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, Nextstrain.org. 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.)
   

Some Thoughts On The COVID-19 Mid-Term

 

 Cut-and-paste from a comment elsewhere on a news story about Dr. Fauci's remarks on the timetable for a return to "normal", and expanded on here. Particularly, this graf:

"I mean, if normal means you can get people into theater without worrying about what we call a 'congregate setting.' Superinfections. If you can get restaurants to open at almost full capacity, if you could have sporting events to be able to be played with spectators, either in the stands or in the arena, then I think that's going to be well, well into 2021 and perhaps beyond. I think one of the things that will be clear that our sensitivity to the potential devastating effects of a pandemic will be extraordinarily heightened. And I don't think that we will have the normal way of interacting with each other, particularly in the sense of wearing masks, which I think will become very commonplace as it is in many countries in Asia, even outside of the context of a pandemic outbreak. Again, I think it's many months."

We’re probably looking at a widely-deployed vaccine in the mid-2021 timeframe. Do not be surprised to see this pushed back as failures occur among the front-running vaccine candidates.

 

We will not know the durability of the immunity it confers. In that regard, it will be a phase III test (the actual term used by vaccinologists is phase IV). We may need to get revaccinated as often as twice yearly, forever. I am modestly hopeful on that front, because SARS-CoV-1 reactive T-cells have been documented as long as 17 years after infection. If T-cell immunity is the primary response, we could be golden.

 

We know that B-cell (antibody) immunity declines rapidly. A recent large-scale UK study showed antibody prevalence dropping from 6% to 4.4% in three months. This is strongly suggestive that we should not expect sterilizing immunity from a vaccine, but only protection from disease. This is not an uncommon outcome. The injected Salk (inactivated virus) polio vaccine has this effect also.

 

Because we will not get sterilizing immunity, we cannot rule out disease transmission even among the vaccinated. And because a vaccine will only confer protection on a (large) fraction of individuals, viral transmission will continue. The hope is that viral loads among the infected-but-vaccinated will be sufficiently low so as to reduce or eliminate transmission, but we cannot count on it.

 

So I can see what Fauci’s saying as not improbable. Masks, occasional lockdowns (hopefully becoming more infrequent as we find out how effective the vaccine(s) is/are) and other measures will probably continue to be necessary for a while.

We’re Gonna Be Doing This For A Long Time: Enola Holmes

 I have had my problems with the social justice types in Hollywood, and mainly because they tend to be entryists. Because they do not have good, original stories to tell, they take up and ruin beloved franchises, viz. Ghostbusters, and to a lesser degree, Star Wars. Enola Holmes doesn’t quite fit that category; it’s more of a cinematic hermit crab, occupying the shell of a beloved franchise. We see almost nothing of her older brother, Sherlock (Henry Cavill), and so the eponymous Enola is mostly on her own when their mother disappears.

The exceptionally talented Millie Bobby Brown plays the title role, fresh off an extraordinary run as the psionically gifted Eleven in the Netflix series, Stranger Things. But as with Hailee Steinfeld’s gobsmacking entry to the screen with the 2010 remake of True Grit, it’s hard not to question Brown’s subsequent choice of vehicles. In this case, much of it comes off as cliché — particularly her willingness to engage in hand-to-hand combat with a larger and older man. She’s an expert in jiu-jitsu, we learn, but it goes on. She outwits her famous brother (who comes off as a bit of a dunderhead). You expect more given the actress, but ... it’s almost a Mary Sue character. There’s too many of those already.

Summary of TWIV 663, "The Joy of Vax": About Accelerated Vaccine Approval

 A summary of Alan Dove's segment of This Week In Virology episode 663, "The Joy of Vax", relating to the status of COVID-19 vaccines, as bullet points. He attended a webinar from the National Adult and Influenza Immunization Summit regarding COVID-19:

• Top level executives from eight of nine companies the furthest ahead in vaccine trials participated (Astra Zeneca declined, for the obvious reason that they had halted their trial): Pfizer, Moderna (CEO participated), Novavax, Inovio, Medicago, Sanofi Pasteur, J&J, and Merck.
  
• "We're all in this together". Cooperation among competitors is significant.
  
• Prevention of disease is the primary goal, not sterilizing immunity.
• The bar is set for a minimum of 80% efficacy. (FDA will accept anything over 50%, but the Bill & Melinda Gates Foundation has set 80% as a minimum.)
  
• Because the goal is protective immunity, it's not clear that sterilizing immunity will occur. Therefore, it's quite likely that even vaccinated individuals could act as asymptomatic carriers. This will have consequences for health care workers and the general population.
• "Herd immunity" therefore doesn't have the meaning people suppose it does, because vaccinated asymptomatic carriers can still spread the virus. We need new language to explain how this works. Infection is different from disease.
  
• Consequently, we will need testing to prevent transmission, even with a vaccine.
• All vaccines are two-dose regimens. (Merck believes theirs could be a single-dose.) All expect full approval, but plan on Emergency Use Approval. If you get a vaccine in 2021, it will likely be on an Emergency basis.
• Many of the vaccines will require adjuvants which will need to be added to the vaccine on-site. This is not a problem in the US and Europe, but will be a big problem in developing countries. The plan is to eventually reach single-dose distribution.
• Scaling is enormous. Sanofi, which regularly provides 100M flu vaccines per year, is building out for a billion doses for COVID-19. "People are building entirely new facilities for this stuff."
• Storage will be a non-problem in the western world, but the extreme cold needed (-70C) for mRNA vaccines (Moderna) will be a problem for the developing world. This is a conservative estimate, and research is ongoing for higher temperatures.
• Cross-testing of vaccines is not occurring, so you will need to get the second shot of whatever vaccine you started with to get the benefit.
• Population diversity is a problem in some cases. (Moderna has slowed their trial because they don't have enough African-Americans in their control group.)
  
• Efficacy is assumed to begin 10 days after the second dose. If someone gets sick after the first dose, it does not count.
• Consequently, it's unlikely there will be good data on any vaccine until mid-November. But Pfizer's CEO thinks there will be enough data to say whether a vaccine works by Halloween.
• Worst-case scenario is a vaccine that actually makes infection worse (as the dengue vaccine).
  
• Protection (from disease) is still important even if a vaccine doesn't provide sterilizing immunity, because you could still prevent hospitalization.
  

The Epidemiologist And Thief

Michael Osterholm of U. Minnesota's Center for Infectious Disease Research And Policy (CIDRAP), and the Minnesota Federal Reserve Bank President Neel Kashkari came out in an editorial in favor of a renewed and stricter set of lockdowns to address the spread of COVID-19:

To successfully drive down our case rate to less than one per 100,000 people per day, we should mandate sheltering in place for everyone but the truly essential workers. By that, we mean people must stay at home and leave only for essential reasons: food shopping and visits to doctors and pharmacies while wearing masks and washing hands frequently. According to the Economic Policy Institute, 39 percent of workers in the United States are in essential categories. The problem with the March-to-May lockdown was that it was not uniformly stringent across the country. For example, Minnesota deemed 78 percent of its workers essential. To be effective, the lockdown has to be as comprehensive and strict as possible.

But how to pay for this? Isn't keeping people alive during this new lockdown going to be terribly expensive? They have an answer for this (emboldening mine):

This pandemic is deeply unfair. Millions of low-wage, front-line service workers have lost their jobs or been put in harm’s way, while most higher-wage, white-collar workers have been spared. But it is even more unfair than that; those of us who’ve kept our jobs are actually saving more money because we aren’t going out to restaurants or movies, or on vacations. Unlike in prior recessions, remarkably, the personal savings rate has soared to 20 percent from around 8 percent in January.

Because we are saving more, we have the resources to support those who have been laid off. Typically when the government runs deficits, it must rely on foreign investors to buy the debt because Americans aren’t generating enough savings to fund it. But we can finance the added deficits for Covid-19 relief from our own domestic savings. Those savings end up funding investment in the economy. That’s why traditional concerns about racking up too much government debt do not apply in this situation. It is much safer for a country to fund its deficits domestically than from abroad.

Such savings are not the government's to spend, though, unless

1. the government confiscates such savings, or
2. taxes them at a very high rate.

Joe Biden has lately said he would institute such a lockdown if scientists recommended it ("I would listen to the scientists"). This has already happened. Given the printing press approach to buffering the population from the consequences of COVID-19, it's unlikely the fiscal oppression approach will get traction, but it's far from guaranteed.

Michael Mina: Diagnostic And Surveillance Tests Need Different Kinds Of Regulatory Approval

Buried in this Harvard Magazine article is a point that I didn't emphasize enough in my previous article on COVID-19 rapid/cheap testing, and that is: diagnostic and surveillance tests are different beasts with different requirements, but the FDA currently treats both identically (emboldening mine, as per always):

Mina has been predicting the advent of more widely available, cheaper tests for months. But those tests have not materialized, largely because of regulatory risk, he says: manufacturers cannot meet Food and Drug Administration (FDA) templates for test sensitivity that use PCR as the standard. The FDA—whose approval process is stringent because it is designed to test the efficacy of clinical diagnostics—has no jurisdiction over public-health testing. But at the moment, there is no alternative regulatory process for tests designed to ensure population-level wellness—such as a certification program that might be run through the Centers for Disease Control (CDC), the agency charged with safeguarding the public health.

“It is time to stop allowing diagnostic definitions to get in the way of absolutely essential public-health interventions,” says Mina, for whom explaining the distinction between the two types of test, and the different ways they can be used, has been an uphill battle. But it is one that he desperately hopes to win—and that the country needs him to win—for public-health measures to stand a chance of reining in the outbreak as schools and other institutions move toward reopening this fall.

It's probably asking too much to have the FDA make a whole different track for surveillance tests on the fly like this, but clearly something has to give.