Why are there so many COVID-19 vaccine candidates?

Posted in Random thoughts, Technology trends at 4:52 pm by ducky

The London School of Hygiene & Tropical Medicine’s COVID-19 vaccine tracker lists 292 vaccines in development as of 2021-01-26, and there is at least one not on that list yet. At least 69 vaccine candidates are currently in clinical trials.

Why are there so many? Surely, you say, we don’t need so many candidates. Why did so many companies try? Why don’t most of them quit now. Why don’t the losers just manufacture the winners’ vaccines?

There are several reasons why there are so many.

  1. There are nearly 8 billion people out there. That huge market means a huge opportunity to make money, so many people wanted to invest.
  2. There are lots of different market segments out there, and not all vaccines are appropriate for all markets. For example:
  3. Countries have a financial incentive to fund domestic development of vaccines. COVID-19 costs a huge, huge amount in lives, money, and social well-being, for every single day that the pandemic continues. Compared to being in a pandemic longer, a vaccine development program is cheap.
  4. Countries have domestic security reasons to develop their own vaccines:
    • Countries would rather not have to inject their citizens with liquids coming from their political rivals. For example, Taiwan might not want not trust vaccines from China.
    • There are (IMHO legitimate) concerns that other countries might slap export controls on vaccines developed in their home countries, insisting that those vaccines go to their own citizens first. Countries have no control over when they can have access to foreign vaccines, but might be able to exert some control over domestic providers’ priority and sequencing choices.
  5. Players — both countries and companies — have an incentive to invest in vaccine technology to ensure long-term competitiveness, especially for mRNA vaccines. The mRNA vaccines are so good that being able to make them domestically is a huge strength, both in terms of being able to make your citizens healthier in the future and in terms of increasing your country’s economic might.

As for the question of why the losers don’t just manufacture the “winners'” vaccines, in addition to #5 above:

  • The “losers” might not have accepted yet that they have “lost”. Even if the pandemic eases in the developed countries in the next year, there’s still going to be billions of people who still need the vaccine. So even if the “loser” vaccine doesn’t get to market for a year, there’s still a lot of time to make money on the vaccine after that.
  • The “winners” might not feel comfortable licensing their manufacturing technology to their rivals. Why should Moderna show Providence Therapeutics how to make mRNA vaccines, when Providence might turn into a competitor later on?
    • It would make more sense for the “winners” to flat-out buy their competitors. The winners presumably are making money right now, so they ought to be able to afford it.
  • The “winners” are busy right now. They are making (and selling!) vaccines as fast as they can at the moment. Technology transfer deals — or outright purchases — take time and attention, and companies like Moderna probably do not have any attention to spare at the moment. Look for deals in a year or two. (Right now, Pfizer is doing an internal upgrade to its factory to boost production, causing a short-term drop in supply, causing people to totally lose their collective shit enormous consternation among their customers.)


Switching strains in mRNA vaccines

Posted in Health, Random thoughts, Technology trends at 12:13 am by ducky

There is a lot of nervousness right now about new strains of the SARS-CoV-2 virus. There is now very good evidence that the B.1.1.7 (“UK”) strain is more transmissible than the original strain (which I will call the “Wuhan” strain because I haven’t seen anyone give it a name). There are also strains out of South Africa and Brazil which have similar mutations and are similarly worrying.

So I have been wondering how fast Moderna and Pfizer/BioNTech could tweak their strains to produce vaccines targeting the UK strain instead of the Wuhan strain. That has not been entirely straightforward to figure out, but I think I have finally pieced it together from reading, mostly from this and this.

The things that need to be done include:

  • Get the DNA sequence of the new strain’s spike protein. That’s something which comes from outside the company. (Zero additional time.)
  • Modify the sequence slightly in completely predictable ways: add a start block on, add an end block, convert all the thymine with 1-methyl-3’-pseudouridylyl, translate some bases into equivalent sequences to get a higher proportion of cytosine and guanine, etc. (See Reverse Engineering the source code of the BioNTech/Pfizer SARS-CoV-2 Vaccine for more on these algorithmic modifications.) (Educated guess: probably fifteen minutes of additional time, not even worth counting.)
  • Modify the sequence slightly to improve manufacturability. This will be a proprietary step that the company will do. Given how small the physical changes are between the Wuhan strain and the UK strain, I suspect that this step will not take long, and possibly could be skipped. (Guess: 0-1 days.)
  • Convert the text sequence into physical DNA, the “template DNA”. This is a completely straightforward, common process, but I don’t know how long it takes to get the amount of DNA needed. (Guess: 1-4 days)
  • Verify that you got the right DNA, I assume using a PCR test. (6 hours, 0.25 days)

After this point, all the rest of the production steps are exactly the same as are already being done for the Wuhan strain. If I were Pfizer or Moderna, I would already have done the previous steps for all of the scary variant strains and have a bunch of DNA on ice, ready to ship out if the green light was given. So it might in fact be zero additional days. (2-6 weeks, 6 weeks)

Addendum 2021-03-02: This article says that finish & fill — testing, getting the serum into the bottles, and labelling — take five weeks.

I have not heard of any official floating the idea of modifying the vaccine, probably because it looks like the Wuhan vaccine will be good enough against the UK strain. (Addendum: the B.1.351 is a different matter.) However, if there started to be rumbling about how the vaccine should be changed, if I were Pfizer or Moderna, I would actually go through all the steps to make enough doses of the UK vaccine for testing if need be.

At this point, the new vaccine would need some testing. According to the FDA officials, this would not need to be a full randomized clinical trial:

It might be the first time we do it, we’ll check an immunogenicity study. But it’s not going to have to be another 30,000 patient clinical trial. Those immunogenicity studies are usually 400 patients, just to make sure that we have the right check of what’s coming out. And even that may not be necessary after we check at the first one or two times. So I think we’ll have a way of evolving here with these.

If I understand correctly, immunogenicity studies are tests of the blood which check to make sure that the vaccine causes the desired immune response.

This would mean that the the company would vaccinate volunteers — apparently about 400 — give them enough time for their immune system to react

  • Recruit test participants. Hopefully they would have volunteers ready to go. (Zero additional days.)
  • Inject test participants with their first dose. One vaccinator plus support staff in a high-throughput clinic can vaccinate 30 people per hour, so with appropriate application of resources, it should be no problem to get them all vaccinated in one day. (1 day.)
  • Wait for the test participants’ immune systems to react to the vaccines. (14 days.)
  • At this point, the test participants’ blood could be tested to see if it mounts the desired immune response. One might think they could stop there, but regulatory agencies probably would want to check after the second dose. Moderna ran their first trials with a 21 day delay; Pfizer did a 28 day delay. (7 or 14 more days) Addendum 2021-03-04: These new vaccines are being positioned as boosters, which means there would not be a second dose.
  • Give all the volunteers their second dose. (1 day)
  • Wait for the volunteers’ immune systems to react to the vaccines. (14 days.)
  • Take blood samples from the test participants. (1 day)
  • Test blood to see if it mounts the desired immune response. (Guess: 2 days)
  • Write up report. I think this wouldn’t take long because they could copy and paste a lot from the Wuhan vaccine’s report. (Guess: 2-7 days.)
  • At this point, it would go to the regulatory bodies.

Add that all up, and it comes out to about 7-8 weeks from finishing the vaccine production to the data delivered to regulators, 3-4 weeks if they only require one dose.

The regulators would need to evaluate the data. Different regulators take different lengths of times, but the Pfizer vaccine took about three weeks from the application to approval by the US Food and Drug administration, and about the same amount of time for Health Canada to approve it. A new strain would have far less data to pore through, so I would guess it would be only a week or so. (Guess: 1-3 weeks) Addendum 2021-03-04: I’m now thinking 1 week is probably too optimistic. Say 1-3 weeks.

In summary, my best guess is 4-6 weeks to manufacture the new vaccine, 7-8 weeks to do clinical trials, and 1-3 weeks for approval, or a total of 12-18 weeks.

Addendum 2021-02-06: According to a Washington Post article on 2021-01-25, Moderna has started working on a vaccine for the P.1 variant.

The scientific and pharmaceutical race to keep coronavirus vaccines ahead of new virus variants escalated Monday, even as a highly transmissible variant first detected in people who had recently traveled to Brazil was discovered in Minnesota.

Moderna, the maker of one of the two authorized coronavirus vaccines in the United States, announced it would develop and test a new vaccine tailored to block a similar mutation-riddled virus variant in case an updated shot becomes necessary.


Addendum 2021-02-07: I forgot that the delay between the first and second dose is not 14 days, it’s 21 (for Moderna) and 28 (for Pfizer). I have adjusted accordingly.

Addendum 2021-02-19: Today, an article in the Washington Post said

A prime inventor of the technology behind mRNA vaccines, Drew Weissman, of the University of Pennsylvania, said he has been told by the leader of BioNTech that it could take as little as six weeks to formulate a new mRNA payload and manufacture it to target a variant. Pfizer chief executive Albert Bourla told investors earlier this month that he anticipates that a variant-specific vaccine could be approved in 100 days, including clinical testing and regulatory reviews.

Addendum 2021-02-23: Pfizer says that it has gotten its manufacturing time down to 60 days (from 100). That’s 8.5 weeks, so my estimate was optimistic.

Addendum 2021-02-24: Moderna has started a Phase 1 trial of a vaccine specifically against the B.1.351 (South African) strain. Pfizer announced that they are going to do a test also.

Addendum 2021-02-25 from an article dated 2021-02-22: the US FDA has released guidelines on what testing vaccines against variant strains will need to do. They need to vaccinate volunteers with the variant vaccine, and look at the blood to see how big of a response to the virus variants the volunteers’ blood makes. If the response is comparable to the one from the Classic vaccines, it’s a go. Addendum 2021-03-04: There’s a consortium of European non-EU countries which says the same basic thing about approving vaccines against new strains.


Moon landing and mRNA

Posted in Random thoughts, Technology trends at 5:34 pm by ducky

It does not seem appropriate to feel proud for things I had no part in. I don’t feel proud that the Sony recording of Saint-Saens: Cello Concerto No. 1 / Piano Concerto No. 2 / Violin Concerto No. 3 is awesome, for example.

However, I am proud of the moon landing. Not personally, but as a human. I am incredibly proud that we — collectively, over the centuries — managed to land on another celestial body.

The Secret of Our Success: How Culture Is Driving Human Evolution, Domesticating Our Species, and Making Us Smarter by Joseph Henrich makes the case that “learning from others” is what sets humans apart from all the other animals. Apparently we are really really good at learning from others compared to other animals.

The moon landing is a great example of this. To get to the moon, we had to build upon many technological achievements. We humans invented writing and governments and paper and books and lending libraries and addition and subtraction and exponents and the zero and protractors and slide rules and furnaces and tin snips and fireworks and rockets and tubes and space suits and we did it! Us humans!

I am also proud, as a human being, of mRNA vaccines.

Not at first — I was a little nervous about the mRNA vaccines when they first got approved for use against COVID-19. The mRNA vaccine was a very new technology, and there was a huge amount of pressure. Did corners get cut, sacrificing safety for speed?

But after reading a bit about it (especially this explanation), I was in absolute awe. The mRNA vaccines are sort of like “pre-vaccines”, which convince our own bodies to make the things we want our bodies to recognize and destroy. Instead of injecting us with millions of SARS-CoV-2 spike proteins, we get injected with instructions for our cells to make bazillions of spike proteins. This makes the mRNA vaccines 95% effective against the SARS-CoV-2 virus.

From xkcd

The mRNA vaccines are so beautiful (and effective) that they make all other vaccines now look primitive to me, like clumsy bumblings of extremely lucky ignoramuses. (“How did they ever work???”, I marvel.)

We humans — collectively, over the centuries — managed to figure out chemistry and anatomy and microscopes and cells and X-Rays and DNA and stop codons and antibodies and sequencing and ribosomes and introns and synthesis and how to do randomized clinical trials lipid nanoparticles and proline substitution and we did it!

Go humans!