The Road To Immunity
The FDA has now approved the emergency use of two vaccines designed to provide immunity against COVID-19. This opens a new phase in America’s fight against the virus that has already taken the lives of more than 330,000 Americans. These two vaccines were brought to market in less than 10 months after the virus claimed its first U.S. victim, a truly remarkable feat considering that it in the past it has taken four or more years to develop a vaccine. The speed at which these vaccines were developed was a product of both the vicious nature of the virus as well as the extraordinary efforts put forth by our federal government and a number of dedicated research scientists. The story behind these vaccines actually long predates the emergence of the coronavirus that causes COVID-19.
The first vaccine to be approved was developed by BioNTech, a small German biotech company in partnership with Pfizer, Inc., the world’s largest pharmaceutical manufacturer. The second vaccine was produced by Moderna, a small American biotech company working closely with the National Institute of Health. Both the Pfizer-BioNTech and the Moderna-NIH vaccines trace their origins back to 1993 when Kaitlin Kariko, a Polish biochemist, began advocating the use of messenger RNA (or mRNA) as a means of fighting diseases. It’s that technology that is utilized in both of the recently approved vaccines. While originally developed as a means of fighting various forms of cancer, the mRNA technology was subsequently employed in research involving prior forms of coronaviruses that gave rise to the SARS and M1N1 epidemics.
RNA is a polymeric molecule that is able to provide instructions to cells in living organisms and the mRNA technology employs these molecules to direct the human body’s autoimmune systems to attack a harmful virus that enters the body. While the humans have an innate ability to detect a virus and mobilize their immune systems against it, this is a relatively slow process and may not be achieved in time to prevent the virus from causing significant harm or even death. By programming mRNA, scientists can instruct an individual’s cells to recognize and attack a specific virus as soon as it enters the body.
The previous research with respect to the mRNA technology in large measure explains why it was possible to so quickly develop a vaccine specifically to combat COVID-19. Still, the mRNA had to be programmed to address the particular virus that gives rise to COVID-19. A critical step in that process was taken last January by the Chinese researchers who identified the virus and mapped its DNA. Armed with that vital information, research biologists all around the world set out to create a vaccine. It’s reported that more than 100 such efforts were immediately launched and that roughly ten of them, in addition to the Pfizer and Moderna vaccines, are currently approaching fruition. The vaccines now being developed by Johnson & Johnson, AstraZeneca and Novavax could be ready for emergency approval within the next sixty days.
Once a molecule for defeating a virus has been created by inserting the virus’ genetic code into an RNA molecule, it must still be formulated into a vaccine. While the Pfizer and Moderna vaccines utilize the same mRNA molecules as their active ingredient, there are differences in the way these vaccines are formulated which give them different properties.
Even though a vaccine may perform well in a petri dish or even in laboratory animals, there is no guarantee that it will be tolerated by the human body and will actually be successful in protecting humans against the virus. This must be determined through a series of clinical tests. The first phase of clinical tests typically involves a limited number of people and are designed to determine whether and the extent to which the vaccine will be tolerated by the human body without causing adverse reactions. Simply stated, Phase 1 tests are intended to ascertain the safety of a potential vaccine as opposed to its efficacy.
The second phase in the clinical testing process seeks to determine the efficacy of the vaccine and generally involves a relatively small number of subjects (no more than a few hundred patients). Like the Phase 1 studies, the Phase 2 studies may test a variety of doses to ascertain what level of dosage is most effective. Phase 2 studies generally involve that class of patients who have proven most vulnerable to the virus, with little effort being made to ascertain the vaccine’s effect on specific classes of patients identified by age, gender or ethnicity. While the principal focus of Phase 2 clinical tests is efficacy, all side effects and adverse reactions will also be recorded because Phase 2 studies will involve far more subjects than the Phase 1 tests and some adverse effects may not have been revealed in the earlier limited patient population. Phase 2 tests will also seek to determine whether a single dose of the vaccine will suffice or whether multiple doses may be required and, if so, the timing of those doses.
Although Phase 2 clinical studies may reveal that the vaccine produces antibodies to a virus, they do not actually reveal the extent of a vaccine’s efficacy which must be determined through large scale Phase 3 clinical tests. In the case of a vaccine for a virus affecting millions of people, Phase 3 studies will usually involve tens of thousands of patients. In fact, it is not unusual for a Phase 3 study of a vaccine to involve over 100,000 subjects. Whereas Phase 3 studies of a therapeutic drug might involve a few thousand subjects, Phase 3 studies of a vaccine must involve many more participants because many of the participants will never come in contact with the virus which is the subject of the study. Unlike the Phase 2 clinical tests, the subjects in the Phase 3 tests will be broken down into two groups, those that receive the vaccine being tested and those that are administered a placebo. Phase 3 studies are conducted in what is called a “double blind” format with neither those participating in the study nor those administering the shots knowing who is receiving the vaccine and who is receiving the placebo.
As a further check to make sure that a new vaccine is both safe and efficacious, the FDA normally requires that two Phase 3 studies be conducted before the vaccine can be approved. In applying for FDA approval, the vaccine developer will have to include in its approval application extensive data from its clinical studies including all adverse reactions to the vaccine. Because a large segment of the population may simply not be susceptible to the virus, a vaccine’s effectiveness can only be measured by comparing the differential in the percentage of subjects receiving the vaccine who become infected with the percentage of those receiving the placebo who become infected. Obtaining FDA approval will require that the differential be statistically significant.
One of the reasons why vaccines take much longer than therapeutics to achieve FDA approval is that it might take weeks, if not months, for the subjects of the clinical trials to actually come in contact with the disease. This possibility makes it necessary that clinical trials for vaccines remain open for a much longer period and involve far more participants than clinical trials for therapeutic pharmaceuticals. In addition, if the vaccine is developed months or years after a virus has run its course, it could be a very long time before a significant number of those participating in the study actually encounter the virus. Unlike the development of earlier vaccines, this was not a factor in the clinical tests of the Pfizer and Moderna vaccines as the virus causing COVID-19 was being freely transmitted throughout the period when their Phase 3 trials were being conducted.
In the case of the Pfizer and Moderna vaccines, the applications for approval were submitted for “emergency use” and did not involve a second Phase 3 clinical trial. The Pfizer application sought approval for inoculations of persons 16 and older and the Moderna application sought approval for the use of its vaccine for persons 18 and older. Both applications were submitted for review by the FDA’s Advisory Committee and four members of that committee questioned whether approval should be granted for individuals under the age of 18. Normally, a separate application for drug approval must be made for minors and/or adolescents. In view of the speed at which the virus is now spreading and its highly lethal nature, the FDA quickly granted approval to both applications
The speed at which the FDA granted its approval of the Pfizer and Moderna vaccines was not without downside risks. In order for a vaccine to be truly effective in stopping the spread of a virus, it must be administered to a very high percentage of the population. This is always a problem as a significant percentage of Americans distrust vaccines and fear their side effects. In addition, by the time the approval applications came before the FDA the coronavirus had been denounced by President Trump as a hoax and not a threat to most Americans. This further reduced the percentage of Americans willing to be vaccinated. It was therefore very important for the FDA appear to have performed a careful and methodical review of the two applications. This would help to avoid the perception that it had simply caved to the political pressure that was being applied by the President and that the vaccines might be unsafe.
The assistance provided by China and the urgency posed by the pandemic does not fully explain why the Pfizer and Moderna vaccines (as well as the others that are yet to be approved) have been produced so quickly. As intimated above, producing a vaccine is a hard and laborious process and can easily entail an investment of more than $100 million. On top of that, a drug developer has no assurance that its efforts will prove successful or if they will come to fruition while the disease remains a problem. If fact, in many cases by the time a vaccine has been developed, the subject virus may have mutated or even been extinguished by the products of another manufacturer. In short, the investment necessary to develop a vaccine is immense and the risks of not being able to profit on that investment are also huge.
This is where the federal government played an important role. In the case of Moderna, the federal government provided $1 billion to help cover its development cost. In addition, the federal government committed to purchasing 100 million doses of the Moderna vaccine for an aggregate purchase price of $1.5 billion. In the case of Pfizer, the federal government agreed to purchase 100 million doses of its vaccine for $1.95 billion. Similar arrangements were made with Johnson & Johnson, AstraZeneca and Novavax. In this way, much of the risk of developing the vaccines were transferred to the federal government. Without such extra incentives, these companies would have undoubtedly proceeded at a much slower pace being careful to take one step at a time so as to minimize their development costs.
Just as important as developing a vaccine is producing it. The economic incentives provided by the federal government enabled these manufacturers to take the extraordinary step of proceeding with large scale production of their vaccines before they had even received FDA approval. As a result, immediately upon approval of its vaccine Pfizer was in a position to ship 50 million doses. It is anticipated that Moderna is now in a position to ship 100 million doses of its vaccine. Thus, there should currently be available enough vaccine to immunize 75 million Americans since each individual must receive two doses.
As noted above, although the Pfizer and Moderna vaccines both utilize the mRNA technology, there are differences between them. The good news is that they are both expected to be 95% effective, an impressive feat for any vaccine. The Pfizer vaccine is to be given in two doses of 30 milligrams three weeks apart and the Moderna vaccine is to be given in two doses of 100 milligrams four weeks apart. The Phase 3 clinical tests of the Pfizer vaccine revealed that it is 70% effective after a single dose which is more effective than most vaccines and equally as effective as the yet to be approved AstraZeneca vaccine. This raises the possibility that the Pfizer vaccine could be utilized as a single dose which would allow the current limited supply of that vaccine to be used to inoculate an additional 25 million Americans.
Because mRNA is not a stable molecule, it must be kept at cold temperatures. The Moderna vaccine coats its mRNA molecule with bubbles made of lipid nanoparticles. This enables it to remain stable at normal freezer temperatures. The Pfizer vaccine, in contrast, must be stored and transported at much colder temperatures. This means that the Moderna vaccine can be utilized in places that do not have the equipment to properly store the Pfizer vaccine. For this reason, it is anticipated that the Moderna vaccine will be shipped to 3,200 U.S. locations in contrast to the Pfizer vaccine which is currently scheduled to be shipped to only 636 locations.
While developing and producing the two vaccines has been a monumental feat, there is still much work that lies ahead to get these vaccines into the arms of Americans so that life can return to a semblance of what their lives were like before the pandemic struck. Already problems in the roll-out process have been encountered.
This past week a number of states reported having received messages that they would not be receiving the supplies of the Pfizer vaccine that had previously been promised to them. When the news media questioned why this was happening, the Department of Health and Human Services responded that Pfizer was encountering production issues. Pfizer quickly responded that it had encountered no production problems and that its warehouses had plenty of vaccine doses on hand awaiting shipping instructions. HHS then changed its story, saying that there had been a miscommunication with the states as to the shipments they were to receive this week. This seemed wholly implausible in view of the fact that more than a dozen states had reported receiving such notices and their shipment shortfalls ranged up to 40%. To explain the problem, four-star General Gustave Perna, the man in charge of the vaccine program, went on television to say that he “takes full responsibility for the miscommunications with the states.” In a wholly unintelligible explanation he pointed out that there was a difference between vaccine doses that are “available” and those that are “releasable.” By this he implied that the distinction has to do with the FDA’s review of vaccines before they they can be released. It didn’t take long for FDA Commissioner Stephen Hahn to point out that his agency’s examination of test samples is not a pre-condition to the distribution of approved pharmaceutical products. When asked for a further explanation, General Perna said that “he wasn’t going to spend any more time talking about the details between fill-finish and releasable.” This SNAFU has all of the earmarks of an act of revenge by President Trump for Pfizer’s having delayed its announcement of the results of its Phase 3 clinical trial until after the election.
The incoming Biden administration has also discovered that the Trump administration has no real plan for inoculating the nation. Just as it left the states on their own when it came to filling their medical equipment needs, testing for the virus and determining what steps should be taken to stop the spread of the virus, the Trump administration has left the job of devising and implementing inoculation plans to the states. This poses a problem since the supplies of the approved vaccines are limited and won’t be available for most Americans for at least a few more months. This is also problematic because the states have been hard hit by the pandemic and the resulting collapse of economic activity. With the enactment this week of additional economic relief legislation, they will now have the resources with which to conduct the vaccination roll-out. The problem isn’t just that the states didn’t have the money or medical supplies with which to carry out the inoculation program; they remain hard-pressed to muster the medical personnel needed to administer the process as they are currently experiencing an onslaught of COVID cases and their hospitals are filled to capacity. Our hospitals are simply not staffed and equipped to run at full capacity as they have been doing for weeks on end.
Although it is widely suggested that essential workers and those over the age of 75 be given priority in receiving the vaccines, it is still yet to be determined the specific order of groups that should have priority in receiving the current limited supplies of the vaccines and what guidance and assistance the federal government should be giving to the states to carry out this unprecedented inoculation program. With the number of new confirmed cases currently exceeding 200,000 each day, the nation will be engaged in a race to immunize its citizens before the virus reaches them.