In 1796 Dr. Edward Jenner performed an experiment that today would have
got him expelled from his Medical Society, and maybe even landed them
in jail. He vaccinated a boy against smallpox by pricking his arms with
pus taken from the sores of a milkmaid with cowpox, a closely related
but milder disease. He based this audacious experiment on his astute
observation that milkmaids, who had been exposed to cowpox, never
contracted smallpox. Let’s not forget what smallpox meant in those
days—it meant an almost 100% chance of death. Could anybody have
guessed that this observation would become the first harbinger of the
field of Immunology?

It took over 200 years before another vaccine was created; in 1914 a
vaccine against whooping cough was introduced. But then, the pace
picked up: in 1928 a vaccine against diphtheria, in 1933 against
tetanus, and so on. Five years ago a vaccine against varicella, causing
chickenpox and shingles was approved. Last year a vaccine against human
papilloma virus (HPV) was introduced. This virus causes endometrial
(lining of the uterus) cancer, and immunization of prepubertal girls
should protect them for life. This is the first successful vaccine
against cancer.

The two most important facts about all these vaccines are that they are
essentially 100% effective, and they don’t cause the emergence of
resistant strains. So why don’t we have more of them?

The advent of antibiotics

Many ancient cultures,
including the ancient Greeks and ancient India, already used molds and
other plants to treat infection. This worked because some molds produce
antibiotic substances. However, they couldn’t distinguish or distill
the active component in the molds.

Sir Alexander Fleming (6
August 1881- 13 March 1955) was a Scottish biologist and
pharmacologist. Fleming published many articles on bacteriology,
immunology, and chemotherapy. His best-known achievements are the
discovery of the enzyme lysozyme in 1922 and isolation of the
antibiotic substance penicillin from the fungus Penicillium notatum in 1928, for which he shared the Nobel prize in Physiology and Medicine in 1945 with Flory and Chain.

Here
is an incredible but true story of a lucky accident, coupled with an
astute observation. Fleming was the first to notice the antibiotic
properties of molds and fungi. By 1928, he was investigating the
properties of staphylococci. He was already well-known from his earlier
work, and had developed a reputation as a brilliant researcher, but
quite careless lab technician; cultures that he worked on he often
forgot, and his lab in general was usually in chaos. After returning
from a long holiday, Fleming noticed that many of his culture dishes
were contaminated with a fungus and he threw the dishes in
disinfectant. But on one occasion, he had to show a visitor what he had
been researching, and so he retrieved some of the unsubmerged dishes
that he would have otherwise discarded, when he then noticed a zone
around an invading fungus where the bacteria could not seem to grow.
Fleming proceeded to isolate an extract from the mold, correctly
identified it as being from the Penicillium family, and therefore named
the agent penicillin.

He investigated its positive
anti-bacterial effect on many organisms, and noticed that it affected
bacteria such as staphylococci, and indeed all Gram-positive pathogens
(scarlet fever, pneumonia, gonorrhea, meningitis, diphtheria) but
unfortunately not typhoid or paratyphoid, for which he was seeking a
cure at the time.

Fleming published his discovery in 1929 in
the British Journal of Experimental Pathology, but little attention was
paid to his article. It was only in 1940 that Flory organized his whole
department of biochemistry at Oxford to solve the problem of
stabilizing the drug and scale up and production that a useful drug was
produced in 1945.

Fleming’s accidental discovery and isolation of penicillin in September 1928 marks the start of modern antibiotics.

Fleming also discovered very early that bacteria developed antibiotic resistance whenever too little penicillin was used or when it was used for too short a period.

Fleming
cautioned about the use of penicillin in his many speeches around the
world. He cautioned not to use penicillin unless there was a properly
diagnosed reason for it to be used, and that if it were used, never to
use too little, or for too short a period, since these are the
circumstances under which bacterial resistance to antibiotics develops.

Fleming was prophetic

Indeed, an avalanche of
discoveries of new antibiotics followed, and one by one they fell
victim to the phenomenon of resistance.

How did that happen?
Exacly as Fleming predicted: by inappropriate use and by under dosing.
But there is another reason for resistance to antibiotics that Fleming
could not have foreseen: widespread use in farm animals in order to prevent
disease to ensure larger and healthier animals (and profits). Together
with the slaughtered cattle, pigs and poultry we get the antibiotics
that they had been fed, in low doses and for a long duration—the “
Fleming recipe” for resistance.

MRSA—a case study

Staphylococcus aureus is
a bacteria that we host quite happily on our skin without much trouble.
Every once in a while the bacteria will penetrate a cut or a wound and
cause an abscess. An abscess can be drained, with excellent long-term
results. But “to be on the safe side” physicians prescribe a course of
antibiotic therapy. This led in the 1970s to the emergence of a strain
of S. aureus that was resistant to many broad specificity
antibiotics, called Methicillin-resistant Staph Aureus, or MRSA. This
strain was restricted by and large to hospitals, until a few years ago
what we feared happened: the resistance spilled over to the community.
MRSA can still be treated with vancomycin or linezolid—but not for
long. Strains of S. aureus resistant to vancomycin are
already emerging. Brace youreself for appearance of the new superbug.
What are we doing about it? Physicians are already adopting the
practice of abscess drainage without antibiotics. Why haven’t we heeded Fleming’s warnings in the first place?

Back to vaccines

None of the vaccines we have been using for many decades has produced resistance. Their track record is superb. The CDC is reporting that
of 13 diseases that children are routinely vaccinated against the death
rates for nine diseases have fallen by more than 90% since the vaccines
were approved. Before the discovery of the polio vaccine the death rate
is estimated to be over 3000 a year, not to mention the tens of
thousands of children who became paralyzed and had to live for many
years in iron lungs. Smallpox, Jenner’s first feat of immunization, has
now been declared completely eradicated. No antibiotic can claim that.

Why weren’t more vaccines developed?

The reasons are many, but the most important ones are:

• Companies
  that developed vaccines were under constant threat of litigation,
  mostly for unfounded reasons. A prime example is the latest crusade by
  true believers that the mercury preservative used in many vaccines is
  responsible for an epidemic of ADHD and bipolar disorders in children.
  The evidence for these claims is bad science, pure and simple. Some
  excellent studies definitively debunked those beliefs, and showed no
  relationship of mercury in vaccines and disease of any kind. In any
  event, vaccines are now available without mercury, using alternative
  preservatives.
• Pharmaceutical companies are populated be
  chemists, not by biologists. The little biotech company I worked for
  had more immunologists in its staff than a giant like Pfizer. Such a
  culture is not conducive to biological thinking. Only recently, with
  the advent of molecular biology, did the wind of biology begin to blow
  in the laboratories and board rooms of these companies.
• Vaccines
  are cheap, and the profit margins are razor-thin. This is a prime
  reason why most of the manufacturers of the flu vaccines exited the
  field.

The future

MRSA is not an isolated
case. More pathogens are on their way to becoming multi-drug resistant.
We are slowly but surely losing the race; the pharmaceutical pipeline
is essentially empty. The answer to this impending emergency is
recognition on the part of industry and government that each of us is
in possession of a powerful tool called the immune response.
Vaccination against all bacteria and most viruses is feasible, and the
immune response has done an infinitely better job than the
pharmaceutical chemists. Why not get back to what works?

Dov Michaeli MD, Ph.D is in the biotech industry