Conception to Delivery of the COVID-19 Vaccine

A fter nine months of clinical trials, the COVID-19 vaccine is finally being delivered. This breakthrough marks the end of a tragic era of unprecedented financial and logistical burdens. For many, the vaccine is an inoculation against both the virus and despair, a shot of hope for a new life outside the confines of home, a light at the end of this long and terrible tunnel.

Yet, the time in which we now find ourselves—nearly but not yet delivered from our trial—is frightening and dangerous. Deeply entrenched in quarantine, Zoom, and mask fatigue, as well as misinformation about the vaccine, we face numerous threats that might prolong the pain we are hoping to escape. We cannot yet declare victory. Just as crucially, we cannot embrace defeatism. We are in desperate need of rational optimism to move from where we are to where we want to be.

In a time where social unity has been strained to the brink of collapse, we must ask ourselves how we want to shape this forthcoming reality. How we proceed will shape future generations and form our generation’s legacy.

Scientists began thinking about a COVID-19 vaccine as soon as the virus was identified. Although still controversial, early data suggested that the novel beta-coronavirus gained the ability to jump from animals to humans on or around December 1, 2019, at or near the Huanan Seafood Wholesale Market in Wuhan, China.1 This cross-species transmission was most likely due to mutations in the virus’s RNA that codes for its “spike” protein, which is the portion of the virus for which it is named (“corona” for its crown of spikes). These modified spikes enabled the virus to infect humans, generating the terrible pandemic that dominates our time.²

SARS-CoV-2, the virus that causes COVID-19, is the seventh coronavirus known to cause human disease.^3,4 The closest genetic relatives of the novel Wuhan-derived coronavirus are strains circulating in bats. The prevalence of this virus in wild animals suggests a zoonotic origin, and supports the idea it was first transmitted from animals to humans around a wholesale market.^2,3

Even more importantly, publication of the virus’s entire genetic code proved to be the crucial step in the race to develop a vaccine. To understand why, we need to go back to 1796, when modern vaccinology began. While smallpox ravaged the Western world, English physician Edward Jenner observed that dairymaids who contracted cowpox (a similar but non-fatal virus) appeared resistant to smallpox.⁵ To test this idea, Jenner took fluid from a dairymaid’s cowpox pustule and scratched it into the skin of an eight-year-old boy, crudely but effectively inoculating him. He then later inoculated the same boy with smallpox. When the boy failed to develop smallpox, it demonstrated the first intentional vaccine (which derives its name from vaccinia, the Latin word for cowpox).⁵ Although it had been known for several centuries that prior inoculation with smallpox could protect against future smallpox infection, a technique known as variolation,⁶ Jenner had critically shown that people could develop immunity without ever having to suffer from the same virus. In other words, exposure to a similar but less deadly virus could train the host’s immune system to recognize and destroy the deadlier pathogen. This process was eventually modified by supplying non-pathogenic viral proteins to the host. For the next two centuries, conventional vaccinology used this basic paradigm to design vaccines that could prevent population-wide infectious diseases ranging from polio to measles to cervical cancer.

Nearly two centuries later, in 1990, a seemingly unrelated study provided a theoretical foundation for the fourth major type of vaccine, after demonstrating successful injection of messenger RNA (mRNA) into the host and production of its encoded protein.⁷ Broadly speaking, mRNA is the intermediate molecule between DNA and proteins. It can be thought of as a recipe that provides a list of ingredients for protein production inside cells. The 1990 study marked the first time synthetic mRNA, a “recipe” from outside the body, produced a protein “dish” using the cell’s own machinery.⁷ Later studies showed that proteins produced by synthetic mRNA could induce a specific response in the host.⁸ Applied to vaccinology, this discovery could allow exogenous (from outside the body) mRNA to incite production of endogenous (from within the body) proteins, including non-pathogenic viral proteins within the host. Production of these harmless viral proteins could then allow the body to develop antibodies against the associated virus, thereby providing immunity without requiring an infection.

This technology could also simplify vaccine design. Rather than laboriously creating a virus’s antigenic proteins in the laboratory, researchers could inject a small, non-pathogenic piece of the virus’s genetic code—a much easier feat. This development meant that vaccines could be designed in a matter of days, rather than years. Applied to a COVID-19 vaccine, this approach could enable vaccine development based solely on the virus’s genetic code. In practice, vaccine manufacturers selected a snippet of mRNA that encoded the coronavirus’s spike protein. Injecting this mRNA into the body created many little spike proteins, which could not cause disease but could teach the immune system how to recognize and quickly destroy the full coronavirus if later exposed.

Unfortunately, despite the promise of this approach, mRNA is unstable and easily degraded. Furthermore, mRNA can activate the host’s immune system to a dangerous extent, dampening enthusiasm for this vaccine development technique.^9,10 It would take another twenty to thirty years for genetic engineering to identify clever ways of controlling mRNA’s degree of immune activation,¹¹ increase its molecular stability,¹² and improve its absorption by the host.^9,10 The hard work behind these innovations should not be taken for granted, as they provided a way to translate the genetic sequence of SARS-CoV-2 into a human vaccine.^2,3

There are over ninety COVID-19 vaccines in development.¹⁵ Notably, two of these vaccines—one by Johnson & Johnson, the other by Merck-IAVI—are based on the same technology as their Ebola vaccines. Undoubtedly, this pandemic has led to the greatest vaccination effort in the history of the world. Newfound success with the mRNA technology may usher in a golden era of vaccinology.⁹

Nonetheless, designing a successful mRNA vaccine was only one piece of a very large puzzle. Translating this computational design into an injectable vaccine took Moderna another 40 days (mid-March 2020), making theirs the first vaccine to reach Phase 1 clinical trials.¹⁶

The most grueling work, however, came during the nine months from mid-March through mid-December, when vaccine candidates from Moderna and Pfizer-BioNTech were tested in three independent clinical trial phases. Under normal circumstances, clinical trials run sequentially. Preclinical animal testing comes first, followed by Phase 1 dose escalation safety trials involving a few dozen subjects. Phase 2 expands trials to a few hundred people. The last phase, Phase 3 efficacy trials, involve many thousands of people, and compare vaccinated people against those who are randomly selected to receive a placebo control.

However, due to FDA emergency authorization, trials were allowed to partially proceed in parallel,¹⁷ meaning that the Phase 1 trial did not have to be fully complete before initiating the Phase 2 trial. For example, the FDA cleared Moderna to start their Phase 2 study on May 6, 2020, just before positive data from the Phase 1 study were announced on May 18, 2020.

While this accelerated procedure saved time, it did not take shortcuts that compromised the end result. The clinical trial process still relied on efficacy and safety data from more than 67,000 subjects between Pfizer-BioNTech and Moderna before the FDA delivered emergency use authorization on December 11 and 18, 2020, respectively.^18–20 (For comparison, two Phase 3 studies for Gardasil, a vaccine against human papillomaviruses that cause cervical and anogenital cancers, collectively enrolled 17,622 patients,^21,22 just over a quarter of the patients in the Moderna and Pfizer-BioNTech trials, to obtain FDA approval.) Additionally, both Pfizer-BioNTech and Moderna are still tasked with continuing data collection and trials to gain full regulatory approval, a process that does not stop with emergency-use authorization.

By all possible measures, these vaccines are miracles of science that shattered past records for vaccine development. The mumps vaccine, which previously held the speed record, took four years from viral sampling to approval.²⁵ Although questions remain about the use of COVID-19 vaccines in several groups—children, pregnant women, the immunocompromised, and those with histories of severe allergic reactions^26–29—the high overall degree of vaccine efficacy and safety suggest that herd immunity may indeed be possible by late summer 2021 if uptake is high enough. (The personal experiences of four family members of mine who have already received their vaccines have revealed no serious side effects except an abundance of hope that this dark and lonely season may soon be over.)

Despite a resounding success for science, the distributional challenges remain, and the public’s willingness to take the vaccine is in constant flux. Some of these issues were anticipated and planned for, such as the requirement that the Pfizer-BioNTech and Moderna vaccines be refrigerated at negative eighty and negative twenty degrees Celsius, respectively, to maintain stability during transport.³⁰ Other challenges have been surprising, including shocking numbers of American healthcare workers who are unwilling to take the vaccine (e.g. forty percent of healthcare workers at Chicago's Loretto Hospital said they would not get vaccinated), despite an abundance of peer-reviewed literature and multi-national regulatory body documentation on its safety and efficacy.³¹

The Wall Street Journal reported that despite more than thirty million doses distributed in the United States, only eleven million doses had been given as of January 14, 2021.³² These figures point to an unacceptable waste of material and financial resources, as the vaccine doses expire rapidly, especially after being thawed. They cannot be refrozen. Meanwhile, the pandemic raged on with ferocious intensity, surpassing more than 300,000 new daily cases in the US on January 8, 2021, just one day after a record-setting 4,000 national daily deaths (January 7, 2021).³³ Simultaneously, Los Angeles alone had an average of ten patients testing positive for COVID-19 every minute. With a death every eight minutes, intensive care units were overloaded to the point that ambulances were circling for hours, waiting for hospitals to accept more patients.³⁴ Failing to recognize that we, as a society, are not yet victorious threatens the outcome that we have worked so hard to achieve.

Declaring victory requires reaching herd immunity, which is the point at which enough people are immune to the virus through either vaccination or infection that it cannot easily spread in communities.³⁵ To calculate what fraction of people need to be immune to reach herd immunity, we need to understand a value called R0, also called the reproduction number. R0 represents the average number of people a COVID-positive individual infects.^36,37 R0 can also be thought of as the “infectiousness” of the virus while accounting for human behavior. Strict quarantining and masking reduce R0 while partying and hanging out in large groups raise R0. Importantly, the herd immunity required to end the pandemic is largely determined by R0. A high R0, brought on by reckless behavior, might mean that 75-80% of people need to be immunized before herd immunity is reached. On the other hand, a low R0 brought about by strict distancing, masking, and stay-at-home measures might mean herd immunity is achieved at just 60% immunization rates. Responsible behavior does not just keep you and the people you care about from getting sick, it directly reduces the amount of time until the pandemic is over.

Even two record-breaking, highly efficacious vaccines cannot fix human behavior that disregards public health guidelines. Those who suggest we can achieve herd immunity via mass infection are propagating a defeatist attitude and false hope that would result in one to two million unnecessary deaths in the US alone.³⁷ Furthermore, this cold, passive approach may not even result in herd immunity, as viral mutations may eventually evade current immunity, effectively resetting the count of immunizations to zero and obliterating hope of herd immunity arriving any time soon.³⁸

The situation really boils down to this: are we all willing to get vaccinated and support those trying to get vaccinated? Are we willing to endure stricter quarantine now to end the quarantine sooner?