The SARS-CoV-2 virus has claimed over 600,000 lives in the United States alone, as of June 2021 [1]. As we faced a once-in-a-generation threat to life as we know it, scientists and public health experts rose to the occasion. In less than a year, the U.S. had multiple vaccines with emergency use authorization by the FDA [2]. Two of these vaccines, those made by Pfizer-BioNTech and Moderna, are a different class of vaccine than any that has been used before. These vaccines use mRNA molecules, or temporary messengers of genetic information, to induce the immune response. This is different from most current vaccines, which instead use inactive versions of the viral proteins [3]. Many people hesitant to receive this new class of vaccine are wondering how the record-breaking vaccine development timeline was possible.
To answer this question we must first look at the driving force behind the mRNA technology, a scientist at the University of Pennsylvania named Katalin Karikó. Karikó worked in this field for decades before she finally discovered a way to modify mRNA to enter cells without triggering a harmful immune response. This 2005 discovery is credited as the basis for mRNA-based immunity [4]. Karikó and her collaborator, Drew Weissman, were granted a U.S. patent for their discoveries in 2012 [4]. University of Pennsylvania quickly sold the license to Cellscript, a company that specializes in mRNA production for clinical research. They primarily use the license to create modified RNA transcription kits for use in laboratory research [5]. Cellscript then entered non-exclusive sublicenses of the technology with Moderna and BioNTech in the summer of 2017 [5].
Prior to the COVID-19 pandemic, there were already multiple mRNA vaccines in phase I, II, and III clinical trials [3]. Moderna currently has twenty-four mRNA-based products in development, including four in phase II clinical trials. These products include a cytomegalovirus vaccine and various immuno-oncology therapeutics [6]. BioNTech currently has almost thirty mRNA candidates in preclinical, phase I, or phase II trials, including various immuno-oncology therapeutics and an influenza vaccine [7]. The average length of time it takes for a drug in the U.S. to travel from preclinical testing in cells and animal models to FDA approval is twelve years [8]. The timeline for an average vaccine to be developed and approved is slightly shorter, at ten years [9]. These earlier mRNA therapeutics were plodding along on the typical timeline that began with Karikó and Weissman’s discovery and subsequent patent. So how did the COVID-19 vaccine effectively lap all the other mRNA-based products in development?
Navy officer receives a first dose of a COVID-19 vaccine. Licensed under CC BY 2.0 by the U.S. Secretary of Defense.
An enormous contributor to the breakneck pace of COVID-19 vaccine development was money. Operation Warp Speed was a program facilitated by the U.S. government to accelerate COVID-19 therapeutic development, production, and distribution [10]. The program spent $12.4 billion as of mid-December, 2020, including a $1.53 billion investment in Moderna [11]. The government had already given Moderna initial grants totaling $955 million, bringing the total investment up to $2.48 billion [12]. The U.S. government also pledged to purchase at least 100 million doses from Moderna for an additional $2.48 billion, which includes a profit for each dose, according to Moderna [13]. Pfizer did not accept money from the Operation Warp Speed project, although BioNTech received the equivalent of $445 million from the German government to accelerate vaccine production [14]. Pfizer also received an advance-purchase order of $2 billion to provide 100 million doses of the COVID-19 vaccine upon FDA approval.
In addition to the money directly invested in these pharmaceutical companies, it was clear there would be a massive market for a safe and effective vaccine. COVID-19 had reached every part of the world, resulting in nearly universal demand. 11 billion doses are required to vaccinate 70% of the world [15], representing enormous money-making potential for companies that contribute to the world’s vaccine supply. Additionally, both Pfizer and Moderna stock prices are trading near all-time highs. Moderna stocks are up 254.3% over the past year (as of June 27th, 2021) [16].
What did all this money mean for vaccine development? It meant that the pharmaceutical companies could ignore the financial risks associated with the high failure rate along the therapeutic pipeline. The companies could overlap timelines between clinical trials, running them concurrently to save time [3]. Normally this is not done, because if the trial fails at an earlier stage the companies do not want to waste money on additional testing. Not only did the companies overlap their clinical trials, they also began manufacturing vaccines before these trials were completed. If the vaccines were ineffective, this would have wasted resources and money.
The flow of money into pharmaceutical companies during the COVID-19 pandemic meant that they could also ignore the financial risks associated with the mRNA supply chain. mRNA vaccines require ultracold temperatures, which makes distribution costly and difficult. The network of refrigerators, freezers, and other supplies required to maintain these temperatures is called the cold chain. Maintaining a cold chain makes shipment of vaccines to remote areas burdensome. Up to 25% of shipped vaccines are compromised due to a broken cold chain, representing a major source of financial waste [17].
Pfizer-BioNTech COVID-19 mRNA vaccine. “Pfizer-BioNTech COVID-19 vaccine” is licensed by U.S. Secretary of Defense under CC BY 2.0.
Furthermore, the pandemic-induced sense of urgency allowed pharmaceutical companies to disregard the time costs associated with regulatory approval of a new therapeutic [3]. No mRNA therapeutics had ever been approved by the FDA before. Despite mRNA vaccines being a new class of therapeutic and an unknown in terms of risk classification, it was clear that companies would be able to acquire emergency use authorization (EUA), which would not be available for the other mRNA products in their pipelines. EUA can be granted after clinical trial participants are monitored for three months. Typical FDA approval requires six months of monitoring to study potential rare side effects and duration of immunity [18].
Despite the accelerated timeline, the pharmaceutical companies were able to complete these clinical trial milestones with the same level of scientific rigor. The step that typically takes the longest in any clinical trial is recruitment. Nearly 80% of clinical trials fail to meet their enrollment deadlines, which can cause delays [19]. Pfizer and Moderna did not encounter these problems, enrolling a combined 73,968 participants in a matter of months [3].
What does the rapid production and distribution of mRNA vaccines to address the COVID-19 pandemic mean for mRNA technology in the future? mRNA vaccines have demonstrated their value in responding to viral outbreaks. Manufacturing capabilities for mRNA synthesis will greatly expand with increased use [3]. Pharmaceutical companies have already had to optimize and invest in their cold chains to respond to the crisis. Additionally, mRNA vaccines are no longer completely unknown to regulatory agencies like the FDA. The social and financial urgency of the pandemic that swiftly pushed the COVID-19 mRNA vaccines forward has also opened the door for additional mRNA therapeutics to come.
References
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