Overview
During this time, we often hear that life goes back to "normal" when a vaccine is developed, but on what timeline is that realistic and will the current infrastructure support the necessary ramp needed (estimated one billion vials)? We spoke with a recently retired head of vaccine development for a Big Pharma program to better understand the timeline and potential type of vaccine that is most likely to bring an eventual end to the mask-clad life we're growing accustomed to. Our expert has made critical contributions in four clinical trials which produced successful vaccines and continues to provide leadership in vaccine development today.
As many have already noted, much has to go perfectly, that is get exceptionally lucky, to produce an effective vaccine. The main issue is in the complexity of the immune system itself and the exponential mechanics of a response. The major stumbling block seems to be the answer heard most often about a COVID-19 vaccine timeline which is "we don't know." While we do expect a vaccine, it seems effective therapeutics are much more likely to have a positive impact on COVID-19 pandemic sooner.
Field Notes
- Developing a vaccine will "take longer than anyone thinks"
- Moderna novel encapsulated mRNA, which protects the RNA, but has not produced an effective vaccine yet, failed in flu
- Regulators will give all these novel approaches the "hairy eyeball," because of "unfortunate episodes" on vaccine safety in the past, especially for coronavirus vaccines
- In RSV, an attenuated viral vaccine made the disease worse
- In Phase II, there are markers of protection such as the concentration of neutralizing antibodies, and cellular markers of an immune response
- For COVID "there are no surrogates" for efficacy because we don't know what response levels confer protection
- There is an extremely wide distribution of response curves at the individual level and among vaccines
- Responses follow s-curve in a population, a vaccine may work but be on the low end of a response curve
- What level confers protection? Who is protected? Is it safe? - answering these questions takes a lot of people and a lot of time
- The neutralizing antibody titer is not equivalent across vaccines
- There are lots of serology tests out there that are not "worth a darn" because we don't know what the measure means, there are no control sera available
- ABT kit will be reliable, Roche, but still what will the result mean?
- DNA vaccines "work like gangbusters in mice"
- RNA based vaccines traffic into a cell via liposome encapsulation
- There are no RNA vaccines on the market or manufacturing capacity
- Oxford non-replicating viral vector "a joke to have it by Fall 2020"
- There is a chance there is reinfection and examples where a viral infection remains dormant
- Herpes infection is dormant, COVID may remain in body too
- Chicken Pox becomes Shingles after a long period of latency
- Infection should confer immunity for a few years at least, but at this point "that is a guess"
- COVID-19 looks like a product of stupidity not malice because of the steps it would take to intentionally create it
- It will be hard to develop neutralizing antibodies, because of high binding affinity of COVID-19 for the cell
- It may be difficult to get an antibody that can effectively compete with COVID-19's spike protein binding to the ACE receptor
- Phase III study size will be based on incidence rate at the time of the study, if incidence rate is low at the time the study begins to enroll we may need 10's of thousands of patients
- Study size will also depend on the endpoint, not dying, or not getting sick, or some other risk mitigation marker
- There are blood based markers that can demonstrate a response, but won't be definitive that a vaccinated person is protected.
- Collect peripheral blood of patients, see if there is a response to a viral challenge, such as the measure the T-cells, B-cell response, and markers like CD8, cytokines, INF, IL-6
- Threshold will be low for showing efficacy, though
- COVID is a slow mutator which helps a vaccine program, whereas HIV mutates fast by comparison
- Manufacturing will be rate limiting; plenty of manufacturing for proteins, little to none for a DNA, RNA, or a viral vector
- Gates Foundation is running out ahead on manufacturing, but even so there are multiple candidates to choose from
- "A good paper" on COVID-19 vaccine development > "SARS-CoV-2 Vaccines: Status Report" Immunity 52, April 14, 2020
Thomas Tobin
Managing Director
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William McMahon
Analyst
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