It began, as many things do, with a need, a curiosity, and an intriguing story. In the 18th century, smallpox was a global scourge. About a third of those who caught the disease died; survivors were left scarred, sometimes disfigured. From uncertain origins, smallpox had spread across the world through human movement – for trade, conquest and exploration. Early control methods such as variolation – scratching pus from smallpox sores into the skin of a disease-free person (named after the virus, Variola) – were only mildly successful.
In 1796, English physician Edward Jenner noted the accepted wisdom that milkmaids who’d caught cowpox – a similar but harmless cousin of smallpox – were more protected from the deadlier virus. Jenner guessed that cowpox might offer protection and, to test his theory, took pus from a cowpox sore on the hand of milkmaid Sarah Nelmes, who’d caught the infection from a milker named Blossom. Then, he injected it into both arms of James Phipps, the nine-year-old son of his gardener. Months later, Jenner directly exposed Phipps several times to variola virus, but Phipps never developed smallpox. After successfully testing his methodology on 23 more people, Jenner published On the Origin of the Vaccine Inoculation in 1801.
Jenner is considered the father of vaccination (he invented the term Variolae vaccinae: smallpox of the cow) – but in truth he built on existing knowledge. Chinese and Indian physicians had pioneered variolation (simple idea: people don’t tend to get sick with the same disease twice), and Lady Mary Montagu imported the idea from Constantinople to England in the 1720s.
Nonetheless, Jenner’s ethically dubious tests provided a critical discovery: that it was possible to give someone immunity to a disease without giving them the actual disease.
The smallpox vaccine is now known as “attenuated”: a live pathogen that is similar to the wild type, but less dangerous (as long as you don’t have a compromised immune system). During the early decades of the 19th century, attenuated vaccines were created to prevent a range of pathogens, both bacterial (such as tuberculosis) and viral (yellow fever).
By the late 19th century, scientists in both the US and France found that if bacteria was killed gently by careful heating, or using certain chemical treatments, it could still provoke an immune response. The “inactivated” vaccine was born, and was used to prevent typhoid and cholera, among other bacterial diseases. It took a few more decades to figure out how to inactivate a virus – they’re a lot smaller than bacteria, and trickier to “kill” – but inactivated influenza vaccines were available by the 1930s.
In 1923, UK researchers Alexander Glenny and Barbara Hopkins made another leap by creating a diphtheria vaccine that contained purified and treated bacteria toxins. Recipients developed immunity to the toxins without ever being exposed to the bacteria itself.
But vaccine invention has remained highly specific to the target disease: a trick for making a measles vaccine is unlikely to help the invention of a protective treatment for meningococcal, for example.
Understanding DNA – and the way it triggers RNA and then protein production – was the next big leap. What if you could just add the DNA for part of a virus to our bodies, and let our cells do all the hard work?
In 2014, spurred by the Ebola outbreak in West Africa, a “viral vector” vaccine began Phase 1 trials. This used a harmless, non-Ebola virus to get a section of Ebola DNA into the nucleus of human cells. Those cells then transcribe the DNA into RNA, which in turn makes Ebola proteins (but not the whole virus), for our immune system to learn how to destroy.
It was the first widespread success for the viral vector. It was officially approved by the WHO in November 2019: safety standards had increased since Jenner’s day, and five years from conception to rollout was remarkably fast.
But researchers were already considering another way to simplify vaccines: would it be possible to skip the vector and DNA steps, and put the messenger RNA (or mRNA) directly into our bodies? Several biotechnology companies – including Pfizer and Moderna – spent the 2010s figuring out the best jacket for the mRNA, and when COVID-19 broke out in late 2019, mRNA vaccine makers were ready.
In this article, we unpack all the ingredients in vaccines – you might be surprised by how many familiar things there are…
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This excerpt is republished online from Cosmos Magazine issue 92, which goes on sale on Thursday 2 September 2021.
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Ellen Phiddian is a science journalist at Cosmos. She has a BSc (Honours) in chemistry and science communication, and an MSc in science communication, both from the Australian National University.
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