Longshot

1. Unprecedented Speed Built on Decades of Science

The truth is the science behind the vaccines had been in the works for at least 15 to 20 years.

Speed was unparalleled. The rapid development of COVID-19 vaccines, taking just 338 days from virus identification to the first public shot, was historically unprecedented. Compared to the polio vaccine (50 years) or the elusive HIV vaccine (four decades and counting), this speed seemed miraculous to many, yet suspicious to others who questioned if corners were cut.

Prior research was key. The foundation for the mRNA vaccines, like those from Moderna and Pfizer, wasn't built overnight. It relied on breakthroughs published as early as 2005 and significant work on coronavirus vaccines that began in 2013 after the MERS outbreak. The COVID-19 vaccine was essentially an adapted MERS vaccine design.

Luck played a role. Had the SARS-CoV-2 virus emerged even five years earlier, science might not have been ready. The necessary scientific groundwork, particularly in mRNA technology and coronavirus structure, had just reached a point where rapid adaptation was possible. The pandemic's timing, while devastating, coincided with scientific readiness.

2. Vaccine History: Triumphs, Tragedies, and Lessons Learned

Creating effective vaccines requires a mixture of science, hunches, and luck.

Early, risky methods. Vaccine science began with practices like variolation for smallpox, a dangerous gamble that sometimes caused the disease it aimed to prevent. Edward Jenner's observation of cowpox immunity led to the safer concept of vaccination, but early attempts were often based on trial and error, sometimes with tragic results.

Lab-made breakthroughs. Louis Pasteur's accidental discovery of attenuation led to the first lab-made vaccines for diseases like chicken cholera and anthrax. His work, along with others, sparked the field of virology and paved the way for vaccines against diphtheria, tetanus, and influenza in the early 20th century.

Learning from disaster. The quest for a polio vaccine involved early failures that paralyzed and killed children. Later, a tragic 1966 trial for an RSV vaccine, similar to Salk's method, backfired horribly, making children sicker and killing two toddlers. These failures taught scientists crucial lessons about vaccine-associated enhanced disease and the need for safer approaches.

3. mRNA: From Overlooked Molecule to Therapeutic Hope

But until recently, RNA seemed like an extra on a movie set.

DNA's overshadowed partner. While DNA has long been the superstar of molecular biology, mRNA, the molecule that carries genetic instructions from DNA to build proteins, was largely ignored by researchers for decades. Despite its fundamental role in life, attempts to use mRNA therapeutically seemed fruitless by the early 2000s.

A lonely obsession. Katalin Karikó was one of the few scientists who remained dedicated to understanding and harnessing the potential of RNA, particularly mRNA. Despite facing constant funding rejections and professional setbacks, she stubbornly pursued her research, convinced of mRNA's promise as a drug or therapy.

Early glimpses of potential. Karikó's early experiments showed that mRNA could indeed instruct cells to produce proteins quickly. This hinted at the possibility of using mRNA to tell the body to make its own necessary proteins, offering a potential alternative to traditional protein-based drugs or gene therapy.

4. The Key Discovery: Modifying mRNA to Evade the Immune System

The cells were rejecting the mRNA.

The immune barrier. A major hurdle for using mRNA as a therapeutic was the body's innate immune response. Cells recognized foreign mRNA as a threat, like a viral invader, triggering inflammation and preventing protein production. This immune reaction was a primary reason scientists lost interest in mRNA.

An accidental insight. Through countless experiments, Karikó and her collaborator Drew Weissman discovered that not all RNA caused the same level of inflammation. They realized that naturally occurring RNA in the body often had slight chemical modifications, particularly to the nucleoside uridine.

The pseudouridine solution. Their groundbreaking discovery in 2004 was that replacing uridine with a modified version, pseudouridine, allowed the mRNA to evade the cell's immune detection. Not only did this prevent inflammation, but it also made the mRNA more stable and led to significantly higher protein production. This simple modification was the key that unlocked mRNA's therapeutic potential.

5. A Patent Lost, a Company Born

Penn officials, not realizing the significance of this discovery, sold the rights to it to an obscure company for next to nothing.

Overlooked significance. Despite the revolutionary nature of their modified mRNA discovery, Karikó and Weissman's findings were initially ignored by the scientific community and rejected by top journals. Their own university, the University of Pennsylvania, also failed to grasp the magnitude of the breakthrough.

Failed commercialization attempt. Karikó and Weissman tried to license their patent from Penn to start their own company, but negotiations broke down over the price. Penn then sold the exclusive rights to the patent for a mere $300,000 to a small research tools company called Cellscript, a subsidiary of Epicentre Biotechnologies.

A new company emerges. Derrick Rossi, a Harvard professor working on stem cells, learned about the modified mRNA technology and saw its potential beyond stem cell research. Leveraging the work of Karikó and Weissman, he co-founded Moderna in 2010, aiming to use mRNA as a platform for new drugs and therapies.

6. Building Moderna: Ambition, Secrecy, and Controversy

If corporations are people, Moderna is Stéphane Bancel.

A dealmaker takes charge. Stéphane Bancel joined Moderna in 2011 and quickly became its driving force. With a background in business and manufacturing, not science, his genius lay in raising enormous amounts of money for the unproven technology, making Moderna a "unicorn" company years before it had any product.

High-pressure environment. Moderna became known for its intense, secretive, and often controversial work environment under Bancel. Critics and former employees described him as demanding, arrogant, and prioritizing the company's valuation over its science and people, leading to high turnover.

Contested origins. Moderna, under Bancel and chairman Noubar Afeyan, developed a narrative of its own genesis that downplayed the foundational contributions of Karikó, Weissman, and even co-founder Derrick Rossi. They claimed Moderna scientists solved the key mRNA challenges, a claim disputed by the original discoverers and early employees.

7. Barney Graham: The Architect of Pandemic Preparedness

For years, Graham had been growing more confident he could create a vaccine fast enough to stop a pandemic.

Pivot from HIV. While the Vaccine Research Center's initial mission was solely an HIV vaccine, Barney Graham, its deputy director, saw the need to prepare for other emerging infectious diseases. Despite initial resistance, he carved out space to pursue research on viruses like RSV and coronaviruses.

Lessons from RSV. Graham's decades-long obsession with solving the mystery of the disastrous 1966 RSV vaccine trial, which caused enhanced disease, provided crucial insights into how to design safer vaccines by understanding viral protein structures and the immune response.

Anticipating the threat. Recognizing the emergence of SARS and MERS, Graham foresaw that another, potentially more contagious, coronavirus pandemic was inevitable. He began focusing his team's efforts on developing a platform approach to quickly create vaccines for novel coronaviruses before they emerged.

8. Structure-Based Vaccine Design: A New Paradigm

In Graham’s mind, the RSV vaccine was more than a single vaccine. It was a new paradigm for vaccines.

Visualizing the enemy. Jason McLellan, a structural biologist, joined Graham's lab and brought the expertise to visualize viral proteins at a molecular level using techniques like X-ray crystallography. This allowed them to understand how viruses like RSV attacked cells.

Targeting the right shape. Their key insight was that the shape of a viral protein before it attacks a cell (prefusion state) was the best target for generating potent neutralizing antibodies. For RSV, they discovered the protein flipped shape, and the old vaccine targeted the wrong, postfusion shape.

Stabilizing the protein. Working with McLellan and others, Graham's team developed a method using protein fragments (prolines) to lock the viral spike protein into its prefusion shape. This "two-proline substitution" was a critical breakthrough, creating a stable antigen that elicited a much stronger and more effective immune response, applicable across different viruses.

9. Near Misses: MERS and Zika Accelerate the Blueprint

We just had two new coronaviruses in the last 10 years, SARS and MERS. And our efforts to make vaccines for those were not very sophisticated.

MERS as a test case. Following the MERS outbreak in 2012, Graham and McLellan applied their structure-based design approach to coronaviruses. They successfully identified and stabilized the MERS spike protein, creating a blueprint for a coronavirus vaccine, even though a MERS vaccine wasn't urgently needed due to its low transmissibility.

Zika tests rapid response. The Zika outbreak in 2015-2016, with its devastating link to microcephaly, became a critical test for Graham's pandemic preparedness concept. His team rapidly developed a DNA vaccine candidate, getting it into human trials in a record 100 days, demonstrating the feasibility of rapid vaccine development.

mRNA's potential confirmed. During the Zika effort, Moderna also developed an mRNA vaccine candidate. Graham was impressed by its potency compared to his DNA vaccine, solidifying his belief that mRNA was the ideal platform for rapid vaccine development in response to future outbreaks.

10. The Race Begins: From Sequence to Shot in Record Time

Graham went to bed confident that, in the morning, he would whip up the genetic code for a vaccine that the untested company Moderna would manufacture.

Immediate action. The moment the SARS-CoV-2 genetic sequence was published on January 10, 2020, Barney Graham's team, having prepared for years, knew exactly what to do. They immediately designed the genetic code for a vaccine using their stabilized spike protein blueprint.

Moderna's role. Based on their prior collaboration and mRNA's speed advantage, Graham chose Moderna to manufacture the vaccine candidate. Production began the day after receiving the sequence, showcasing the "plug-and-play" capability of the mRNA platform.

Record-breaking trial. Despite the escalating pandemic and logistical challenges, the first human trial for the Moderna vaccine, overseen by Lisa Jackson in Seattle, began just 66 days after the sequence was released. This shattered previous records and demonstrated that rapid vaccine testing was possible.

11. Science Delivered, Society Hesitated

For the first time in vaccine history, science didn’t win.

Extraordinary efficacy. The clinical trials for the mRNA vaccines, including Moderna's and Pfizer's (which used a nearly identical design), showed astonishing efficacy rates of over 94% at preventing symptomatic COVID-19 and 100% at preventing severe disease. This far exceeded expectations and FDA requirements.

A scientific triumph. The rapid development, testing, and authorization of these highly effective vaccines represented a monumental scientific achievement, built on decades of foundational research by scientists like Karikó, Weissman, Graham, and McLellan.

Vaccine hesitancy prevails. Despite the scientific success and vaccine availability, a significant portion of the population, particularly in the United States, refused vaccination. This widespread hesitancy, fueled by misinformation and political polarization, hampered efforts to achieve herd immunity and allowed the virus, particularly new variants, to continue spreading, leading to preventable illness and death.

12. The Ongoing Threat: Variants and Future Pandemics

Someday a variant is going to appear that the vaccines don’t work against at all.

Variants emerge. As the virus continues to replicate in unvaccinated populations, it mutates, leading to new variants like Delta and Lambda. These variants can be more contagious and potentially evade the protection offered by existing vaccines, although current vaccines still provide significant protection against severe disease.

The need for universal vaccines. Scientists like Drew Weissman, Barney Graham, and Jason McLellan are now working on developing "universal" coronavirus vaccines that would be effective against any current or future variant of SARS-CoV-2, as well as potentially other coronaviruses that could cause future pandemics.

Preparedness remains crucial. The COVID-19 pandemic, while devastating, is unlikely to be the last. With thousands of coronavirus strains in bats and other viruses capable of spilling over into human populations, continued investment in pandemic preparedness, rapid response platforms, and universal vaccine research is essential to prevent future catastrophes.

Last updated: May 19, 2025