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An ounce of prevention...
by One of the most frustrating things about being a public health professional is that so much of the disease, suffering, and death we see is preventable. Clean water, sanitation and vaccination have combined to make dramatic strides increasing both the length and quality of life, but even these basics are scarce in many parts of the world. Fully a sixth of the world's population lacks clean water, and 2.6 billion go without adequate sanitation. Vaccinations are also lacking in many areas, and a recent measles vaccination campaign has shown just how much of an impact a vaccination can make:
Largely due to the technical and financial support of the Measles Initiative and commitment from African governments, more than 200 million children in Africa have been vaccinated against measles and one million lives have been saved since 1999. Measles cases and deaths have dropped by 60%, thanks to improvements in routine and supplementary immunization activities in Africa.
While we typically think of these common human vaccine-preventable diseases--measles, mumps, rubella, even smallpox back in its day--there is another that's almost completely preventable with a cheap, highly effective vaccine--if it's given to dogs: rabies.
Rabies is a zoonotic disease: it's transferred between animals and humans. Though bats and other wild animals are the natural reservoir, most human infections are due to bites from infected dogs. While human rabies is incredibly rare in the United States, it's much more common in Asia and Africa. Evolutionary biologist Olivia Judson notes this in a recent post on her New York Times blog:
Each year, the disease kills about 55,000 people -- that's 150 a day -- almost all of them in the poorest parts of Africa and Asia, and more than 7 million people receive post-exposure treatment after being bitten by a rabid animal. Treatment is not just expensive, but time-consuming: a full course of vaccination requires five visits to a hospital or health clinic during one month. Which, if you live in rural Africa, can mean many hours of travel and time not working. Indeed, the global economic cost of rabies is estimated to be more than $583 million. And that doesn't count the trauma that deaths from rabies inflict on families and communities. For though rabies kills many fewer people than malaria, it causes far, far more fear.
But the worst part about rabies, perhaps, isn't it's horrendous death toll, or the hideous way most of those infected--usually children--die:
Episodes of madness continue until the victim falls into a coma; this is followed by paralysis and death. Sometimes the madness includes ferocious, biting, attacks on anyone nearby.If you arrived in a Western hospital with symptoms of rabies, you'd be sedated until you died. In poor countries, where hospitals are scarce and sedatives scarcer, often nothing can be done, and the victim may be locked into a room, alone, to die.
What could be worse than that? How about the fact that, as Judson notes, all of these deaths could be prevented, and rabies could be all but eliminated as a human disease in a scant 5 years if only we had the will and would fund dog vaccination campaigns in these hard-hit countries. Dog vaccines cost only around $1.50/shot, and are highly effective, whereas post-exposure treatment for humans who have potentially been exposed to rabies is much more expensive and difficult to administer.
Scientists often speak of the big problems, as Judson acknowledges: war. Climate change. The Big Three in infectious disease: Tuberculosis, Malaria, and AIDS. Rabies is a big problem, but far from an insurmountable one; if we acted, relatively little funding could make a huge difference. Will it happen? While the old adage about prevention still holds, it's simply difficult to get people to care about a disease that's not affected them (or their loved ones) yet. I agree with Judson that action should be taken now--but I'm afraid I and other public health professionals will still be pounding that drum in another decade or two.
Tags: Africa, Asia., disease, public health, Rabies, vaccination, viruses
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January 29, 2008 4:01 PM
Andrew Maniotis
Dear Friends,
Tara has hit on a live wire, once again (regards to you Tara!), so here goes: I'll try to be brief, but I'm not gifted with words, so please forgive.
In reading many of the memoirs and histories of Pasteur and his work, one of the best I've read is by Patrice Debre, entitled simply, Louis Pasteur. What I found fascinating, and also dead-on relevant to all of the blogs and discussions we've had over the last year, are Patrice's recounts of how Pasteur solved a fundamental paradox regarding the "art" of vaccination with rabies. As many of you probably know, Pasteur was stricken early in life as a young boy by a particular incident involving a rabid dog attack on a boy in his town. This event is discussed several times in the biography, and like Dr. Gallo, with the story of his sister's leukemia, this early event served to galvanize his resolve to conquer disease early in his life.
Without quoting precise passages or segments of the book, what stimulated several years of work in my lab was the recapitulation of Pasteur's solution to a molecular conundrum regarding how to attenuate a pathogen or epitope (antigen) enough so that it would not cause disease in the vaccinated, yet not attenuate the pathogen too much as to cause it to not protect against potential highly lethal strains that might arise, or which were not used to generate the vaccine.
With two lab helpers (one of them the famous Roux), Pasteur and his small research team (and without the $875,000,000 that VAXGEN was awarded for not providing a GP120 vaccine I might add) wrestled with rabid dogs, bare-handed. One of these brave men (ah those were the good old days before IRB's) would hold the animal down, the other would take a lab pipet that looked like a turkey baster, and extract the saliva from the writhing, deadly beast to use as inoculum in non-infected hamsters, rabbits, and other dogs.
Here's where it gets interesting...enough for me to launch experiments in experimental cancer therapeutics based on a principal he discovered.
When Pasteur and his two associates turned to dogs as their experimental model, the records show that at first, only about half of the non-infected dogs he innoculated orally or sub-dermally would go on to develop hydrophobia. Therefore, with his experimental genius, he then went to using intracranial lavages of hydrophobic saliva directly into a small hole drilled in the recipient dogs' crania. What resulted was a nearly perfect if not perfect animal model: 100% of the dogs now would contract rabies. A perfect cohort to now test a vaccine.
How to attenuate enough so the innoculum won't kill, yet, be potent enough to protect against potentially highly virulent strains?
Rabbits! Develop a rabbit model via intracranial innoculation so you achieve hydrophobia in 100% of the bunnies. Then serially infect rabbits over time in succession to get the incubation period down from about 29 days to about 8 days. For some reason (I don't understand), he achieved using this method a means of amplifying the pathogenicity of the rabies strain he was using, so that it killed in 8 rather than 29 days. Finally, it was time for The experiment.
Remove the infected, day 8 rabbit spinal cords, place them in a dessication flask and dry them out. Then, place the tissue into the innoculum and inject the inoculum after 2 days, 3,4,5,6,7,8,9,10,11, and finally 12 days into healthy rabbits. See what happens.
All the rabbits died at 2-11 days, but on day 12, and beyond no rabbits died (when rechallenged with fresh highly virulent innocula). Success! By DRYING out the material for 12 days or more, he preserved its potency, yet, at the same time, through serial amplification and getting the virus to kill the rabbits in 8 days, he first developed an incredibly virulent strain to work with. Two birds with one innoculum. Similar to the Medieval Chinese blowing year-old (dried) small pox up the nostrils of infants as opposed to harvesting fresh pox as was done in Britain during some of the small pox epidemics).
What happened to the vaccine making after Pasteur? Start with Hep B and molecular cloning. Purification of components, and of course, the use of aqueous instead of dried material might influence the results. That's why adjvants like Freund's incomplete (deadly toxic adjuvant) and such molecules as squalene were tried and are still tragically used today in our era of "molecular vaccines" (beginning with the deadly hep B vaccine that tops the CDC's list of adverse reactions) to non-specifically boost the immune system because the antigens are "dead" because of molecular biology and modern biochemical methodology.
Despite the addition of these adjuvants, the antigens of real pathogens (not "HIV" of course) are probably often rendered completely denatured and become ineffective at stimulating an immune response in significant numbers of recipients, as was shown recently for example in the announced failed MERCK STEP trail (I don't know if squalene was used here because I'm still trying to find out the ingredients that were put into this one, but I'd bet a nickel that squalene or something like it probably was added based on past "HIV" vaccine trials, and based on the history of military anthrax and "HIV" trials conducted on soldiers directed by Edmond Tremont circa 1990-perhaps why there are 325,000 permanently disabled Gulf-war I vets today including those that never went to Iraq but stayed stateside but were vaccinated, and every sick one of them has squalene antibodies, which of course are used in biomedical research to induce a multitude of autoimmune diseases such as demyelinating syndromes, arthritis, chrones, etc. Evidence that vaccine adjuvants like squalene (MF-59), when they have been added to certain lots of anthrax (and "HIV" vaccines given to soldiers on threat of court martial if they don't roll up their shirt on command, have induced autoimmune syndromes in almost 100% of every sick Gulf-War I veteran tested, and have evoked antibodies to squalene in their blood can be found in a book written by Gary Matsumoto. Vaccine A, Basic Books Publisher, (2005). Squalene and other adjuvants have also been used by scientists for many years to induce rodents to develop arthritis, macrophagic myofasciitis, mutliple-sclerosis (demyelinating syndromes), and lupus (Holmdahl et al. Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis Immunol Rev. Dec;184:184-202, 2001; Gherardi NK. Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome. Rev Neurol (Paris). Feb;159(2):162-4), 2003).
It is my belief that modern, especially "molecular vaccines," as suggested by Pasteur's successful solution to the rabies conundrum he faced, have little hope of stimulating anything, compared to Pasteur's admittedly dangerous, yet effective vaccine. I've been saying this for some time, with no interest by the good sages that "know" about vaccines.
The rub is in the case of Pasteur, that Joseph Meister, the boy he first tried the vaccine out on during an emergency and shortly after the boy was bitten dozens of times, could have been like the dogs before the intracranial trick he learned: he might have been among those who would not have contracted hydrophobia. We'll never know, because the vaccine probably worked. The study of rabies should be at the heart of experimental vaccinology, and immunogenics.
It also helps in vaccinology, in addition, if you have the components of a pathogen, unlike the STEP trail, in which endogenous retroids and HERV's were used, which as you see resulted in stimulating an "HIV-positive" signature in only 24 of the vacccinated out of more than 700, whereas the dummy shot evoked "HIV's" molecular signature in about 18 if I recall in one arm of the trial and only 9 in the African arm of the trial. 'Tis a pity, and it makes me sad that "HIV's" components probably represent nothing but endogenous retroids and HERV's, which of course are not very immunogenic.
Cheers,
Andrew
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