In 1796, Dr. Edward Jenner performed an experiment that today would have got him expelled from his Medical Society, and maybe even landed him 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 the 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 a 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 the 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? Exactly as Fleming predicted, by inappropriate use and by underdosing. 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 yourself for the 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 3,000 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 boardrooms 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, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

3 COMMENTS

  1. you could expand explanaition by saying there was a time when, pre-flemming, vaccination was about the only process available for combating disease on a large scale; obviously, with the progress made in chemistry during 18th & 19th centuries, it was possible to treat certain conditions and effect a cure with the application of certain compounds (i.e. – Cyllin) – however, until the discovery of penicillin & sulfonamides (for e.g.) vaccination was widely employed with either ‘live’ or ‘dead’ cultures.

  2. While we applaud the work of Edward Jenner, let us not forget that it was built largely upon discoveries made almost a century earlier by Lady Mary Montagu. This British thinker and wit introduced smallpox variolation to England after observing Turkish women inoculate fellow villagers with live virus. Lady Mary is credited with reducing the death rate from smallpox is England from 30 percent mortality to 2 percent mortality, saving tens of thousands of lives a year.

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