In early March, infectious disease expert Dr. Michael Osterholm appeared on the popular podcast, the Joe Rogan Experience. At this point, COVID-19 was spreading but the world still seemed mostly “normal” with very few countries on full lockdown. Osterholm, director of the University of Minnesota’s Center for Infectious Disease Research and Policy, brought sobering predictions of our future — all of which have come to fruition — and explained why we are years away from a COVID-19 vaccine, not months:
I don’t mean to sound glib again but, I could make a vaccine for it overnight. The question is whether it is safe and effective. That’s the challenge.
At the point of making this statement, progress had already been made with understanding the virus. China shared the genetic makeup of the virus two months prior and labs were able to grow the virus in high enough numbers to map out its structure. What Osterholm was saying is that, at this point, making something that could show promise for triggering immune responses for COVID-19 is the easy part. The hard part is getting a vaccine approved. Even if you have something that has shown efficacy in lab tests, it still needs to go through rigorous clinical testing before it can be approved for manufacture. Rushing through any of these steps can result in a potentially fatal final product.
How do vaccines get approved?
Before entering clinical trials, there must be sufficient pre-clinical data to justify progression into human tests. In order to move into human clinical trials you basically have to show that the vaccine protects cells grown in a lab against the virus and, more importantly, it has not proved fatal when injected into animals. This can take months but, if successful, the vaccine can progress into phase 1 of clinical trials. At the moment, our most promising candidates are at this stage. If a vaccine passes phase 1, there are still at least 2 more phases to navigate.
During phase 1, the candidate vaccine is likely to be given to a small group of healthy volunteers. In the case of something like a cancer vaccine, patients with the condition may also be used in this phase but for COVID-19 it is most likely healthy recipients. The main goal here is to ensure the vaccine does not carry any major safety issues. The volunteers are closely monitored and the small numbers allow researchers to manage each individual in the unlikely event of a severe reaction to the vaccine. Tests are conducted to ensure the vaccine reaches the area of the body that is being targeted and remains long enough to have a positive effect. In particular, researchers may assess antibody levels in the volunteers to make sure the vaccine has been successful in generating the antibodies required to create immunity to COVID-19. If the vaccine appears to create immunity without harming the volunteers, approval for phase 2 trials can be sought.
Several vaccines have started limited human trials, including the Monday [May 5] announcement by Pfizer that its new offering is being tested on 360 volunteers. In mid March, Moderna started its human trial in Seattle with 45 volunteers. And in late April, Inovio selected 40 volunteers for its first clinical trial.
In phase 2, researchers increase the number of volunteers and conduct a more thorough analysis of how the vaccine performs. At this stage, volunteers who have the condition that the vaccine is designed for may be drafted in for testing but this is not always the case. Volunteers are usually divided into two groups with one receiving the vaccine and the other receiving a placebo injection (no active ingredients). This gives the researchers a reference point and it is expected that those injected with the actual vaccine will show significant differences to those given the placebo. At this stage the researchers will once again assess how effective the vaccine is at preventing/treating the condition. More importantly, research will be conducted to ensure appropriate doses of the vaccine are being used.
This latter analysis is extremely critical to vaccine development and must not be rushed. In his interview on the Joe Rogan Experience, Osterholm stressed the importance of getting vaccine doses right:
There is a condition in humans called antibody dependent enhancement (ADE). It turns out if you have no antibodies you get the disease and if you have a lot you are protected. If you have this in between level (of antibodies) and you get the disease it actually enhances the disease and the immune response is really destructive.ADVERTISEMENTADVERTISEMENT
To put it simply, researchers need to ensure the dose they are providing is high enough to produce the antibodies required to prevent infection from COVID-19. The one thing they have to avoid is creating a dose that results in an “intermediate” antibody response that leaves the patient vulnerable to ADE. If this is not researched thoroughly, you can end up with a situation like the one seen with the Dengvaxia dengue fever vaccine in the Philippines which as caused ADE-related deaths of over 600 people, most of which were children, and resulted in criminal indictments for the developers.
If phase 2 is passed and the vaccine progresses to phase 3, the vaccine is then tested in a much larger trial which can include thousands of volunteers. The goals are similar to phase 2 regarding ensuring efficacy, safety and appropriate dosing but these larger trials allow the researchers to identify any side effects or safety concerns that are perhaps less common. For example, if you have a vaccine that can cause a serious side effect in 1:1000 patients, you will not identify this until you start to test it on high enough numbers to see it occur. This is why these larger trials are so important. They are lengthy, lasting months to years, but they are essential.
If all phases are passed, approval for the vaccine can then be sought. Once approved, large scale manufacture and distribution of the vaccine can take place. When we get to this stage with the COVID-19 vaccine it is likely that vulnerable people with underlying health concerns will receive the vaccine first but we are probably looking at a 2021 date before this can happen. Large scale manufacturing provides its own set of challenges and there are many hurdles we have yet to clear from a scientific perspective.
The process is, therefore, a long one but there is a very good reason for that. COVID-19 is something that we will have to co-exist with for some time. The alternative is to rush out a vaccine without proper testing and that would be far more dangerous than the disease itself.
Sam Moxon has a PhD in regenerative medicine and is currently involved in dementia research. He is a freelance writer with an interest in the development of new technologies to diagnose and treat degenerative diseases. Follow him on Twitter @DrSamMoxon