Over the past week there have been conflicting statements from our politicians on the upcoming availability of vaccines for COVID-19. We all hope for successful tests that demonstrate effective and safe use of the new vaccines being developed.
I want to take this opportunity to discuss the nature of the vaccine testing and the time restraints that will dictate availability.
Currently, there are three vaccines in Phase 3 tests. Let’s understand the differences between these three vaccines.
First, Moderna. This is a new type of vaccine. It is created in the laboratory. It consists of a little fat bubble that has a “transmembrane” protein on its surface along with another enzyme. These two proteins allow for the fat bubble to be incorporated into the membrane of a human cell. Inside the fat bubble is a piece of genetic material called m-RNA, or “messenger” RNA. This type of RNA is the specific template for a cell to manufacture a protein. In this case the m-RNA codes for the Spike protein of COVID-19, the most important protein target for a protective immune response. The idea behind this vaccine is that the little fat bubbles will deliver the m-RNA to the cells in the body; those cells will manufacture the Spike protein and export them either onto their own membranes, or into the blood; this will allow the immune system to mount a response to this protein and thus protect the individual from virus challenge in the future.
Results have been very encouraging; however, this type of vaccine has never been used before to combat a human disease in the population, so until tests are complete there will be questions about the approach itself.
A problem with this vaccine is that it requires the vaccine to be stored at -70 degrees and this capability is not available in many locations; this will create significant problems for distribution and inoculation.
Next, Pfizer. This vaccine is quite similar to the Moderna vaccine. The chief difference is the m-RNA that is encapsulated into the fat bubbles. In this case, rather than including the instructions to make the entire Spike protein, the Pfizer vaccine m-RNA codes only for the “RBD”. This is the end piece of the Spike protein; the piece of that protein that binds to the receptors on cell surfaces. This is the piece of the Spike protein to which an immune response will allow neutralization (protection) against infection.
Results here have also been encouraging, but the novel vaccine has the same cautions as the Moderna vaccine.
Finally, AstroZeneca. This is a more standard approach. In this vaccine an “adenovirus vector” is used to deliver genetic material to a cell and that genetic material instructs the cell to produce the COVID-19 proteins and export them. Adenoviruses are very common in the environment; there are hundreds of them, and they can cause infections of the respiratory tract, the digestive tract and other areas. Most are very mild infections. Several of these viruses have been modified over the past 50 years, creating viruses that can infect specific cells and have virtually no clinical disease of any sort.
The AZ vaccine uses one of these adenovirus vectors, with the COVID-19 protein genetic material incorporated into its own DNA. When the virus infects human cells, it produces the COVID-19 proteins and generates an immune response.
These results have also been encouraging, and this vaccine, with the characteristics identical to multiple other successful vaccines does not have the same distribution problems as the Moderna or Pfizer vaccines.
WHAT ARE THE PROBLEMS THAT WILL CAUSE DELAYS?
RECRUITING.
As an example, Moderna received authorization for a phase 3 trial in mid-July. They need to recruit 30,000 people into the trial. As of today, they have only recruited a little over 23,000. The study will not be fully filled until at least the end of September. Until these studies are fully filled there can be no good analysis of the results, and those studies will not be able to even begin until October.
DIVERSITY.
It is not only important to recruit 30,000 people, but those panels need to be diverse with respect to age, sex, race, ethnicity and medical condition in order for fair results to be analyzed. This restriction makes the recruitment of people more difficult. Initial studies will still be restricted. For example, children will not be tested. Pediatric studies are generally separate from adult tests.
TESTING TIMELINES.
Remember that each of these vaccines require 2 doses. Those doses need to be given 4 weeks apart. So, even if the studies are fully enrolled by October 1, and if every patient in that study is inoculated within one week of that point, the second dose will not have been given prior to early November.
Next, the scientific papers writing on these vaccines have reported that the antibody immune response to the virus does not reach full levels until about 4 weeks AFTER the second dose. That means that studies of the protective effects of these vaccines will not be able to even begin until mid-December. Cellular immune responses (T-Cells) rise even later and there is evidence that this cellular response is even more important that the antibody response.
Finally, remember that these Phase 3 trials have two goals.
The first goal is to determine if the vaccine actually protects people from infection. Previous trials determined that the vaccines could create an immune response. These trials are designed to determine if that immune response actually protects people from acquiring infection. That is why there are two groups, a vaccine-immunized group and a placebo-immunized group. Effectivity is then determined by looking at the two groups to see if there is a difference in the amount of infection seen in these groups.
Now, infection does not show up in an individual until between 5 and 14 days AFTER contracting the virus. This means that no results of effectivity can be even recorded until at least 2 weeks after the beginning of the analytical period which is 4 weeks after the second dose of vaccine. This takes us to the beginning of 2021. And those results won’t appear instantaneously. Subjects in these trials will be leading their normal lives. It may take weeks, or even months until they are exposed to virus and infections will occur.
Effectivity rate data will not be sufficiently accumulated until well into 2021.
The second goal is to determine if the vaccine is safe. Adverse events, medical problems, side-effects and other issues need to be tabulated. With a test group of 15,000 people (remember that only half of the people actually get the vaccine), the rate of adverse events may be extremely small, although very significant. It is often difficult to identify those events in such a small population, so it takes quite a bit of time before they can be truly well-tabulated.
Additionally, every adverse event identified needs to be fully investigated to determine if it was directly linked to the vaccine, or serendipitously associated. Was the cardiac arrest in patient #22,967 due to heart disease, the vaccine, or a heart issue complicated by the vaccine?
Safety and Effectiveness data will not be available until the second quarter of 2021. Premature distribution of vaccine prior to the accumulation of this data has potential problems including, an unwarranted belief in the efficacy of the vaccine and unintended medical issues that are not only health problems but that reduce the public’s willingness to take the vaccine.
ANALYSIS HURDLES
One issue that I have not seen discussed is the difficulty in analyzing the data from these trials.
The simplistic view is that if you test 30,000 people, half with vaccine, half with placebo, you wait a few months and then you look to see how many of those people were infected; you compare the two groups and you get a percentage of protection for the vaccinated individuals.
Unfortunately, this is not so simple. Here is why.
Patients recruited into the Phase 3 trials are diverse. We know that the diversity is of age, sex, race and ethnicity. However, it is also diverse geographically. There is a variety with respect to urban/rural, high-infection areas/low-infection area, state, country and continent. With this diversity, how do you actually compare infection rates, hospitalization rates and death rates?
- Is someone who has been hospitalized in the suburbs of London comparable to someone who was infected in Oakland, CA? Or Brazil? Or Taiwan? Were the hospitalization criteria the same or different? What was the infection rate in the two areas? What was the positivity rate? Were both viruses identical or were there mutations between the strains?
- Are low infection rates for people over the age of 60 due to the fact that ALL of them observed CDC guidelines including masks and limited travel outside of their house? Is that why there is little difference between vaccinated and non-vaccinated people in that age group?
- What were the viral spread conditions present in the area when someone got infected? Was it increasing? Decreasing? Is there a difference?
There are many more issues. The point here is that analyzing this data is not simple. The complexity of the analyses add to the time before submission of results to the FDA can be made and add to the time it takes the scientists at the FDA, CDC and NIH to review that data and make conclusions.
These are the reasons that the educated scientists in the government are looking to late 2021 before distribution of vaccines can be made…REALITY.