Saturday, October 31, 2020

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.

Monday, October 19, 2020

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.

Tuesday, September 15, 2020

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.

Saturday, August 22, 2020

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.

Monday, August 10, 2020

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.

At Last, Something Approximating A Plan In Portland

I recently despaired at the problem of Black Lives Matters offering no policy directions to improve policing and diminish police abuse of blacks. It therefore came as welcome news when I found out about Reimagine Oregon's surprisingly meaty list of policy demands, particularly their section on police divestments. A great deal of this has already been accomplished in some form or another (banning the use of chokeholds, mandated duty to report/intervene in cases of violence, making officer disciplinary records visible to the public) with many other particulars still on the table. Some correspond to reforms I have already proposed, but many strike me as commonsense beyond those:
  • Prevent contract arbitration from limiting disciplinary action.
  • Demilitarize the police, including ending (a) tear gas use, (b) sound cannons, and (c) flashbang grenades. (a) will be extremely difficult to implement (crowd control is still a legitimate function of government), but the other two ((b) especially) are so overused as to be serious problems.
  • Decriminalize public transportation fare evasion.
  • Prohibit public transportation fare evasion as justification for search warrants.
  • Remove sworn and armed officers from public university campuses. This is probably unlikely to happen, and in any case, how much of a problem does this realistically present? University campuses are hardly a hotbed of crime to begin with.
  • Ban the receipt of militarized equipment (1033 transfers). This is well overdue.
  • Reconsider personnel public records requests. Police disciplinary records need to be public. Despite a nearly 60-year-old Supreme Court case, Brady v. Maryland, that has frequently been read to imply that police disciplinary records germane to court proceedings must be made available to the defense, it is frequently flouted in practice.
  • Consider the laws that allow expunction [expungement] without costs for people with no convictions in a certain number of years.
  • End 48 hour rule that delays police officer questioning after a charge of excessive force is raised.
  • Eliminate qualified immunity, duh.
There are other items aimed at the county and municipal levels, but this strikes me as a fine first crack at achievable line-items. The biggest single item missing, and the hardest one to implement, is ending police unions. The question in my mind is whether the Portland protesters have anything whatsoever to do with this group.

Saturday, July 18, 2020

How Cheap, Daily Tests Could Stop The Spread Of COVID-19 — If The FDA Will Let Us

Thursday's Episode 640 of This Week In Virology had some astonishing remarks from Michael Mina, who lately has had a paper published advocating that rapid throughput is more important than high sensitivity when it comes to COVID-19 surveillance tests.

1. Viral Load Ramps Up Early And Declines Slowly

COVID-19 viral load expands rapidly — in a matter of hours — after initial infection.

2. The Window Of Infectiousness Is Brief [EDIT: If Caught Early], Only 2-3 Days In Most Cases

3. High-sensitivity tests are expensive, and have long throughput times.

Early tests from the CDC and WHO were designed to be as sensitive as possible. A large part of this was because it was thought that infection buildup took place over days, and thus the need to capture early, lower viral loads. But because the buildup is so rapid, it avails us little. More, because the reagents are so expensive, it is uneconomical to do the tests. Conventional PCR nasal swab tests are expensive, costing "from $50 to $150" each. Mina states that such tests "often have sample-to-result times of 24-48 hours". In the real world of limited lab capacity, I have heard of delays of as much as eight days.

4. Low-sensitivity, rapid, cheap daily tests can work to prevent disease spread.

Because of the rapid acceleration of viral growth early in the infection cycle, a surveillance test needs to only detect a relatively high amount of virus. These tests should be cheap — cheap enough for everyone to use daily, and capable of being mass-produced in the billions.

The good news is that such tests already exist:
E25Bio, Sherlock Biosciences, Mammoth Biosciences, and an increasing number of academic research laboratories are in the late stages of developing paper-strip and other simple, daily Covid-19 tests. Some of the daily tests are in trials and proving highly effective.

The strips could be mass produced in a matter of weeks and freely supplied by the government to everyone in the country. The price per person would be from $1 to $5 a day, a considerable sum for the entire population, but remarkably cost effective.
The bad news is that the FDA still looks at this problem from the standpoint of regulatory certainties, and the understanding we had of disease mechanics back in March. In TWIV 640, Mina participated in the following exchange:
Michael Mina: ... [H]igh-frequency testing using a less sensitive test goes much further than low-frequency testing using the best test in the world. We pretty much found that if you test less than ... every two weeks, you're not going to be able to contain pathogens.... What I would suggest is we have really cheap, low-sensitivity, from a molecular perspective, low-sensitivity tests that are a dollar, that people take every day. And so then it doesn't have to catch you in your incubation period, it doesn't have to catch you 20 days later, it just has to tell you the morning of that you have enough virus that you could be transmitting.

Rich Condit: Do such tests exist? Or will they?

MM: You know, they do. So this is the other bit that really led to that. They do exist, and I've been advising a lot of companies on their reagents and their tests and their test characteristics that might be needed. And the most frustrating thing for me is that these tests exist, but they're all getting slammed. Especially when they look at what happened with Abbott IDnow getting slammed for having a sensitivity that's a few Ct values worse than PCR, which is nothing. If you have a sensitivity that gets you to a Ct value of 36, great, that's amazing. But these companies are shaking in their boots, saying we can't go to the FDA, we can't try to market this test yet, because its sensitivity is three orders of magnitude worse than PCR, analytically, on the molecular level. And so I've been saying this: the FDA and the CDC and the NIH have to change their messaging. They have to say, look, there is actually a technology — that a test could exist right now — I have some sitting in my office next to me — they're paper strips. They're just little pieces of cardboard printed with monoclonal antibodies that can pick up an antigen. Essentially a lateral flow assay, can be printed in the millions, and could probably be done by the federal government and be funded by the federal government.
Mina's faith in the FDA et al. to manufacture anything is suspect given the CDC's role in delaying a working test back in February, but the funding part is much more likely. This sounds promising, which means it will all but certainly be ignored.