by Louis Pasteur by exposing the virus to dry air to create a weaker strain. To cultivate a
source of consistently virulent virus, Pasteur inoculated rabbits with a strain of rabies extracted
from a rabid street dog (Rappuoli par. 3). Once the virus was confirmed to be consistently
virulent, he took spinal cord sections from the rabbits and exposed them to dry air (par. 3). This
exposure weakened the virus until its virulence disappeared and all that remained were the rabies
antigens (par. 3). Testing his new vaccine on dogs, Pasteur discovered that those dogs inoculated
with his new weakened form of the virus became immune to the disease (par. 4). Hearing of this,
a family arrived with a young boy – Joseph Meister – who had been bitten over thirteen times by
a rabid dog two days earlier, arrived to ask for help (par. 4). Applying his knowledge from
testing on the dogs, Pasteur and his colleagues injected the boy with pieces of spinal cord
material that had been dried for increasingly shorter amounts of time, starting at fifteen days and
ending with one day (par. 5, 6). Joseph survived the treatment despite his extreme exposure,
setting the precedent of administering vaccine after possible exposure. Rabbit testing had shown
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that the spinal cord segments that had been exposed to air for nine or more days were not
dangerously virulent, whereas the material used on the last day was fully virulent, meaning that
Meister had survived both the dog bites and direct exposure to the fully virulent virus. (par. 7).
Since then, a new vaccine has been developed using human diploid cells. “The virus is
harvested from infected human diploid cells, MRC-5 strain, concentrated by ultrafiltration and is
inactivated by beta propiolactone,” (Food and Drug Administration 1). It is applied through
intramuscular injection (1). This approach, aided by modern technology, is much simpler, using
beta propiolactone rather than air dried spinal material. Because of this, it has replaced Pasteur’s
method in many areas, (although it is important to note that his was very effective, but not as
efficient,) while in other places the ancient method is used because it is cheaper. In addition to
the human diploid cell vaccine (HDCV), purified chick embryo vaccines and purified Vero cell
rabies vaccines are available. These are often preferred for their lower prices compared to
HDCV.
While these vaccines are effective and useful, not everyone needs them. Vaccines are
administered to most dogs and cats, but are only given to those humans who are considered
“high risk” for rabies exposure based on their jobs or activities. The FDA says that people
working as veterinarians or animal handlers and people traveling to certain countries where
rabies is prevalent should have the vaccine administered to them (6).
The importance of the human rabies vaccine is not that it prevents the disease entirely but
that it assists in curing the disease. After exposure, patients will require medical help regardless,
but those with the vaccine will require less doses of post-exposure vaccine, and will not require
the Rabies Immune Globulin (RIG) (FDA 7). This is particularly crucial for travelers to places
where medical attention is hard to find or poor in quality.
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2. Post-Exposure
Exposure to the rabies virus can fall into one of three categories; each level of exposure
calls for different measures. Furthermore, a person’s history – including whether or not they have
previously had the vaccine – may affect a doctor’s approach in treatment. The rabies virus is
most commonly spread through animal bites, but can travel in saliva through any open wound,
such as a scratch, or any mucous membrane, such as the eyes. The most common treatments
include washing the infected area and administering rabies vaccine.
Category I exposure includes having a suspected rabid animal lick your skin, but not an
open wound. The procedure following this is simply to wash the area with soap and water; this is
mostly to prevent further exposure such as the patient touching a mucous membrane and
inoculating the disease. There is no immediate danger from this and the vaccine does not need to
be administered.
Category II exposure is much more serious; it includes “nibbling of uncovered skin,
minor scratches or abrasions without bleeding,” (World Health Organization, “Rabies). This sort
of contact is almost sure to transmit rabies; the treatment consists of local cleaning with soap and
water and vaccine administration. Category III is similar to Category II: it is described as
multiple bites and/or direct salivary contact with the mucous membranes and requires both rabies
vaccine and Rabies Immune Globulin – unless the patient has had a previous vaccination, in
which case the RIG should not be administered. (WHO, “Rabies”)
The rabies vaccine, unlike many other vaccines, is not only used before exposure, but
also after exposure, as seen in Meister’s case. It works by exposing the immune system to nonvirulent antibodies in order to mount an immune response, allowing the body to protect from
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infection. Unfortunately, while these vaccines are very effective, they are not perfect. In one
case, a 74 year old woman was traveling in a country where rabies was widespread. Here she
was exposed to possible rabies by a monkey bite, and she had an ineffective response to the
vaccine treatment (Kopel et al. 1). The vaccine was administered according to standard
procedures, but tests showed that her antibody levels were below the WHO recommended
amount (Kopel et al. 1). This faulty immune response was due to her immunocompromised state;
she died of nosocomial sepsis, likely induced by her weak immune system. (Kopel et al. 1). This
was not an exclusive case; Kopel and his colleagues researched further and found 15 cases of
immunocompromised patients receiving the rabies vaccine. Many of these patients had AIDS or
HIV, others had problems such as lymphoma or kidney transplants. According to the reports, 7
of the 15 patients did not reach the WHO cut-off for antibody levels at any point in the process.
(1, 2).
The RIG works alongside the vaccine to boost patients’ antibody levels. The vaccine’s
purpose is to make the immune system form its own antibodies, whereas the immunoglobulin –
only administered in emergencies – directly boosts a patient’s antibody levels. Patients
previously having the rabies vaccine already have antibodies; thus, they do not need RIG
injection. There are two types of Rabies Immune Globulin: Equine (ERIG) and Human (ERIG).
Because HRIG is extremely expensive and hard to acquire in poor countries (where rabies is
most prevalent), ERIG is commonly used instead.
3. The Milwaukee Protocol
The rabies vaccine and RIG are very effective in fighting the rabies virus in most cases,
but they are only useful if inoculated soon after suspected exposure. One problem facing this
concept is that many patients may not realize they have rabies until it is too late. The virus
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typically has an incubation period of three to eight weeks. This means that clinical signs may not
show up until the disease has been working for up to two months. One case of this took place in
Wisconsin in 2005, where a 15-year-old girl was treated with an experimental new method of
treatment called ‘The Milwaukee Protocol.’ This treatment is described in a case report by Dr.
Rodney E. Willoughby, Jr. and his colleagues, the doctors who performed the treatment. Jeanna
Giese had rescued a bat that had flown into her window; while freeing it, she suffered a small
bite (par. 1). Her family treated it with hydrogen peroxide and decided not to seek further
treatment (par. 1). Because of its relatively long incubation period, the virus showed no
symptoms until one month later, when she experienced fatigue, nausea, muscle tremors, and
other clinical symptoms (par. 1). At this point, vaccination was useless; she had already mounted
an immune response, but the disease was at a life-threatening stage (par. 5).
This situation called for drastic measures; Willoughby and his colleagues attempted the
untested procedure after receiving Jeanna’s parents’ full consent (par. 3). They induced a coma
using ketamine and midazolam, slowing down the virus while a full immune response matured
(par. 4). Oxygen delivery was managed by red blood cell transfusion to maintain optimal
hemoglobin levels (par. 4). Once she was comatose, the doctors conferred with CDC scientists to
institute antiviral therapy (par. 5). Using ribavirin to protect the Central Nervous System and
various other drugs to fight the infection, the doctors fought off the virus in a slow recovery (par.
5). “Neither rabies vaccine nor rabies immune globulin was administered because of the patient’s
demonstrated immune response and the potential for harm from a potentiated immune response,”
(Willoughby et al. par. 5). Jeanna was continually treated with drugs, and showed signs of
improvement by the 10th day; by the 19th day she could wiggled her toes and fingers, and by the
30th day, she could look around, sit up, and cry because of sadness rather than pain (par. 8-10).
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On her 31st day in the hospital, she was considered healthy based on her antibody response and
the doctors’ inability to find the virus in her saliva. (Willoughby et al. par. 11).
“In a clinic visit 131 days after her initial hospitalization, [we learned that] she… was
able to dress herself, ate a normal diet, slept well, and attended high school part-time,”
(Willoughby et al. par. 11). Not all cases go as well as Jeanna’s did; only five out of thirty six
attempts at this method ever succeeded. The Milwaukee Protocol is very controversial; many
scientists argue that the survivors were exposed to less virulent strains of the virus, or that they
had previous genetic protection against it. Nevertheless, the procedure achieved something that
had never been done before – it cured rabies.
Rabies has been approached from many different angles; doctors have used vaccines,
antibody injections, and even induced coma to stop the virus. Within these categories lie
different versions of the treatments: Pasteur’s air dried nerve tissue versus the later human
diploid cell and purified chick embryo vaccines, or equine immunoglobulin compared to human
immunoglobulin. However, they all serve the same purpose as most viral treatments – to increase
antibody levels in order to neutralize the virus. Whether it was by teaching the body to react
against a vaccine, helping it out by injecting it directly with antibodies, or giving it time to
mature by slowing down the virus, all of these treatments had the common goal of helping the
immune system neutralize the virus.
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Works Cited
Kopel, Eran, Gal Oren, Yechezkel Sidi, and Dan David. "Inadequate Antibody Response to
Rabies Vaccine in Immunocompromised Patient." Emerging Infectious Diseases 18.9 (2012): n.
pag. Centers for Disease Control and Prevention. Emerging Infectious Diseases, Sept. 2012.
Web. 26 July 2015.
"Rabies Vaccine." The Lancet 267.6918 (1956): 342. Food and Drug Administration. 25 Apr.
2013. Web. 26 July 2015.
"Rabies." World Health Organization. World Health Organization, Sept. 2015. Web. 26 July
2015.
Rappuoli, Rino. "Inner Workings: 1885, the First Rabies Vaccination in Humans." Proceedings
of the National Academy of Sciences of the United States of America. N.p., 26 Aug. 2014. Web.
26 July 2015.
Willoughby, Rodney E., Jr., M.D., Kelly S. Tieves, D.O., George M. Hoffman, M.D., Nancy S.
Ghanayem, M.D., Catherine M. Amlie-Lefond, M.D., Michael J. Schwabe, M.D., Michael J.
Chusid, M.D., and Charles E. Rupprecht, V.M.D., Ph.D. "Survival after Treatment of Rabies
with Induction of Coma — NEJM." New England Journal of Medicine. N.p., 16 June 2005.
Web. 26 July 2015.
Yousaf, Muhammad Z., Muhammad Qasim, Sadia Zia, Muti Ur Rehman Khan, Usman Ali
Ashfaq, and Sanaullah Khan. "Rabies Molecular Virology, Diagnosis, Prevention and
Treatment." Virology Journal (2012): n. pag. Virology Journal. 21 Feb. 2012. Web. 26 July
2015.