COVID-19 drugs that work

[jyl]

Chinese Sinovac vaccine seems to work better in monkeys than the Oxford U/Astrazeneca vaccine.

Sinovac: https://www.sciencemag.org/news/2020/04/covid-19-vaccine-protects-monkeys-new-coronavirus-chinese-biotech-reports#

Vaccinated monkeys who received highest vaccine dose had no detectable virus in respiratory system 7 days after exposure to SARS-CoV-2. Lower dose monkeys had detectable virus for a while but then suppressed it.

Oxford: https://www.biorxiv.org/content/10.1101/2020.05.13.093195v1.full.pdf

Vaccinated monkeys had detectable, shedding virus in respiratory system after exposure, but did not have accelerated breathing, lung damage, or other clinical effects of disease. They were infected but asymptomatic. However, the monkeys were euthanized after a while (to biopsy lungs), they didn’t follow them to see if they’d eventually become symptomatic.

EDIT: I probably shouldn’t have posted that without doing more research. The Oxford vaccine mentioned is not the one that went into human trials.

[jyl]

Moderna teases partial data from 45 patient phase 1 of MRNA1273 vaccine candidate. 25 and 100 um single dose arms showed dose-dependent antibodies at levels equal/greater than in recovered patients. 1 Grade 3 adverse effects (redness at injection site). High dose 250 um arm had 3 Gr 3 AEs, that arm is discontinued. A new 50 um arm established. This very small trial was in 18-55 y/o patients. 55-70 y/o and 70+ y/o trials underway. 600 patient phase 2 starting "soon", company claims Phase 3 potentially starting July. Will take "several quarters" to get to 1 BN dose/yr manufacturing rate at 50 um dose.

I think there will be multiple vaccine candidates that show antibody response - Sinovac and Oxford did in monkeys, now Moderna in (a few) humans. They will all move into phase 3 trials as fast as they can, probably 4-5 phase 3 trials will have data in 4Q.

Unclear to me how robust the data will be: if 1% of population contracts Covid-19 each month (most parts of US are much lower now, NY/NJ were higher at peak, potentially more states could get there by late summer/fall), how large a trial do you need to get efficacy and safety data strong enough to start vaccinating 10s or 100s of millions? Typical vaccine phase 3 trial is 20-40K persons. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551877/

[RWebb]

I expect health care workers will get vaccinated first, then results will be obtained form that popn. before moving to a more general vaccination scheme.

In fact, that will pretty much have to happen due to production limitations.

[jyl]

If you have a choice, would you choose to get a vaccine made from attenuated virus or from mRNA? Or just {shrug}?

[pmax]

Moderna

Immunogenicity data are currently available for the 25 µg and 100 µg dose level (ages 18-55) after two doses (day 43) and at the 250 µg level (ages 18-55) after one dose (day 29). Dose dependent increases in immunogenicity were seen across the three dose levels, and between prime and boost within the 25 µg and 100 µg dose levels. All participants ages 18-55 (n=15 per cohort) across all three dose levels seroconverted by day 15 after a single dose. At day 43, two weeks following the second dose, at the 25 µg dose level (n=15), levels of binding antibodies were at the levels seen in convalescent sera (blood samples from people who have recovered from COVID-19) tested in the same assay. At day 43, at the 100 µg dose level (n=10), levels of binding antibodies significantly exceeded the levels seen in convalescent sera. Samples are not yet available for remaining participants.

At this time, neutralizing antibody data are available only for the first four participants in each of the 25 µg and 100 µg dose level cohorts. Consistent with the binding antibody data, mRNA-1273 vaccination elicited neutralizing antibodies in all eight of these participants, as measured by plaque reduction neutralization (PRNT) assays against live SARS-CoV-2. The levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera.

mRNA-1273 was generally safe and well tolerated, with a safety profile consistent with that seen in prior Moderna infectious disease vaccine clinical studies. The sole incidence of a grade 3 adverse event in the 25 µg and 100 µg dose cohorts was a single participant at 100 µg who experienced grade 3 erythema (redness) around the injection site. To date, the most notable adverse events were seen at the 250 µg dose level, comprising three participants with grade 3 systemic symptoms, only following the second dose. All adverse events have been transient and self-resolving. No grade 4 adverse events or serious adverse events have been reported.

Preclinical results from a viral challenge study in mice conducted in collaboration with NIAID and its academic partners are also available. In this study, vaccination with mRNA-1273 prevented viral replication in the lungs of animals challenged with SARS-CoV-2. Neutralizing titers in Phase 1 clinical trial participants at the 25 µg and 100 µg dose levels were consistent with neutralizing titers that were protective in the mouse challenge model.

[KFC911]

Originally Posted by jyl

...

Small trial (no control arm, only 25 patients) of treatment with transfusion oof convalescent plasma (plasma from recovered Covid patients). Patients were severely ill, over half on ventilators and rest on oxygen. 18 were discharged, one died, 4 remained hospitalized with severe disease, by end of three week trial. (I must have missed a couple in counting.)

Since there’s no control arm, hard to say if these patients did better than you’d expect with no treatment. But 18/25 recovered seems promising.

....

Thanks! I missed this earlier...probably still giggling about heat lamps ...

If it does prove to be statistically significant, is it viable on a large scale?

[jyl]

Originally Posted by KC911

Thanks! I missed this earlier...probably still giggling about heat lamps ...

If it does prove to be statistically significant, is it viable on a large scale?

Dunno, but some hints here

https://www.nature.com/articles/d41587-020-00011-1

[RWebb]

Originally Posted by jyl

If you have a choice, would you choose to get a vaccine made from attenuated virus or from mRNA? Or just {shrug}?

mRNA

[jyl]

Observational study of patients receiving systemic anticoagulation (AC).

"Among 2,773 hospitalized COVID-19 patients, 786 (28%) received systemic AC during
their hospital course. The median (IQR) hospitalization duration was 5 days (3-8 days). Median
(IQR) time from admission to AC initiation was 2 days (0-5 days). Median (IQR) duration of AC
treatment was 3 days (2-7 days). In-hospital mortality for patients treated with AC was 22.5%
with a median survival of 21 days, compared to 22.8% and median survival of 14 days in
patients who did not receive AC (Figure 1A). Patients who received AC were more likely to
require invasive mechanical ventilation (29.8% vs 8.1%, p<0.001). Overall, we observed
significantly increased baseline prothrombin time, activated partial thromboplastin time, lactate dehydrogenase, ferritin, C reactive protein, and D-dimer values among individuals who received
in-hospital AC as compared to those who did not. These differences were not observed, however,
among mechanically ventilated patients. In patients who required mechanical ventilation
(N=395), in-hospital mortality was 29.1% with a median survival of 21 days for those treated
with AC as compared to 62.7% with a median survival of 9 days in patients who did not receive
AC (Figure 1B). In a multivariate proportional hazards model, longer duration of AC treatment
was associated with a reduced risk of mortality (adjusted HR of 0.86 per day, 95% confidence
interval 0.82-0.89, p<0.001)."

https://www.onlinejacc.org/content/early/2020/05/05/j.jacc.2020.05.001?_ga=2.25452607.368525428.159006 6962-1524494810.1590066962&fbclid=IwAR38sgFLfONiXc9XWTkhW-b7oJSH7G2kVTCN3JtPeDX5ARLd1jnJqRWBe7w

This suggests to me that anti-coagulants have a modest benefit. Selection bias effect unclear.

[jyl]

Growing data in NHP (non human primate aka monkey) supporting presence of at least some degree of immunity after recovery from SARS-CoV-2. Add SinoVac monkey data showing their vaccine candidate protects monkeys from SARS-CoV-2 infection. Odds of successful vaccine development improving, I think. Time for this remains uncertain.

https://science.sciencemag.org/content/early/2020/05/19/science.abc4776

“ We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. Following initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with primary infection. Anamnestic immune responses following rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against re-exposure in nonhuman primates.”

[jrdavid68]

Originally Posted by jyl

...

Incidentally, I think Trump has stopped publicly pushing HCQ as a covid treatment. At least I haven’t heard of him doing so lately. I don’t know if political appointees are still trying to pressure for the drug’s use, or if they’ve decided to wait for better data.

That seems to have changed.

[jyl]

Largest HCQ observational study I’ve seen. Similar results as the others.

Still a chance for HCQ in prophylaxis (prevention). Trial ongoing.

https://marlin-prod.literatumonline.com/pb-assets/Lancet/pdfs/S0140673620311806.pdf

“96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.”

[jyl]

CanSino vaccine phase 1 data - 108 healthy patients, three dose groups, results were neutralizing antibody and T-cell responses through 28 days, w/ dose dependent, about 50-80% mild-moderate adverse effects including injection site pain, fever, and fatigue. High dose will not be taken to phase 2 due to 17% Grade 3 AEs. No patients over 60 y/o. No data on longer-term response. Some pts had pre-existing antibodies to the viral vector used, a hindrance. Unknown what level of antibody/T-cell response is needed to protect from infection in human (they have only animal data on protective effect, so far). Phase 2 starting.

https://marlin-prod.literatumonline.com/pb-assets/Lancet/pdfs/S0140673620312083.pdf

More: Some reactions to this are “underwhelm” due to the antibody to vector problem, the modest SARS-CoV-2 antibody titer level achieved, and the discontinuation of the high dose.

[jyl]

Extremely interesting. https://www.statnews.com/2020/05/21/coronavirus-hijacks-cells-in-unique-ways/ SARS-CoV-2 virus blocks genes that create interferons (which slow viral replication), does not block genes that create chemokines (that attract antibody-making B-cells and virus-killing T-cells). Result is virus can replicate freely, and body has a large inflammatory response. In vitro, interferon reduced viral replication by 1K to 10K times. Different from SARS1 that is unaffected by interferon.


https://www.cell.com/cell/fulltext/S0092-8674(20)30489-X

[group911@aol.co]

Shocking
https://www.reuters.com/article/us-health-coronavirus-hydroxychloroquine/france-bans-hydroxychloroquine-to-treat-covid-19-amid-safety-concerns-idUSKBN233197

[pavulon]

Next up...insulin! Thank God our stable genius connected the dots between insulin and Covid. Were it not for his prophylactic consumption of Plaquenil, this breakthrough may have never happened!

[Shaun @ Tru6]

Will anyone with negative side effects from hydroxchoroquine sue Trump?

[jyl]

His lawyers are arguing to the Supreme Court that a US President is immune from and can block any and all criminal and civil process, under federal or state law, including the power to nullify subpeonas issued to third parties. In short, that a US President is above the law.

This court might well agree . . .

Back to HCQ - there is still a prevention trial and at least one treatment trial ongoing, I mean large, well-run randomized and blinded trials, so the jury is still out. The prevention trial has continued through a couple of interim reviews, which means there is still some hope for positive HCQ data. These trials are probably the last hope, though.

[RWebb]

https://www.nejm.org/doi/full/10.1056/NEJMcibr2007042

[group911@aol.co]

Sad statement.
https://www.nytimes.com/2020/05/01/world/europe/coronavirus-blood-samples.html

"After 10 terrible days of chills, nausea, a fever of 103 and a headache of such intensity that her nose bled, Aleacia Jenkins knew she had been stricken with the coronavirus even before she tested positive.

So when a friend told her about an obscure Californian company that was asking for blood donations from people who have recovered from the virus to help researchers develop tests for antibodies, she didn’t hesitate.

“If my blood donation could help save someone’s life who is older or more vulnerable,” said Ms. Jenkins, 42, of Shoreline, Wash., “it would be crazy not to want to help do that.”

But what she did not know at the time was that the company, Cantor BioConnect, was selling those donations to laboratories and test manufacturers at sometimes exorbitant prices: from $350 up to $40,000 for a rare sample from a single donor."