From outbreak to immunity

The COVID-19 pandemic sparked vaccine development at unprecedented speeds.

Vials filled with the Pfizer-BioNTech vaccine to prevent COVID-19 move through the company's manufacturing facility in Kalamazoo, Michigan, in November 2020.

An English country doctor's bold use of one contagion to fight another in 1796 ushered in the modern era of immunology. By then, though, the idea that something virulent could be made beneficial was not new. The painful, deadly variola virus had killed hundreds of millions, but it also revealed a fundamental insight: Pus from smallpox patients' sores could protect the uninfected. 

This early version of inoculation against smallpox, known as variolation, was practiced around the world for centuries. Our experience with the novel coronavirus is far shorter, and the lessons it has for us have not yet concluded. But more than 220 years of vaccine development have led humans to the current moment. We are witnessing another historic breakthrough, this time with an entirely new method of fighting disease.

The cowpox connection

The smallpox vaccine was a departure from variolation because it employed a similar but less dangerous virus: cowpox. The country doctor, Edward Jenner, theorized that dairy workers in Gloucestershire routinely contracted the latter, but seemed to escape the dreaded smallpox. He verified the effect by inoculating an 8-year-old boy with fluid from a woman's cowpox lesions.

After the inoculation, young James Phipps did not develop smallpox, despite deliberate exposure. Jenner detailed the findings from this and other experiments shortly afterward, deriving the word vaccine from the Latin word for cow, vacca.

The idea behind many conventional vaccines is to introduce some piece of a virus to the body so it can mount an immune response. In the case of smallpox, using a similar organism, rather than the smallpox virus itself, created a far safer path to immunity than variolation. The U.S. established a national vaccine agency in 1813 to encourage smallpox immunizations, and the 20th century saw a succession of landmark vaccines for polio, mumps, measles, and other devastating illnesses.

How vaccines work

Scientists have developed a variety of ways to jumpstart the body's immune system by exposing it to a pathogen. Inactivated vaccines, such as those for hepatitis A and rabies, use a dead form of the virus or bacteria. Live-attenuated vaccines, which tend to produce strong immunity, allow a weakened version of the pathogen to replicate in the body—measles and mumps vaccines use this method. Subunit vaccines, used for HPV and shingles, among other infections, use only specific parts of the germ to produce an immune response.

No matter the type, an ideal vaccine will spark an immune response, stimulating the body's white blood cells to fight off the real thing if exposure occurs.

The latest generation of vaccine development uses new and different ways to further refine the body's response to infectious disease. In addition to subunit vaccines, two other main types are in the late stages of development for COVID-19. Vector vaccines use a weakened carrier virus bearing genetic material from the targeted virus. And in mRNA vaccines, messenger RNA—essentially a set of genetic instructions—tells the body to produce a benign protein unique to the virus, training it to fend off an attack.

These latter strategies represent the cutting edge of vaccine development. Two of the COVID-19 vaccines currently being administered in the United States are based on mRNA technology—one from Pfizer, developed with BioNTech using its proprietary mRNA technology, and a second from Moderna. Each capitalizes on the fact that in early January, Chinese researchers released the genetic sequence for the virus, which is related to the one that caused the outbreak of Severe Acute Respiratory Syndrome (SARS) in 2003.

"[An] amazing thing about this platform is that it can be industrially produced in large quantities very rapidly, something that took a long time in the past," says Frank Snowden, historian and professor emeritus at Yale University, of the mRNA type.

Regulators mainly look at three criteria in a vaccine: Does it work? Is it safe? And finally, can it be produced reliably at scale? For Pfizer, developing the current mRNA-based coronavirus vaccine was a $2 billion bet that the answer to those questions would be "yes." Based on data from a clinical trial of more than 40,000 people, the Pfizer-BioNTech vaccine received Emergency Use Authorization from the U.S. Food and Drug Administration (FDA) on December 11, 2020. Within hours of authorization, the first doses were being packaged up to reach patients.

From the outset of Pfizer's vaccine development process, CEO Albert Bourla said the company would move "at the speed of science" while ensuring patient safety remained a priority. With several other companies now in the final stages of testing their own vaccines within a year of the initial outbreak, the speed of science has been astonishingly swift. Before this one, the fastest vaccine ever developed was for the mumps—that took four years.

If smallpox taught the world how to make vaccines, coronavirus may teach us how to make them faster than ever. And while the virus still poses many unanswered questions, it also illustrates how a crisis can spark global innovation.

"There are so many lessons that this pandemic taught us, and they touch the spectrum of human activities," Bourla said. "[But] something that really stands out, I think, is the lesson of the power of science."

National Geographic CreativeWorks was granted unprecedented access to document Pfizer's race to deliver a COVID-19 vaccine to the world. 

Mission Possible: The Race for a Vaccine premieres Thursday, March 11th 10/9c on National Geographic.

The Pfizer-BioNTech COVID-19 vaccine has not been approved or licensed by the U.S. Food and Drug Administration (FDA), but has been authorized for emergency use by FDA under an Emergency Use Authorization (EUA) to prevent Coronavirus Disease 2019 (COVID-19) for use in individuals 16 years of age and older. The emergency use of this product is only authorized for the duration of the declaration that circumstances exist justifying the authorization of emergency use of the medical product under Section 564(b)(1) of the FD&C Act unless the declaration is terminated or authorization revoked sooner. Please see EUA Fact Sheet at www.cvdvaccine.com.


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