In a previous post I discussed the possibility that a vaccine may not be the expected “silver bullet” society is waiting for due to current event rates and historical vaccine effectiveness. I did not address how long individuals may have to wait for a vaccine, which is very important considering governments, businesses, and schools are basing policy decisions on its arrival.
Currently, there are 100 vaccine programs. Of these hundred, testing has started on eight of them.1 I won’t go through much immunology, but there is a brief explanation below for those interested.* COVID-19 has a unique protein on its surface called the “spike” protein.2 Since it is unique your immune system can recognize it as foreign.
The current vaccine candidates can be broken down into two categories; genetic material and recombinant vaccines.3 Both take advantage of the spike protein to generate an immune response. I have briefly explained this below.+ Over the weekend Moderna released preliminary phase 1 data of 8 patients that have received their RNA based vaccine. All 8 developed antibodies against COVID.4 This is the current pole position. Companies developing genetic material vaccines estimate they will be ready for use this fall. Recombinant vaccines are estimated to be ready in early 2021. Are they being optimistic? Let’s find out.
Most companies are estimating between 30,000-100,000 participants for their trial. When a new pharmaceutical product is made it goes through three phases of testing. Phase 1 is a toxicity assessment on healthy volunteers and generally takes a couple of months. Phase 2 is a safety and efficacy assessment and is usually about 10x the size of phase 1. These can take up to a year or longer. Phase 3 establishes therapeutic effectiveness. When proving efficacy (phase 2), the researcher just wants to show the product does what it is supposed to do and the potential benefit outweighs risk. Researchers tend to use surrogate outcomes for this. More to come on this topic. This is different than effectiveness which is the aim in a phase 3 study. When proving effectiveness, researchers want to show that the product has an effect on the disease. This phase generally takes at least 12 months to complete.5 Phase 3 studies are much larger and rigorous. Several years can pass from the first patient recruited until the final data analysis. The study period of a new product can take between 2-10 years.
You don’t believe me? Here are a few phase 3 trials from start to finish of other vaccines. The most recent vaccine on the market is the recombinant shingles vaccine shingrix. About 30% of people will experience shingles in their lifetime.6 The phase 3 study was registered on July 19th, 2010 with first results posted May 1, 2017, FDA approval May 17th, 2019. They recruited 15,000 patients in each arm for the study. They had roughly 215 events in the placebo arm and 6 in the experimental arm. They followed subjects for 3.7 years.7 This is just phase 3! Another example is the recombinant pneumonia vaccine Prevnar. Pneumococcal pneumonia is a common cause of pneumonia.8 This phase 3 study was first registered on May 21st, 2010. FDA approval August 22nd, 2017. This trial had 80,000 patients in each arm. There were 40 events in the experimental arm and roughly 80 in the treatment arm.9 Sound familiar (see previous post)? The FDA has never approved a genetic material vaccine.
So far logistical execution and historical examples do not line up with the current timelines reported. There are several other logistical issues these companies will face. One of the biggest is recruitment. I’m sure many of you reading this would shoot your hand in the air at the opportunity to volunteer for an experimental vaccine against COVID. Then someone would go over the consent form with you. This is where they explain everything that can happen to you due to the vaccine with the caveat that it may not protect you from COVID. Then you have to agree to be followed for the entire study period. Usually this includes phone calls, clinic visits, blood draws, etc. A volunteer in a medicine trial truly has a heart of gold. Most people walk away at this point. Clinical trials often extend their recruitment period due to refusal, attrition, and withdrawal of consent. 10
Next, they have to figure out an observational period. How long will it take for enough people to be exposed to the pathogen, to have enough events, to tell a difference between the two groups? The trials above ran for more than 3 years. The current estimated timeline is less than 6 months.
Finally, outcomes need to be chosen. Each with their own advantages and disadvantages. Outcomes like death and hospitalizations due to the virus are easy to measure, but effectiveness is difficult to prove because there are fewer events. You need more subjects in your trial. This increases your recruitment and observation period. Infection rates are more difficult to measure but you will not need as many subjects since the event rate will be higher. Infection rates require manpower for periodic follow-up, frequent testing, and serology. If you want to measure spread you will need even more resources, not only to test subjects but those they contact. You may miss many data points as subjects and contacts are more likely to be lost to follow-up. This could make your data unreliable. Which outcome matters to society? If you chose to measure them all, expect a lengthy complicated protocol. This is the scientific method at the highest level. It is difficult, arduous, and slow.
So, how will these companies meet these timelines? Likely by taking shortcuts.
One avenue all of these vaccines are likely to take advantage of is the FDA Emergency Use Authorization (EAU).11 You can read the details of the distinction on the FDA’s website. There are three elements I would like to highlight. First, the effectiveness criteria. According to the statute the product only needs to clear the “may be effective” hurdle. Not a high hurdle. Second, the “no alternative criteria.” There are several scenarios that qualify for no alternative. A previously approved product may be inadequate. There may be short supply of a product. There could be conflicting data. This grey zone led to many diagnostic COVID tests being released into the market place without any kind of validation.12 Third, the FDA commissioner has the power to authorize products under the EAU distinction. No Pressure!
You can foresee a scenario in which multiple unproven COVID vaccines are allowed to enter the market under these criteria. Most of the vaccine programs will use this distinction in the race to market. Fortunately, the EAU can be rescinded when the pandemic ends. This is the first shortcut.
Many of you are probably thinking, “What’s the harm of using a vaccine that meets these criteria?” One, it could provide everyone with an incorrect sense of safety. Two, it could stifle further investigation for an effective vaccine since the market is taken. Three, it could place people at risk for side effects from the vaccine. Four, it may not affect the disease at all.
To understand this final point requires a discussion about efficacy vs. effectiveness. Most of these vaccine candidates will use serology to determine efficacy. Remember efficacy is different than effectiveness. They will give a subject the vaccine. A month later they will measure antibodies in their blood against COVID-19 (serology) and report those results. The antibody outcome is known as a surrogate. Surrogate outcomes are used because researchers neither have time or resources to measure firm outcomes. In this case outcomes that effect the disease, which is what we care about. We want to know if the vaccine prevents infection and spread of infection, and if it will keep you from dying. Antibodies will stand in for these outcomes under the theory that if you have antibodies it must protect you from all of those other things. But that’s a little different than having the proof you want. This could be a big mistake.13 This is the second shortcut.
The final shortcut will be the age range they choose to study. This will be 18-55. This is likely strategic. For those under 18 the explanation is simple. Trials of pediatric patients have stringent safety protocols that make experiments more difficult. Consenting parents is more difficult than consenting sovereign adults for clinical trials. This will take too much time. Those over 55 are less likely to have a robust immune response to the vaccine.14 Since serology is the likely outcome being measured this could make the vaccine appear less effective reducing the chance of approval. One would expect a decent immune response in pediatric patients, but we won’t know for our poor folks over 55.
Even if the companies running the trials wanted to measure firm outcomes like death, hospitalization, infections, and spread they face significant hurdles due to the many restrictions recommended by government officials. If no one is participating in society the subject in your study is less likely to come in contact with the virus. This will reduce your event rate, significantly lengthening the observation period. We aren’t behaving normally right now. This limits your ability to apply results to standard living situations. I don’t make guarantees, but if I did, I would guarantee that there isn’t a single scientist in any board room recommending the use of any outcome other than serology because they understand the timeline they’re up against. If society opens up again, you could consider running a simultaneous trial looking at firm outcomes.
In conclusion, vaccines are a powerful technology. However, thinking that an approved vaccine will provide safety is thinking in simplistic terms. There are a large number of probable outcomes from a new vaccine that will vary from country to country, person to person, in different demographics. My hope is it will provide a great deal of safety, so do many of our elective officials. But the makers of policy may be biased by optimism, and they aren’t the only ones. The vaccine may provide safety, or a little bit of safety, maybe it will induce antibodies without safety, maybe it does nothing. Those are just a few of the possible outcomes. Not considering all the plausible outcomes may result in unnecessary suffering. Given the shortcuts many of the vaccine programs will take, the ability to predict effectiveness will be less certain. It may be years before we know if it had an effect on the disease.
All the while we are waiting. With that wait comes consequences. So far emergency room visits are down forty percent15, 36 million people are without jobs16, 130 million people live in countries at high risk for famine due to covid17, anxiety and depression are accelerating18, the list goes on and on. I will get the vaccine when available, but waiting another 6-8 months for a vaccine with uncertain outcome is not based on sound logic.
*Your immune system has many functions, but the most important is to detect and destroy foreign pathogens (viruses, bacteria, parasites, etc). COVID-19 has a particular protein on its surface known as the spike protein. This makes it unique and recognizable by your immune system. When you are infected with a pathogen there tends to be a lot of destruction at the site. You have special cells called macrophages that get called in when parts of your body are being destroyed. They process everything in sight. You could consider them similar to a forensics team. They take what they’ve processed and present evidence from the scene of the crime to another type of cell known has a helper-t cell. Helper-t cells determine if any of the evidence is foreign. If so, they will grab a b-cell and tell it to start making antibodies against the foreign protein. When the infection is suppressed most of the t-cells and b-cells will die, but memory cells will remain. They will float around with the capability to reproduce the antibodies if needed. HIV is a virus that kills helper t-cells, which is why their immune systems essentially doesn’t function after the virus destroys these cells.
+ Genetic material-based vaccines take millions of copies of the RNA that code the spike protein and then place it inside a capsule (also known as a vector) that can enter your cells. Once inside, the RNA is processed by your cell and the spike protein is made. Millions of spike proteins are released. Your white blood cells recognize them as foreign and develop antibodies against it. This developmental process is more efficient than traditional techniques because it charges your own body with making the protein instead of some other entity. Traditional vaccine techniques will give the RNA to bacteria cultures or tissue cultures in petri dishes then extract the spike protein from the material they produce.
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