Vaccines, Regulations and Expediency

When might we get a vaccine and what regulations are or might be relaxed or expedited?

Disclaimer: I have studied biochemistry including immunology (which is still fascinating). I am have little experience with clinical trials, regulations, time lines etc. But I understand it usually takes billions and >5 years. I’m also not going to attempt to discuss the serology of Covid-19, the SARS CoV-2 glycoproteins and their immunoreactivity etc. more than to say there are many smart people working on it to see if it’s possible and I’m glad we have them.

Update 1 (2020-04-25)

Karthik Dinakar from Satori shared the following Stat news article [14].

Researchers rush to test coronavirus vaccine in people without knowing how well it works in animals

Which states that whilst there is no specific regulation requiring animal validation and therefore it is not illegal, there has been no animal testing data that can be relied upon yet.

Additionally it links to their annual SEC 10K filing [15].

The mRNA-1273 program is to develop a vaccine against SARS-CoV-2. Clinical supply for this mRNA vaccine was designed and manufactured in 25 days.

In the UK, the first patient has been injected with the COV001 vaccine according to this BBC article [16].

The post from Imperial COV001 vaccine group on the ambitious 18 month target for mass manufacture of a safe and efficacious vaccine [17].

Original post (2020-04-24)

However I would contend we have already seen some “relaxation” of regulations. I’m not for or against this. I’m just reporting my limited understanding of how clinical trials are usually conducted and why it takes so long. This perception of relaxation of regulations is based on my inability to find preclinical data for Moderna mRNA-1273 after a couple of hours of searching. This has now entered Phase 1 vaccine trial [3]. The closest I’ve found is:

The mRNA-1273 vaccine has shown promise in animal models, and this is the first trial to examine it in humans. [13]

That’s all I’ve got so far. They’ve only got data for other viruses like RSV (Respiratory syncytial virus) linked on their website [4, 5].

We’ve also got a phase 1 / 2 trial of the “COV001” vaccine based on the ChAdOx1 virus expressing the S protein[11]. 800 volunteers will be vaccinated [12]. I can’t find (nor am expecting to find) any preclinical data for that either. Again it might be out there but I just can’t find it.

The vaccine candidates deployed should normally have a lot of pre-clinical testing data[1]:

The development and licensure of an efficacious […] vaccine requires the consideration of many factors, but first and foremost, an experimental vaccine must undergo rigorous pre-clinical testing and demonstrate protection in an appropriate animal model of the disease. This animal model should be susceptible to infection when challenged with the pathogen, or closely related strains, and should ideally recapitulate hallmarks of the human disease

The vaccine is similar to something that’s been tested already

If that were true it does not (normally) matter and for good reason. Even small changes can have disasterous consequences. After the researchers of ZEBOV had sent hundreds of doses for the first phase 1 trial, they found out it had been manufactured using a different protein and therefore was not the same vaccine as use in the animal models[8].

Feldmann believed the switch would have no impact on whether the vaccine was effective. “Quite frankly, from a scientific prospective, it doesn’t matter,” agreed Kobinger. “From a regulatory perspective, it matters a lot.”

Ebola

It’s obviously very different to compare to Ebola. However:
The 2014-2016 EBOV epidemic likely started in Dec 2013 [1].
On Aug. 8, 2014, the WHO declared the outbreak a global health emergency. [8]
It was coming under control by Dec 2014 [2].

In contrast with SARS CoV-2 there were several very promising vaccines that had already been explored in robust pre-clinical models before the outbreak.

A few days after the WHO made their Aug 8th announcement a vaccine “ZEBOV” was provided for a Phase 1 trial[10].

Due to the circumstances in West Africa, after the phase 1 trial was conducted successfully it went straight to 3 & 2 running concurrently[1].

the lack of an approved effective vaccine combined with the dire circumstances in West Africa led to an expedition of vaccine trials from Phase 1 safety studies directly to Phase 3 efficacy studies, alongside Phase 2 studies

It’s not unreasonable to expect a similar approach might be taken with SARS CoV-2.

This vaccine had been tested and shown to be very effective in a non human primate cynomolgus macaques animal model[9][ref 5-7 within reference 10]. And had been shown to be not dangerous in a human subject[8].

This paper[1] goes into detail about various Ebola vaccines. “VRC-EBODNA023-00-VP”… though it not deployed initially along side ZEBOV (VSV) or ChAd3-EBO Z as the other vaccine mentioned in [8] but it had a phase 1 starting August 2014 [6] and it’s actual first phase 1 (but perhaps is a related compound) was 6 years early in Jan 2008 [7].

The point of this is that it was only August when the first Phase 1 trials emerged. However, yes granted the Ebola outbreak took a lot longer to grow and “smouldered”. But the trials of at least one of the compounds was already well tested in a very good animal model.

Dengue

I had a quick look at Dengue phase 1 vaccine trials. Again Dengue the disease and circumstances are very different. All phase 1 trials though had a placebo arm (I can’t find it now but I think one did not).

Participants
VaccinePlaceboStart dateTrial
189April 2010ref
2412September 2015ref
189February 2010ref
5819December 2011ref
7214May 2010ref
Placebo numbers are sometimes estimates

Compare to Moderna mRNA-1273 has no placebos. COV001 has >300.

Current conclusion?

The fact Moderna mRNA-1273 and ChAdOx1 COV-001 was in someones arm so quickly is unsual. Again, not necessarily good or bad.

References

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841470/
[2] https://en.wikipedia.org/wiki/Western_African_Ebola_virus_epidemic
[3] https://www.clinicaltrials.gov/ct2/show/NCT04283461
[4] https://www.modernatx.com/modality/prophylactic-vaccines
[5] https://www.nature.com/articles/s41541-020-0163-z
[6] https://clinicaltrials.gov/ct2/show/NCT02231866
[7] https://www.clinicaltrials.gov/ct2/show/NCT00605514?term=VRC-EBODNA023-00-VP&phase=0&draw=2&rank=1
[8] https://www.statnews.com/2020/01/07/inside-story-scientists-produced-world-first-ebola-vaccine/
[9] https://www.nature.com/articles/nm1258
[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490784/
[11] https://www.clinicaltrials.gov/ct2/show/NCT04324606?term=vaccine&cond=Sars-CoV2&draw=3&rank=15
[12] http://www.ox.ac.uk/news/2020-04-23-oxford-covid-19-vaccine-begins-human-trial-stage
[13] https://www.niaid.nih.gov/news-events/nih-clinical-trial-investigational-vaccine-covid-19-begins

[14] https://www.statnews.com/2020/03/11/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing/
[15] https://www.sec.gov/Archives/edgar/data/1682852/000168285220000006/moderna10-k12312019.htm
[16] https://www.bbc.co.uk/news/health-52394485
[17] https://covid19vaccinetrial.co.uk/blog-how-long-will-it-take-get-oxford-vaccine-deployment

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