The first news I saw when I awoke last Friday was that Pfizer would ask the U.S. Food and Drug Administration (FDA) for emergency use authorization of Pfizer’s Covid-19 vaccine, BNT162b2. This is a milestone in humanity’s battle against infectious disease, an epic struggle few of us in the modern world fully appreciate. BNT162b2 is based on a completely new biological approach to stimulating an immune response. BNT162b2 uses of a manufactured strand of mRNA (messenger ribonucleic acid) to stimulate an immune response. Messenger RNAs are transient organic molecules that are a critical step in translation our genetic material into the proteins that are the building blocks of life. Sixty years ago the idea that mRNA even existed was only a hypothesis. Now a molecule of mRNA, the one that carries the instructions for the spike protein that protrudes from the surface of SARS-CoV-2, the virus that causes Covid-19, may offer humanity a way out of the Covid-19 pandemic. But I’m getting ahead of the story I want to tell. The story is rather long, and for that reason I want to tell it in two parts.
The very first vaccine arrived on the scene only a little more than 200 years ago in London, England, as the very first example of stimulating immunity to a horrific disease without experiencing a bout of the disease itself. The story of that discovery explains why the word vaccine itself comes from a Latin word that meanscow: vacca.
In the late 18th century, when the United States was an infant country, smallpox (aka variola, a Latin word meaning “pustule”) killed 10-20% of the population (the higher percentage in densely populated cities) and disfigured countless others. In Eurasia death from smallpox was a fact of life, something to be feared–but endured–an experience almost seen as a rite of passage. The disease was so common in Eurasia and Africa that the majority of people had acquired immunity to the disease. Not so in the Americas. There, when smallpox arrived with some of the first European contacts, it devastated native populations, wiping out the structure of whole civilizations. (Guns, Germs, and Steel).
Regardless of that startling and rarely recounted history, the disease smallpox is now gone from the planet (although the virus that causes it still exists in a few laboratories–a fact that fuels a whole genre of dystopian science fiction. Smallpox was conquered by the very first vaccine–and its expanding use over almost two centuries.
Smallpox survivors were immune to the disease–and they also were often identifiable by the scars, called pockmarks, left on their skin from the healed pustules. (It is called “small” pox to distinguish it from “The Great Pox,” syphilis, another major scourge.) The observation of post-infection immunity to smallpox led to a centuries-old practice called variolation, in which people seeking immunity were intentionally infected with smallpox (by scratching smallpox pus into their skin) under relatively controlled conditions. The roughly 1 in 50 death rate (2%) from variolation was a big risk, but an improvement on the 1 in 10 death rate from the epidemic disease. In the mid-1700s variolation was the best method available to become immune to smallpox.
Then came Edward Jenner (1749-1823), an English physician, and Blossom the cow. The story goes that Dr. Jenner astutely noticed that milkmaids who had suffered cowpox were immune to smallpox. Jenner saw the chance to test an idea based on this observation when Sarah Nelmes, a local dairymaid, presented to him with a case of cowpox. She had contracted it from the udder of her cow (Blossom). Jenner used pus from a cowpox pustule on Sarah’s hand, scratching it into the skin of his gardener’s young son, James Phipps. Six weeks later Jenner variolated James (Jenner had been practicing variolation just like many other physicians of the time). As Jenner expected, James was immune to the smallpox inoculation (variolation); James did not demonstrate the typical painful sore in response to the scratched in smallpox pus. Voila! the smallpox vaccination was born. (Cowpox is a disease similar to smallpox but much milder, much less common, and not nearly as transmissible.)
Like many inspiring and rather mythic stories of famous events, Dr. Jenner’s story is a convenient summary. The fuller, fascinating story, can be read here. Scientific progress, like properly raising a child, “takes a village.” One Dr. John Fewster, a practitioner of variolation, years previous to Jenner’s experiment had observed that some dairy farmers did not develop the reaction other patients did when variolated with smallpox pus. After their sub-usual reaction to variolation these same farmers were, nonetheless, immune to smallpox. Dr. Fewster, noting this fact, learned from these farmers that all who did not react to variolation had at some point suffered a case of cowpox. There were no medical journals at the time, but doctors got together in London to eat, drink, and share stories like Fewster’s. There is good evidence that Jenner was exposed to Fewster’s story decades before he saw the opportunity and screwed up his courage to test his idea by vaccinating young James Phipps. Memory being what it is, it is entirely possible Dr. Jenner by that time had forgotten where he’d acquired the original idea, but he spent a lot of time thinking about it. Records show that before the vaccination of Phipps, Jenner had already gotten a reputation as “the cowpox bore” at local medical society gatherings. The point here is not to denigrate Jenner’s achievement, but only to cite the medical culture that set the stage. Communication, the sharing of stories, is essential to the progress of science.
Most of us have been exposed at one time or another to this story of Jenner’s discovery, but usually without much context. At the time Dr. Jenner scratched cowpox pus into young Mr. Phipps arm, the term “virus” mean “an infective material.” No one had any idea of a submicroscopic particle that could cause disease, what we now call a virus (See Viruses–an Orientation). Chemistry as a science was in its infancy, biochemistry was unheard of. Cells and their nuclei could be seen with the some optical microscopes, but DNA, RNA, mRNA, and protein chemistry weren’t even dreamed of. All of that understanding comes from scientific developments that belong to the mid-20th century, one hundred and fifty years later.
The whole idea of vaccination is to cause the body’s immune system to develop immunity to a disease without suffering the effects of the disease itself. Jenner’s use of cowpox to induce immunity to smallpox, that is, using a live virus of one disease to immunize against disease caused by a different virus is nearly unique in the history of vaccination. Almost all vaccines for the last two hundred years following Jenner have used live, but weakened (“attenuated”) or killed forms of whole disease-causing virus to stimulate an immune response. (At least that is true for vaccines against viral diseases; “toxoid” vaccines to bacterial toxins, like those against diphtheria and tetanus, are a slightly different story.) All of these attenuated and killed virus vaccines present a whole array of antigens (chemical parts of the virus recognized as foreign material by the vaccine recipient’s immune system) to which the body might form an immune response. Key idea (1): Both Pfizer’s and Moderna’s Covid-19 vaccines are meant to induce immunity to one specific chemical, the spike protein that lives on the surface of the viral particle. This is a whole new idea. I’ll expand on that in the next email.
So if smallpox vaccination (using cowpox) is so highly effective, why it did it take a hundred and eighty years (1980 declaration by the World Health Organization [WHO]) to eradicate smallpox from the globe? Again, we are taught simplified stories in school, while the truth is almost always more complicated. There was opposition smallpox vaccination within the medical profession itself for technical and economic reasons. And there were anti-vaccinationists even then:
People quickly became fearful of the possible consequences of receiving material originating from cows and opposed vaccination on religious grounds, saying that they would not be treated with substances originating from God’s lowlier creatures.
A half century after Jenner’s original work the British government became involved:
Variolation was forbidden by Act of Parliament in 1840 and vaccination with cowpox was made compulsory in 1853. This in its turn led to protest marches and vehement opposition from those who demanded freedom of choice.
It was another 130 years before this same vaccination technique proven by Jenner succeeded in the eradication of smallpox, a disease that has no animal reservoir (like Covid-19 does). That 130 years was spent by countless people teaching about the vaccine and the good that could come from its use, figuring out how to make quantities of uncontaminated cowpox material, and establishing distribution networks, knowhow, and standardization to accomplish world wide vaccination. Arguably, this would never have been accomplished without the cooperation of the United Nations and its associated World Health Organization (WHO), the organization recently defunded by the Trump administration, and the work of WHO’s parent organization, the U.N., an institution derided from some pulpits as part of the evil “New World Order.” Many of us older folk remember the scab that developed over the vaccination they received in their youth–and the exhortation not to pick at it. Today routine smallpox vaccination of the general population is not recommended.
Key idea (2): Application of complex logistics is essential to vaccine success. We read today of the challenges of producing, distributing, and administering sufficient quantities of anti-Covid-19 vaccine to relieve the world of this scourge. We might reflect on the necessity of worldwide cooperation to make that happen–and on the fact that it took 180 years and intensive international cooperation to eradicate smallpox.
In Part II I hope to explain these novel mRNA vaccines for Covid-19 in a bit more detail.
Keep to the high ground,
Jerry