email Dr Kerns
Successful immunization methods for preventing smallpox were actually discovered in China, India and Africa more than a thousand years ago. "As early as the 10th century, the Chinese were taking the dried scabs of previous smallpox victims and blowing them up the nose of healthy people to ward off the disease." One early Chinese medical text actually listed five different methods of inoculating persons against smallpox.
(1) the nose plugged with powdered scabs laid on cotton wool, (2) powdered scabs blown into the nose, (3) the undergarments of an infected child put on a healthy child for several days, and (4) a piece of cotton smeared with the contents of a vesicle and stuffed into the nose. In addition, a century before Jenner, the Chinese used white cow fleas for smallpox prevention. The white cow fleas were ground into powder and made into pills, which presumably was the first attempt at an oral vaccine.
In the fifth century BC, Thucydides' account of the Peloponnesian war between Athens and Sparta, contains one of the first written accounts of the idea of natural immunity, that is, the idea that a person who contracts a disease once and who survives it, is then immune from contracting the disease again. Thucydides describes a terrible plague that struck Athens in 429 and 430 BC. His description sounds very much like an account of a smallpox epidemic, and includes the statement that "the same man was never attacked [by the same disease] twice". Therefore, says Thucydides, persons who recovered from an attack of the disease
received not only the congratulations of others, but themselves also, in the elation of the moment, half entertained the vain hope that they were for the future safe from any disease whatsoever.
They were not , of course, immune
from all diseases, but they did seem to be immune from that particular
one.
It was then later discovered that some other diseases also seemed
to induce a natural immunity to further attacks of the disease.
This then led to the notion of trying to artificially induce mild
forms of disease in people, in hopes of immunizing them against
future more virulent attacks of that disease. Jules Bordet, in
his Traite de l'immunite dans les Maladies Infectieuses,
in 1920, summarized the matter thus.
Since a first attack, which strengthens the host, often provides valuable safeguards for the future, it must be considered desirable, on condition, of course, that it does not produce too much serious damage. Artificially putting the host into a state comparable to that in which it would be if it had been cured of a spontaneous attack of the particular illness is the object of active immunization or vaccination.
This idea must doubtless have been
the origin of the concept of artificial immunization.
In the early 1700s, a few travelers to the Near East, Africa and
India brought word of artificial immunization practices back to
Europe, particularly to England where it became a relatively common
practice. Then, in 1796, Edward Jenner conducted experiments to
determine whether inoculation with cowpox disease would produce
immunity to smallpox disease.
But whether the immunization procedures were done in 10th century
China with powdered scabs, in late 18th century England with lancets,
or in the late 20th century US with needles or sugar cubes (polio),
the principles of vaccination are identical. When a body is vaccinated,
immunized, variolated or inoculated (all of which words derive
from different etymologies, but mean approximately the same thing)
that body is artificially introduced to a pathogen. Or, more precisely,
a pathogen is introduced into that body. Or to be still more precise,
some form of the pathogen (e.g., an attenuated form of the virus,
a form that has been somehow artificially weakened), or some form
of something very like the pathogen (as in using cowpox virus,
for example, to inoculate against smallpox), or some fragmentary
portion of the pathogen (e.g., using only the coat of the virus,
minus the genetic material inside its core), or some artificially
grown unit that looks like a fragmentary portion of the pathogen
(e.g., a genetically engineered molecule which is identical to
a molecule on the coat of the virus) is introduced into the body
by injection, scarification, ingestion or suppository.
This constitutes the inoculation.
In some cases the body does get moderately sick from that inoculation,
and sometimes it does not get sick at all. In either case, it
mounts an immune response against that pathogen, and - most importantly
- it remembers how a successful response was accomplished. The
immune system is thus alerted, ready and charged, waiting for
a time when it might see a realworld, wild variety of that pathogen
trying to get in. When it does see such an invader, that is, when
it is "challenged" with a wild virus (or bacterium or
whatever it was vaccinated against), it will be ready. It will
be able to fight off that invading pathogen without the person's
body ever feeling any sickness at all. The vaccine, you could
say, "took". It worked. The person will not get sick
from that pathogen for as long as the immune system memory cells
remember that invader and that successful response.
That is how vaccines work. They prepare a body for the battle,
so that when the real wild virus comes along, the immune system
will be able to a) recognize the virus by its coat, and b) fight
it off before the pathogen can replicate itself in large enough
numbers to cause disease. Vaccines, in other words, do not prevent
initial infection with the invading virus; they prevent disease.
Infection occurs, the immune system fights off the pathogenic
invading microorganism, and disease does not occur.
But what does "fighting off the pathogen" mean? In the
case of an invading virus it may mean either of two things. It
may mean that a) the immune system is able to completely eliminate
all the invading virus particles from the body, or it may mean
only that b) the immune system is able to keep the invading viruses
in check, and somehow under control. If the immune system does
not completely eliminate the invading virus, then there remains
the theoretical possibility that the virus particles which remain
in the body could, at some future date, break free and again threaten
to cause disease. (For a fuller discussion of possible modes of
vaccine protection, see chapter 9 below: Criteria of effectiveness.)
The important key, however, is that before any immune response
at all can happen, the invading wild virus must first of all be
recognized by the immune system as the same virus that it was
vaccinated against. If it is not so recognized, then the immune
system does not mount a response, the invader's invasion succeeds,
and the person gets the disease.
And that is the key problem that worries researchers and makes
many of them skeptical that there will ever be a vaccine for HIV.
For, as Robert Gallo has said, "every HIV isolate has been
different". They are all wearing different coats. When the
immune system is prepared for a virus that is wearing one coat,
and is then challenged with a virus wearing a different coat,
it does not respond in the way it was trained to respond. It has
to make up another new response, and that will probably be an
ultimately unsuccessful response. The person will get the disease.
7.1 Cell-associated
transmission
One additional problem that
concerns researchers, and that makes some of them skeptical that
there will ever be a successful HIV vaccine, is the problem of
cell-associated transmission. HIV can be transmitted from one
person to another either as viral particles floating freely in
the bloodstream (or other tissues or fluids), or it can be transmitted
from one person to another within certain cells. This is
analogous to the way Agamemnon's warriors got inside the walls
of Troy by hiding inside a large hollow wooden horse which was
then wheeled into the city. If the virus is hiding inside the
cells of an HIV-infected person, and some of those infected cells
are transmitted to another person via one of the usual modes of
transmission - sexual intercourse, needle-sharing or some other
blood-borne path, for example - then the newly infected person's
immune system would not be alerted to the presence of the viral
invader in the same way it is alerted when the virus is floating
free. The virus would have successfully sneaked into the new host
as a stowaway inside a cell. That virus, in fact, could continue
to replicate itself by the thousands inside that cell or cells,
and not be recognized by the new host's immune system until well
after the virus had replicated itself enough times to insure a
successful assault. This, in fact, is probably a common form of
transmission of the virus from one host to another, and it causes
a serious problem for vaccine protection. Paul Ewald explains:
Compounding all of the problems associated with HIV's variability is the fact that HIV can infect susceptible people...without leaving infected cells.... Vaccines that are effective against free virus may have little effect on the progression of disease because HIV apparently often infects people within the disguising cloak of our cellular membranes; and infected cells may be far more effective than free virus at spreading infection.... The successes at vaccination are therefore only mildly encouraging.
Complicating this problem is the
likelihood that almost all sexual transmission is probably of
the cell-associated type. Since by far the most common mode of
transmission of HIV in the world is sexual transmission (86 per
cent) , this means that most HIV transmission in the world is
of the cell-associated type. It is clear, therefore, that any
vaccine that does not successfully address the difficulty of cell-associated
transmission will not be a very successful vaccine.
These two problems alone, high replication and mutation rates
of HIV, and cell-associated transmission, are what make many researchers
skeptical of ever finding a successful vaccine against HIV.
But there are additional problems as well. One is that "the
successes at vaccination" to which Ewald refers in the passage
above are few and far between, and have occurred in animals rather
than humans. Furthermore, they have been in animals that were
vaccinated against simian immunodeficiency virus (SIV) , not against
HIV. This raises the thorny issue of the "animal model,"
which every medical researcher sorely hopes to have for their
research.
7.2 Animal
models
If you do not have an animal
that you can infect with the pathogen you are studying, then it
is virtually impossible to do most medical research involving
infectious agents. AIDS researchers, unfortunately, are not blessed
with any very adequate animal model for their researches. They
do have animals that can be infected with the human immunodeficiency
virus, (chimpanzees) but the animals do not get sick from it.
They do develop HIV antibodies, but for some reason they do not
get AIDS. So vaccinating them against HIV in order to prevent
disease doesn't make any sense. The animals don't get sick anyhow.
An additional problem with chimps is that they are in short supply
and are very expensive to maintain. So expensive in fact - they
cost between $60,000 and $100,000 each to purchase - that there
are only about 70 chimps in AIDS research in the entire US.
Other animals (laboratory raised rhesus macaque monkeys) can be
infected and caused to get sick and develop AIDS, but their AIDS
is not caused by HIV. It is caused by SIV. Consequently, much
AIDS vaccine research is done with SIV models. SIV vaccines have
sometimes yielded protection against disease in monkeys, but even
in those cases, the protection occurred only when vaccinated monkeys
were challenged (some months after the experimental vaccine was
administered) with an SIV of the exact same (homologous) strain
as the strain that the vaccine was modeled after. Those vaccines
did not protect against any other wild strains of SIV. Any HIV
vaccine that protected against only one strain of HIV would have
very limited usefulness.
Another potentially promising animal model, announced in 1992
by scientists at the Washington Regional Primate Center in Seattle,
is a colony of pigtail macaque monkeys which do seem to develop
AIDS-like conditions when infected with HIV. The Seattle group
is still hopeful about the success of this animal model, and so
are some other researchers. Shortly after the 1992 announcement,
there was a big run on the importation of pigtail macaques for
US AIDS laboratories.
Not everyone feels so optimistic, however, about the pigtail macaque
model. It has been found, for example, that
in larger tests, pigtails have not gotten consistently sick or stayed that way. In some animals, the infection seems to be a passing thing. In many of the monkeys, antibodies against the virus show up and then seem to just start disappearing, as if the virus had made a feint and backed off. "I'm skeptical," admits [virologist Nick] Lerche. "It doesn't seem to be living up to the potential or hopes of that model. What I'm hearing now is yes, you can infect, but the infection is transient.... It doesn't seem any better than the chimp model."
Even this hopeful animal model, it seems, may have some serious weaknesses. Actually, most animal models in medical research have some weaknesses; many drugs that are safe in humans are not safe in some animals, and vice versa. For example, penicillin is toxic in guinea pigs and hamsters, but not in most humans. Aspirin is toxic in cats and causes birth defects in mice and rats, but not in humans. Thalidomide, which causes severe birth defects in humans, causes no birth defects at all in at least 10 different strains of rats, nor "in 15 mouse strains, 11 rabbit breeds, 2 dog breeds, 3 hamster strains, and 8 other species of monkeys". Almost no animal model in medical research is a fully adequate analog to human experience. For this reason, whatever we learn in laboratories and whatever we learn from tests in animals must be taken with a large grain of salt when we use those data to make predictions about what results to expect when we test the vaccine or drug in human subjects. The animal model may turn out to be a moderately accurate predictor of what to expect in human subjects, or it may turn out to be a quite inadequate predictor. In either case, at least with HIV candidate vaccines, we will not really know how good the animal model was until after we actually test the vaccine in human subjects. As Robert Levine says of animal models:
Ordinarily, there is some background of experience derived from research on animals that will help predict with varying degrees of confidence what the risks might be to humans. However, it must be understood clearly that one never knows what the adverse (or, for that matter, beneficial) effects of any intervention in humans will be until the intervention has been tested adequately in humans.
All these current problems with animal models for AIDS and HIV infection are, of course, subject to change. A successful animal model may in fact be developed at some point. Within the week previous to my writing this sentence, for example, Science reported the development of a possible baboon model for HIV-2 infection that may prove to be valuable. Nevertheless, we need to be always mindful of the fundamental predictive limitations of relying very heavily on any animal model.
For all these reasons, many researchers have become skeptical about the possibility of ever developing a successful vaccine against HIV: the virus is too mutable, it can temporarily escape immune detection by intracellular transmission, and we do not yet have any very reliable or successful animal models that have given promising results. Paul Ewald expresses some of this skepticism when he compares our vaccine successes in the past to today's efforts:
The success of vaccines against smallpox, yellow fever, whooping cough, and measles raised hopes that all pathogens could be controlled by vaccines. But as it turns out, some of the conquered pathogens were particularly oafish adversaries. A smallpox virus, for example, carried antigens that were also carried by virtually all other smallpox viruses as well as its taxonomic relative, the vaccinia virus [which causes cowpox], which is the virus used in the smallpox vaccine.... Some individual parasites, like those causing sleeping sickness, may change their coats regularly to avoid detection. Mobilizing the immune system to destroy pathogens wearing one coat is not terribly useful if parasites with different coats are continually being generated [as is the case with HIV].
What a vaccine does, in other words, is stimulate the immune system to fight off this specific non-self invader when it tries to get a foothold in the body. Unfortunately, says Ewald, "the available data suggest that a person's immunological defenses are a surmountable obstacle for HIV".
Still, in spite of these quite serious
barriers to hope, the work to create a vaccine is still being
engaged.
Why? I believe the reason is this: If HIV is indeed the etiologic
agent for AIDS, and if a vaccine that effectively protected against
HIV were to be discovered, and if that vaccine protected a high
proportion of those who were vaccinated with it, and if the vaccine
were inexpensive, easily transportable, easily storable, easily
administered and required only one or two doses, perhaps three
at the most, then that vaccine would be an enormous benefit to
humankind.
Besides, there have always been skeptics and nay-sayers, people
who were convinced that the improbable was really impossible.
Nay-sayers criticized Wilbur and Orville Wright, vociferously
characterizing their belief in the possibility of heavier-than-air
flight as absurd and a foolish waste of time. They also mocked
Edward Jenner and his belief that cowpox inoculation could protect
people against smallpox infection. Furthermore, skeptics always
seem to have plentiful evidence on their side, and numerous cases
of failure to which they can point.
But sometimes the skeptics are wrong. And when they are, the believers
should take credit for having had the courage to persevere with
their research.
At the Tenth International Conference on AIDS in Yokohama in August
1994, Dr William Paul, head of the US Office of AIDS Research,
stressed that "Despite recent setbacks, an AIDS vaccine still
offers the best hope for stopping the epidemic." Other investigators
say in even stronger language, "the HIV vaccine research
effort is of compelling public health importance". While
some thinkers may be concerned about the ethical propriety of
expending so much money, time, and effort on vaccine development
projects about which so many scientists have so many doubts, Dr
Dani Bolognesi at the Duke University Medical Center explains
that the "biomedical establishment cannot become passive
or discouraged" by these doubts and obstacles. Instead, we
need "to redouble our efforts and be prepared to maintain
a long-term, solid commitment until an effective vaccine against
this devastating pathogen is achieved".
Perhaps precisely because a vaccine would be such a benefit, and
everyone knows that it would be, HIV vaccine research is still
going on. Two Seattle researchers express the feelings of many
in the AIDS research community when they say that "the rapid
development and testing of an HIV vaccine seems to be the highest
priority research in the field of HIV".
Furthermore, despite all the difficulties and research obstacles
(some few of which have been detailed above), there still have
been enough successes in the research to produce a small number
of candidate vaccines for trials with human subjects. Some of
these candidate vaccines have actually gone to phase I, and some
to phase II, human trials. All of these have been of the subunit
variety.