It’s Time To Appreciate A Great Success Story
From innovation in early 2020 to approved vaccines in later 2020, what has been accomplished is awesome and demonstrates what America can achieve when it comes together to aggressively respond to a serious threat.
The Food and Drug Administration (FDA) has granted emergency use authorization to three vaccines against the virus that causes Covid-19, and all three have been extremely effective with no hospitalizations and no deaths among the vaccinated volunteers. Home runs. Two more vaccines are nearing home plate with no reported hospitalizations or deaths among the vaccinated individuals. Progressing from nothing at the beginning of the pandemic to three and soon five authorized vaccines is truly awe inspiring. The innovative concepts and science and the manufacturing prowess of the pharmaceutical firms is impressive. Three of the vaccines were developed by very small companies and another by a modest size company. The first three linked up with major international pharmaceutical giants with their expertise in clinical trials, manufacturing and distribution.
The United States government created a unique public/private partnership called Operation Warp Speed (OWS) to smooth the testing, authorizing and manufacturing pathways necessary for success and assured funding for this work and for purchasing hundreds of millions of doses well before success was proven.
The basic aim of Operation Warp Speed, according to its then director Dr. Moncef Slaoui, was to “accelerate control of the pandemic by advancing manufacturing and distributing of vaccines, therapeutics and diagnostics.” Slaoui was the former long-term head of vaccine development for GlaxoSmithKline, a major international pharmaceutical firm with a long history of vaccine development. The chief operating officer of OWS was and is Gustave F. Perna, a four-star general who and former commander of the Army Materiel Command (logistics.)
The public/private partnership includes the innovators and the large pharmaceutical firms along with their partners in the supply chain necessary to produce and manufacture the vaccines. On the government side it includes the Department of Health and Human Services (National Institutes of Health, Food and Drug Administration, Centers for Disease Control, Assistant Secretary for Preparedness and Response (ASPR) and the Biomedical Advanced Research and Development Authority (BARDA.). It also includes the Department of Defense with its Defense Advanced Research Projects Agency (DARPA) and military Logistics.
Initially construed by then HHS secretary Alex Azar as the “second Manhattan project,” the concept was to fundamentally restructure how the United States government typically supports product development in order to bring vaccines to market in record time. This was done by providing support to the companies that had promising candidates early in the spring of 2020 so as to enable expeditious parallel steps towards Food and Drug Administration authorization. A fundamental principle was assuring financing for the entire development process at the start of clinical trials. This meant that the drug companies knew that they would have financial support going forward whether or not the vaccines ultimately proved effective and safe. This allowed industry to prepare for phase III while still in phase I. They were encouraged and funded to establish manufacturing scale up from the beginning. They also received purchase commitments upfront from the government for hundreds of millions of vaccine doses.
It is instructive to think about how vaccines normally come to market. The timeline is usually about a decade, although the mumps vaccine was brought out in four years, a record until now. The first steps are conceptualizing and developing a vaccine. If all seems well, then it is tested in animal models. If that works well, the FDA is requested to authorize a phase I human trial. The phase I trial utilizes a few volunteers to test various doses of the vaccine to determine if and at which dose it produces a useful antibody response. If phase 1 is successful, the company goes back to the FDA with the data and requests permission to start a phase 2 trial. The phase 2 trial uses a few hundred people to test whether or not the vaccine will consistently produce an antibody response in a larger more diverse group of people. The phase 2 trial is also looking for any unusual side effects. Many candidates are jettisoned either at or during the initial laboratory testing, the phase 1, or the phase 2 trials. But if the phase 2 trial is successful, the company goes back to the FDA and seeks approval to begin the very large-scale phase 3 trial. This is the randomized double-blind placebo-controlled trial that compares the vaccine in volunteers to those who receive a placebo. Then they have to wait over a period of time while some number of the volunteers develop the disease in question. Frequently this will take a year or more if the disease is not extremely prevalent. If the phase III trial goes well, the company goes back to the FDA and seeks approval. The FDA usually has many questions and reviews the data over an extended period of time. All of this takes a good while, and it is not until late in the trial that the pharmaceutical firm, seeing that the results will probably be positive, begins production, quality testing and packaging. This is a simple financial decision; there is no point in making the vaccine if it is not going to be approved. These many steps take time back and forth between the company and the FDA, both of whom have many other priorities in place. The whole process has substantial “downtime.”
With Operation Warp Speed, the concept was to run everything possible in parallel yet at the same time not bypass any steps required for safety and effectiveness. This meant having the FDA reviewing results of the phase 1, 2 and 3 trials in real time rather than waiting for final data. It also meant having uniform criteria for evaluation of each candidate vaccine established well in advance of the start of phase 3 trials.
The development of the coronavirus vaccines only began in earnest in January 2020. In mid-January the Chinese government released the genetic sequence of the virus and enterprising, innovative individuals and companies, often quite small, believed that they could produce a vaccine using both new and old technologies. The phase 1studies began in March and the phase 3 studies began in July with, as everyone now knows, the first FDA authorizations coming in mid-December 2020.
Only a few companies were selected for support in Operation Warp Speed. The criteria included having robust pre-clinical data; strong results from the phase 1 trial, the potential to enter phase 3 by the summer or at least the early fall; and an expectation that there would be efficacy outcomes by the end of the year or shortly thereafter. The latter requirement meant that the phase 3 trials would need to enlist 30–40,000 volunteers in short order so as to have enough comparative data, including at least two months of safety data, by late fall. Each company selected needed to demonstrate that it could produce tens of millions of doses by December 31, 2020 and 300 million doses by mid-2021.
It was determined by OWS leaders that they would place their bets on multiple technologies and multiple companies because vaccine trials so often fail. They wanted to be sure that at least one but preferably more of the supported vaccines would eventually be authorized.
Four technologies or “platforms” were selected that were believed would offer multiple opportunities for success both with efficacy and safety and the ability to produce the necessary numbers of vaccines should the vaccine be authorized. The four platform technologies included using messenger RNA (mRNA,) a viral vector, a recombinant subunit protein, or an attenuated replicated live virus. The last one is an old technology that has been used for many vaccines over the years such as the Sabin polio vaccine. The others are relatively new technologies although each has been under study for many years and some had been used for approved vaccines in the recent past.
It was decided that the government would support two vaccine candidates from each of the four platform technologies and that in order to get an answer fast enough they would support those very large phase III trials. Ultimately, only six vaccine candidates were chosen.
For the messenger RNA (mRNA) platform they chose Moderna which had been working with the National Institutes of Allergy and Infectious Diseases, and the Pfizer-BioNTech candidates. For the viral vector platform, they chose the Oxford — AstraZeneca and the Johnson & Johnson (Janssen) candidates. For the subunit recombinant protein, they chose Novavax and Sanofi-GSK (GlaxoSmithKline.) Merck was the single candidate in the last technology. The decision to choose multiple candidates and multiple technologies proved to be wise because the two Merck vaccines failed and were withdrawn and the Sanofi-GSK (GlaxoSmithKline) vaccine is far behind in development.
The basic approach was to run all “streams” in parallel to the extent possible and to be sure that each of these streams were fully resourced, meaning funded. Unlike the usual approach of waiting to see if the phase I studies are done and accepted by the FDA and then running through the phase 2 trials before deciding on whether to move ahead with phase 3, Operation Warp Speed gave resources early in the phase I process so that the companies could begin to prepare for the phase 3 trials and begin developing their manufacturing processes. This meant giving government money upfront to help the companies with development and then commitments to purchase vaccines. (Pfizer chose not to take government funding for the development aspect, preferring to have more independence.) Another key was to establish what the endpoints would be for the phase 3 studies well before those studies were begun such that all the vaccines would be evaluated on an equivalent basis and the companies would know from the beginning what the criteria were. This established a level playing field for all the candidates.
The support given to the selected companies allowed them to commence vaccine development and manufacturing long before FDA authorization. This meant that there would be millions of vaccine doses available immediately upon FDA authorization. Of course, if the vaccine proved to be inadequate, the money spent would be for naught. It is worth noting that Operation Warp Speed recognized that not all candidates might make “the cut,” as time and experience proved correct.
The FDA committing to reviewing data in real time rather than waiting for the completion of each phase. This eliminated substantial “down time” while not sacrificing quality of the review and authorization process.
OWS was not without controversy. The rollout in late December and beyond was troublesome at best with finger pointing in many directions. In the early days, the leadership was heavily citied for a lack of transparency in selecting candidates/companies. It being a presidential election year, there was plenty of criticism that the vaccines were being rushed before they could be properly evaluated. And there were numerous conspiracy theories along with negative comments from the anti-vaccination groups. President Biden merged OWS (the name has been dropped) into his new Covid-19 White House team, replacing Dr Slaoui but retaining General Perna.
Despite the criticisms, as of mid-March, 2021, the United States has three FDA authorized vaccines with the Oxford-AstraZeneca and Novavax vaccines are getting close. More than 124 million Americans have had at least one dose (as of April 14, 2021) or 37% of the population (48% of those 18 and above) and the number vaccinated per day is ramping up rapidly. Had the system worked as in the past, it would have taken much longer, months at least, and likely a year or more to reach the same endpoint.
Most important is to recognize the genius of the innovators, the rapidity with which they worked, the small company/large pharmaceutical firm collaborations, the enormity of arranging and conducting huge international trials, and the development of the manufacturing technologies and supply chains for types of vaccines that had never before been created and distributed in massive numbers. Add to this the government’s major assistance to smooth the way, get “silos” working together, eliminate “downtime,” assure adequate funding for both research and manufacturing and the results speak for themselves.
According to Dr. Moncef Slaoui, obviously proud of what was accomplished, “By any standard this is absolutely exceptional.” It is indeed. We can and should all proud and very thankful.