Vaccines, Drugs and Other Treatments

First, a couple of links to external sources that are updated regularly with stuff about how US doctors are treating covid today:

https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults

https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-outpatient-evaluation-and-management-in-adults

(lots of other interesting pages on this site, many related to covid research)

Some posts stolen from the old actuarial outpost:

posted by Campbell:
https://theconversation.com/we-found-and-tested-47-old-drugs-that-might-treat-the-coronavirus-results-show-promising-leads-and-a-whole-new-way-to-fight-covid-19-136789?fbclid=IwAR1rnC908I7WNCL-yPkiXNzI2DAkEXcY5624W9M0EMWRRJ1gRuP9GAICruU

Posted by me (in response to above):

That’s really interesting. And rather hopeful. Although the bit about dextromethorphan helping the virus replicate sounds bad.

It’s important to know how a drug works, because it matters for WHEN to give it in the course of the infection. I was talking to a friend (Call him James) who is researching covid, and he tells me there are 4 stages of immune response

  1. immediate & non-specific, the first cells to be infected signal other cells to slow down their RNA replication. Because this stage isn’t mediated by immune cells, it’s called something weird like “acellular”, and because immunologists mostly study immune cells, it’s not much studied. But it’s critical to our immune response to viruses.

  2. innate immune response, where immune cells go out to kill infected cells and generally attack “not self”. This is the part of the immune response where cytokines are generated, to call other immune cells to battle.

  3. adaptive immune response, where the body generates antibodies specific to this virus. It usually takes a week or two for this to gear up. This is the immune reaction that typically clears the virus from your body, assuming the other stages kept you alive and well enough to mount an effective active immune response.

  4. the creation of memory cells, where your body catalogs this virus as “something to deal with if it shows up again”, and creates long-live immune cells that can spit out antibodies quickly. Creating these is the goal of vaccines, I think.

So, the first two steps are critical. James tells me that because of the effect of stage 1, the second generation of cells that are infected often produce only 1/100th of the number of viral particles as the first generation of infected cells. This is one reason why disease is dose-dependent, despite the exponential growth of pathogens in your body.

Stage 1 is also the immune response that is mimicked by drugs like tamiflu and remdesivir, which is why they mostly work if you take them early-on. Tamiflu works best if you take it within 12 hours of being infected, and doesn’t work at all once you are really sick with the flu. The same is likely true of remdesivir, except that with covid there is probably a second window of effectiveness, because the virus has the odd property of jumping from the respiratory system to other types of cells, and that process may resemble an initial infection. HOWEVER, remdesivir interferes with cell reproduction in general, not just with the reproduction of viral RNA, and stage 3 of the immune response (the stage that can actually clear the virus) depends on ramping up reproduction of immune cells. So if you take drugs like these too late into the infection, they can prolong illness.

Other drugs, like steroids, ramp down inflammation and can protect against a “cytokine storm” or ARDS, where your body’s immune response goes into overdrive and can kill you. (James says that in China, the current covid protocol is to administer steroids on day 8 of the infection.) BUT, that same immune response is critical to stage 2, which is what prevents the virus from infecting all your cells while the rest of the immune system ramps up. (And every infected cell dies. You recover by clearing out the virus and the debris of the infected cells, and then growing new cells to replace the ones that died. People feel sick and weak for a while after the flu because it can kill 15% of the cells liming the lung, and it takes a couple of weeks to regenerate them.)

Anyway, that was a long post. But the point is that some drugs might be helpful prophylactically, some may be helpful at the onset of symptoms, and others may help those who are already critically ill. But those might be different drugs. So studies in cells that investigate the precise mechanism through which a drug works are important in developing treatment protocols.

From campbell:

Critically ill patients given higher doses of chloroquine diphosphate were more likely to die than those given lower doses.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2765499

Summary

Importance There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug.

Objective To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19.

Design, Setting, and Participants This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon.

Interventions Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days).

Main Outcomes and Measures Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4.

Results Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).

Vitamin D deficiency may increase covid mortality: cross population review

https://www.medrxiv.org/content/10.1101/2020.04.08.20058578v3

Note that this article still hasn’t been published. The authors made some changes and resubmitted it. I’m not sure what that means for it’s ultimate fate.

Vitamin D deficiency may increase covid mortality: retrospective review of individual patients with varying severity of disease

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3571484

Vitamin D deficiency associated with more severe disease: another retrospective review of individual patients with varying severity of covid-19

https://www.medrxiv.org/content/10.1101/2020.04.24.20075838v1

By the way, a few comments about the vitamin D link, which I’m not going to bother to source:

  1. Not only does it help explain the disparity in outcomes between darker and lighter skinned individuals, it also helps explain the disparity of outcomes between obese and slim individuals. While poking around for these studies, I found a lot of articles pointing out that fat cells tend to take up vitamin D, and serum vitamin D levels in obese people are lower than those in slimmer people, and vitamin D deficiency is more common in obese people. As a fat person, I have dug out the vitamin D supplement my doctor recommended a couple of years ago, when I randomly tested low, and I’m taking it again. I’m also trying to spend some time in the sun. Some study in the UK found that 13 minutes of sunlight on 1/3 of the skin, 3 times a week, was adequate to increase vitamin D to healthy levels in most of the (presumably pale-skinned) people in the study.

  2. The potential importance of the innate immune system (which is bolstered by vitamin D) and the risk of an overactive adaptive immune response (vitamin D helps reduce the risk of a cytokine storm) are sort of bad news for vaccines. Vaccines are all about the adaptive immune system, and there are cases where vaccines increase the risk of the adaptive immune system over-reacting to a virus. (That being said, there ARE some veterinary vaccines for animal coronaviruses. I am still hoping we’ll get a good vaccine.)

  3. Apparently calves are sometimes treated with vitamin D for a bovine coronavirus.

But note that another possible reason obese people are hot harder is that obesity tends to lead to higher levels of inflammation throughout the body. I didn’t mean to imply vitamin D was the whole story, but it might be an important piece of the story.

From Campbell (5/18)

https://ctmirror.org/2020/05/17/cautious-enthusiasm-for-plasma-treatment-in-covid-19-cases/

5/18

You know, those two articles Campbell posted are great news, but they make me nervous.

I don’t know that we want to immunize every healthcare worker immediately… Vaccines don’t always work, they occasionally make matters worse, and these ones are going to go to market with very little testing. I suppose there will be limited supply, so not all the front-line workers will be vaccinated right away whatever the official goal is.

Still, a really strong benefit to convalescent serum is not only a good thing all by itself, it also speaks to the plausibility of a vaccine working. So that article is all good news. I hope the formal tests pan out and prove it really is effective.

1 Like

MayanActuary 5/18

By the time they would be able to be rolled out to every healthcare worker we should have some decent testing.

Moderna’s (greenman’s article) completed Phase 1 on 45 participants. 3 had adverse reactions, all were in the highest dosage group (250mcg), and all recovered on their own. The two lower doses work well, so they are going to stop the higher dose trial.

Phase 2 has hundreds of people.

Phase 3 this summer (assuming Phase 2 goes well) usually has thousands of people.

If that goes well, they would up it again and get 10s of thousands of people for a trial. Each phase has to wait the mandated 42 days between trials to observe adverse effects.

Mass injection wouldn’t happen until probably early 2021.

So, while rushed, safety would be at a point that it wouldn’t just incapacitate every healthcare worker upon injection, and should significantly help them. I DO want to immunize everyone right away once a vaccine successfully passes through those multiple phases.

5/21

Experimental vaccines and recovering from covid both provide (at least short term) immunity in rhesus macaques.

https://news.harvard.edu/gazette/story/2020/05/vaccines-found-that-may-protect-against-covid-19-in-animal-models/?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20Gazette%2020200521%20(1)

Summary

BY
Jacqueline Mitchell
BIDMC Communications
DATE
May 20, 2020

With nearly 5 million confirmed cases globally and more than 300,000 deaths from COVID-19, much remains unknown about SARS-CoV-2, the virus that causes the disease. Two critical questions are whether vaccines will prevent infection with COVID-19, and whether individuals who have recovered from COVID-19 are protected against re-exposure to the virus.

Now, a pair of new studies led by researchers at Harvard-affiliated Beth Israel Deaconess Medical Center (BIDMC) suggests the answer to these questions is yes, at least in animal models. Results of these studies were published today in the journal Science.

“The global COVID-19 pandemic has made the development of a vaccine a top biomedical priority, but very little is currently known about protective immunity to the SARS-CoV-2 virus,” said senior author Dan H. Barouch, director of the Center for Virology and Vaccine Research at BIDMC. “In these two studies, we demonstrate in rhesus macaques that prototype vaccines protected against SARS-CoV-2 infection and that SARS-CoV-2 infection protected against re-exposure.”

In the first study, the team found that six candidate DNA vaccines — each formulation using a different variant of the key viral protein — induced neutralizing antibody responses and protected against SARS-CoV-2 in rhesus macaques.

Barouch and colleagues, who began working toward a COVID-19 vaccine in mid-January when Chinese scientists released the SARS-CoV-2 genome, developed a series of candidate DNA vaccines expressing variants of the spike protein, the part used by the virus to invade human cells and a key target for protective antibodies. The vaccines are designed to train the body’s immune system to recognize the virus swiftly upon exposure and respond quickly to disable it.

To assess the efficacy of the vaccines, the researchers immunized 25 adult rhesus macaques with the investigational vaccines. Ten animals received a sham version as a control group. Vaccinated animals developed neutralizing antibodies against the virus. Three weeks after a booster vaccination, all 35 animals were exposed to the virus. Follow-up testing revealed dramatically lower viral loads in vaccinated animals, compared with the control group. Eight of the 25 vaccinated animals demonstrated no detectable virus at any point following exposure to the virus, while the other animals showed low levels of virus. Moreover, animals that had higher antibody levels had lower levels of the virus, a finding that suggests neutralizing antibodies may be a reliable marker of protection and may prove useful as a benchmark in clinical testing of SARS-CoV-2 vaccines.

The vaccines are designed to train the body’s immune system to recognize the virus swiftly upon exposure and respond quickly to disable it.
In the second study, the team demonstrated that macaques that recovered from COVID-19 developed natural protective immunity against re-infection with the virus. The results shed much-needed light on the critical question of just how much, if any, immunity does infection with SARS-CoV-2 provide against subsequent encounters with the virus.

“Individuals who recover from many viral infections typically develop antibodies that provide protection against re-exposure, but not all viruses generate this natural protective immunity,” said Barouch, who is also professor of medicine at Harvard Medical School, a co-leader of the vaccine development group of the Massachusetts Consortium on Pathogen Readiness, and a member of the Ragon Institute of MGH, MIT, and Harvard.

After exposing nine adult macaques to the SARS-CoV-2 virus, the researchers monitored viral levels as the animals recovered. All nine animals recovered and developed antibodies against the virus. More than a month after initial infection, the team re-exposed the rhesus macaques to the virus. Upon second exposure, the animals demonstrated near-complete protection against the virus. These data suggest that animals develop natural protective immunity against the virus and the disease that it causes.

“Our findings increase optimism that the development of COVID-19 vaccines will be possible,” said Barouch. “Further research will be needed to address the important questions about the length of protection as well as the optimal vaccine platforms for SARS-CoV-2 vaccines for humans.”

Future studies will test the Ad26 based vaccines that Barouch is developing in partnership with Johnson & Johnson.

Campbell 5/21

from 2005

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

Campbell 5/26

https://www.wsj.com/articles/study-points-to-efficacy-of-convalescent-plasma-for-covid-19-11590177304

6/16

I don’t have time right now to look up the actual study, but a cheap steroid, dexamethasone, has been found to reduce the risk of death in patients who are on oxygen or ventilators.

https://www.bbc.com/news/health-53061281

6/16

That’s not super-exciting news, though, because corticosteroids have been widely used outside the UK to treat inflammation in covid patients for a while. For instance

https://emcrit.org/ibcc/covid19/#steroid_for_severe_hypoxemic_respiratory_failure

Notice the dates of those studies. (bolding added)

still, there are a lot of guidelines out there advising against using steroids, which apparently didn’t appear to help for SARS1.

This article is graphics-heavy, so I won’t post any of it, but it gives a good explanation of the timing issues around using steroids to treat covid.
https://emcrit.org/pulmcrit/steroid-covid/

That’s what I scraped from the old AO. I guess it’s time to add new stuff about vaccine trials, etc.

Oh, here’s something I saw yesterday – more promising news re vitamin D

The Journal of Steroid Biochemistry and Molecular Biology

Volume 203, October 2020, 105751

https://www.sciencedirect.com/science/article/pii/S0960076020302764

“Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”

Basically, a prospective, randomized (but not blinded) study looked at 76 people hospitalized for covid-19. 50 of them were treated with a vitamin D metabolite that is more rapidly absorbed than vitamin D, and the others weren’t. They were all also treated with the then-best-available treatment. Of the 50 given vitamin D, 1 ended up in the ICU, and all 50 recovered. Of the 26 controls, 13 ended up in the ICO and 2 died.

They controlled for what they understood to be major risk factors at the time, but did not record BMI, which has since been found to be highly predictive of covid 19 outcomes.

I don’t remember seeing this posted on the AO, and it’s not in any of the posts you’ve ported over…

Has anyone seen anything about the “bradykinin hypothesis” ?

https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63

Thoughts?

It reportedly explains many of the strange symptoms of COVID. Also, apparently vitamin D has a role in regulating bradykinin in the body, so all of your vitamin D posts are relevant for this hypothesis, Ms. Ball.

A good thing about this is that it should be a testable hypothesis and suggests several possible treatments.

I have seen it – it was even posted on the ao, but in a much longer thread. Thanks for bringing it here.

Yes – if that proves to be true, there are apparently several widely available drugs that can help regulate bradykinins, and which might become useful treatments.