The Covid-19 pandemic is one of the most challenging public health crises the United States has contended with in over a century. During a state of emergency, the benefits of creating effective vaccines and the risks of delaying their release are extremely high. Vaccinating the population as soon as possible decreases loss of life and allows economic activity to resume, but the vaccine approval process must be completed diligently with particular attention paid to the statistical rigor of the clinical trials. If a vaccine is released that lacks adequate efficacy, the relaxed behavior that occurs in people who are vaccinated could lead to the paradoxical result of more infections. If a vaccine is released that has a high occurrence of unpleasant and/or deadly side effects, vaccine hesitancy may negatively impact the number of people who choose to get vaccinated. These realities caused a dilemma for public health authorities—every month the Covid-19 vaccines delayed cost tens of thousands of lives, but prematurely releasing the vaccine could have caused just as much, if not more, damage. In response to this historic pandemic, the federal government and biomedical research companies cooperated to develop effective vaccines in just under a year, a speed that is historically unprecedented.
Coordinated efforts by the United States to develop a Covid-19 vaccine began with the announcement of Operation Warp Speed (OWS) on May 15th 2020. OWS was a private-public partnership between the United States Federal Government and pharmaceutical companies with the goal to “produce and deliver 300 million doses of safe and effective vaccines with the initial doses available by January 2021, as part of a broader strategy to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics”. OWS was an interagency program which consisted of several components of the Department of Health and Human Services (HHS) including the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the National Institutes of Health (NIH), the Biomedical Advanced Research and Development Authority (BARDA), and the Department of Defense (DoD). BARDA functioned as the leadership and financial interface between the federal government and the biomedical industry, providing funding for research and manufacturing to the companies that produced the most promising vaccine candidates. OWS received nearly 10 billion dollars of initial funding, 6.5 billion of which went towards medical countermeasure development and the other 3.5 billion towards NIH research. As clinical trials progressed, OWS funding was expanded to over 18 billion dollars. Six vaccine candidates (out of over one hundred) received substantial funding from OWS.
Rather than pursuing a Biologics License Application (BLA), the standard licensure requirement for distributing vaccines to the general public, pharmaceutical companies were able to acquire Emergency Use Authorizations (EUA). The federal government established the use of EUAs as a means to quickly produce and distribute unproven but potentially life saving drugs to the general public following the declaration of a public health emergency by the Secretary of Health and Human Services. Once a state of emergency was declared, the FDA published several guidelines for issuing EUAs. By pursuing an EUA as opposed to a BLA, pharmaceutical companies were able to expedite vaccine research, clinical trials, and mass production. The Covid-19 EUA also standardized the clinical trial protocols that pharmaceutical companies had to follow. Standardizing the clinical trial protocols ensured that all of the vaccines met the same efficacy and safety standards. Due to the dangers of releasing ineffective vaccines, the FDA required certain efficacy standards.
While the Covid-19 vaccines had to comply with the same safety criteria as every other preventative vaccine for an infectious disease, certain parts of the process were shortened. Normally the periods between phase 1 and 2, and phase 2 and 3 of the clinical trial have six month observation periods to observe if any side effects develop. This six month observation period was reduced to two months in the EUA, with the rational being that 95% of adverse reactions occur within 6 weeks.
Another way that the Covid-19 EUA expedited the process was by encouraging pharmaceutical companies to engage in financially high-risk vaccine development. In normal situations, vaccine development is not a highly profitable endeavor. Pharmaceutical companies spread out the financial risk over a longer period of time by completing each step sequentially in the development process. In the standard paradigm, the process usually occurs as follows;
- In vitro laboratory research,
- In vivo animal studies,
- Phase 1 clinical trial,
- 6-month observation,
- Phase 2 clinical trial,
- 6-month observation,
- Phase 3 clinical trial and manufacturing scale up,
- Manufacturing process and product validation,
- Biologics License Application (BLA) approval (standard licensure requirement for distributing vaccines to the general public),
- Production at a commercial level
This entire process can take anywhere between 5-15 years, and given that less than 10% of vaccine prototypes end up acquiring a BLA, spreading out the steps is a financially smart decision. If a vaccine were to fail in the early clinical trial stages, the financial losses would be minimized since little investment was made towards manufacturing. In financially high-risk vaccine development, however, many of the steps occur simultaneously. In vivo animal studies and phase 1 of the clinical trial are often merged, as well as phase 2 and 3 of the clinical trial. This reduces the clinical trial time substantially without undertaking significant safety and efficacy risks since all of the steps that would have occured in a normal biologics license application trial have still occurred, albeit in a merged or overlapped manner. Most importantly, manufacturing scale up and commercial manufacturing of the vaccines occur simultaneously to the clinical trial. This is a financially high-risk strategy since significant investments are made into manufacturing before knowing if the vaccine is safe and effective. In this case, the federal government provided funding for the large manufacturing scale up, removing the financial-risk from the pharmaceutical companies.
Although this was an expensive and financially high-risk strategy, it led to vaccines being created, tested, and distributed in an unprecedented timeframe. Covid 19 vaccines were available to the first qualified members of the general public in just under a year, significantly faster than the normal 10-15 year timeframe. Of the six vaccines that received research funding from OWS, just two vaccines (Moderna and Janssen Pharmaceuticals) received an EUA from the FDA. The total funding for the other four vaccines that did not receive EUAs amounts to nearly five billion dollars. Two of the vaccines (Astrazeneca and Merck) have been either paused or terminated, and the other two vaccines (Norovax and GlaxoSmithKline) are still in development. Although OWS did not fund research for the Pfizer-BioNTech Covid-19 vaccine, an EUA was granted following submission of data from their phase 3 clinical trial and two billion dollars worth of vaccines were pre ordered.