Thursday, December 24, 2020

A Necessarily Incomplete Overview Of COVID-19 Vaccines

Being a post I wanted to expose on a private Facebook group originally, only here I can add links when needed, and update as well. As ever, I Am Not A Virologist, etc. Info here is culled from This Week In Virology, assuming I understand them correctly, the Milken Institute's vaccine tracker, and the London School of Hygiene & Tropical Medicine vaccine tracker.

  • The biggest gun out there right now is the mRNA approach used by Moderna and Pfizer/BioNTech. It consists of a nanoparticle container housing messenger RNA that eventually gets into your body’s cells. Once inside, the mRNA instructs your cells to manufacture a protein that looks like the “spike” protein from the disease — the protein SARS-CoV-2 uses to gain access to your body’s cells and eventually cause disease. Essentially, it tells your body to make a wanted poster, readying your immune system for real disease. 

    The super cool thing about mRNA is rapid turnaround. Once you have a virus sequenced, you can make a vaccine very quickly — Moderna had theirs two days after the Chinese published the genetic sequence. Everything else is safety/efficacy testing and approval. (You can read a very nice summary of how mRNA vaccines work here.)
  • Next is the vectored vaccine approach used by AstraZeneca/Oxford, their  ChAdOx1. That name is a portmanteau of chimpanzee adenovirus Oxford (1). Originally developed for MERS, it was hoped it would readily translate to SARS-CoV-2 (COVID-19). Basically, they take a virus, in this case a chimpanzee adenovirus known not to infect humans, slice out the gene sequence for replication, and add genes to express the SARS-CoV-2 spike protein. Their testing is not going well — looks like a 62% overall efficacy, with a mistake group getting a half-dose first at 90% efficacy — and lately have started doing trials with other vaccines as a means to hopefully still be useful. My take on this is that such vaccines are functionally dead ends, because you can’t know whether the immune system is learning the vector proteins or the target protein(s), so a second injection might be useless. This in fact is why some vectored vaccines use a second viral backbone for the second shot. The Johnson & Johnson and Russian (Gamaleya's "Sputnik") vaccines are also vectored, and we shall see whether the former encounters the same problem.
  • On to the inactivated vaccines. This is one of the oldest types of modern viral vaccines, including the polio, rabies, and annual influenza inoculations. Basically, you grow active virus in a medium (typically chicken eggs, but others are used) and then "inactivate" it. (Viruses aren't alive, but they can be made to fall apart by heat or chemical means.) This process leaves you (hopefully) with the outer proteins that the immune system needs to know about without all that infectious virus. These have a spotty record, which is part of the reason why, when you get one that does work, it becomes enormous news, as with the Salk polio vaccine (though there were other reasons for that). The inconsistent efficaciousness is also part of the reason we do extensive testing on vaccines. Sinopharm (the Chinese state entity) is using this approach and licensed theirs months ago. As you can imagine, I do not have a lot of faith in their trials or data.
  • Protein subunit vaccines are by far the most popular approach with this disease, and is currently used in vaccines for shingles, hepatitis B, and human papilloma virus. Sanofi Pasteur is the most prominent name going to war with this approach, but a number of Chinese entities are also doing this. Basically, all this does is create the proteins of interest (here, the spike protein) and inject them straight into patients. It can produce a really strong immune reaction to the one protein in question, which is why it should in theory work well for SARS-CoV-2. (Coronaviruses tend to genetic stability because they have a proofreading ability most viruses lack.) The bad news for the US and Sanofi is that they had to pause their trials because the target population of people 65 and over did not respond well to the vaccination
Stay tuned, kids.

Don't Panic About The New UK Coronavirus Strain

 As ever, I use the word "strain" in the title here with some hesitation, because it hasn't been shown (yet) conclusively to affect pathogenicity or transmissibility, but some very good stuff in yesterday's This Week In Virology Episode 697. This doesn't cover all of it, but it hits the big points I think people are most interested in:

  • Increased transmissibility has not been conclusively shown but the genomic data is suggestive. The mathematical models can be tweaked to show any result, and don’t take into account founder effects or population-level changes that might be affecting transmission.
  • Spike protein changes are sufficient to require new primers for PCR tests, so they have had to rely on other genes for diagnosis.
  • The spike protein change is NOT enough to alter antibody response. This has been verified in animal models. Existing vaccines will most likely work fine on the new variant.
  • Underdiscussed: the ORF8 deletion may make a less-virulent disease course. (SARS-CoV-1 had one midway through that outbreak with that consequence.) It’s not that the disease is intrinsically more transmissible, but if you don’t feel sick you’re more likely to be out and shedding virus. We do not definitively know this to be the case at this point, however. 
Update 2020-12-29: I wanted to address a point that @politicalmath raised on his recent Substack post on COVID-19 strains; the consensus on TWiV seems to be that the US does much less viral sequencing than they do in the UK, although it’s unknown if what we do is enough to adequately assess spread by particular isolate. In any case, he links to a useful new (to me) site that tracks viral spread, Bookmarked.
Update 2020-12-30: It was pointed out to me on Twitter that the strain is actually called B.1.1.7, which "has an unusually large number of genetic changes, particularly in the spike protein". I'm still not terribly worried about antibody response to this variant, for several reasons:
  1. It's not clear that this has enough difference from other isolates to prevent existing vaccines from mounting an effective immune response.
  2. We have known for months that other (possibly zoonotic) coronaviruses leave antibodies capable of reacting with SARS-CoV-2. It doesn't have to be perfect to work.
  3. If B.1.1.7 is really a major shift, changing the mRNA vaccine to include the new spike protein should be a simple thing that could be turned around rapidly. (Of course, that assumes the FDA will allow an altered vaccine to be delivered without widespread testing first.)