COVID19 update, June 30, 2020: droplet and aerosol transmission; herd immunity requires as little as 20%?

Been a very busy day at work, but let me just share with you two things:

(a) a long essay that Jeff Duntemann drew my attention to:

Aerosols, Droplets, and Airborne Spread: Everything you could possibly want to know by Justin Morgenstern MD, an emergency physician located in the greater Toronto area.

The essay is long but very much worth your while.

(b) Coronavirus: could it be burning out after 20% of a population is infected? We pointed earlier to a preprint that showed that, if susceptibility to the infection isn’t assumed to be all or nothing, that this leads to a second-order mathematical model that predicts much lower herd immunity thresholds than the common first-order model. See also (h/t: masgramondou): https://judithcurry.com/2020/05/10/why-herd-immunity-to-covid-19-is-reached-much-earlier-than-thought/ 

But it is unlikely that lockdowns alone can explain the fact that infections have fallen in many regions after 20% of a population has been infected – something that, after all, happened in Stockholm and on cruise ships. 

That said, the fact that more than 20% of people have been infected in other places means that the T-cell hypothesis is unlikely to be the sole explanation either. Indeed, if a 20% threshold does exist, it applies to only some communities, depending on interactions between many genetic, immunological, behavioural and environmental factors, as well as the prevalence of pre-existing diseases. 

Understanding these complex interactions is going to be necessary if one is to meaningfully estimate when SARS-CoV-2 will burn itself out. Ascribing any apparent public health successes or failures to a single factor is appealing – but it is unlikely to provide sufficient insight into how COVID-19, or whatever comes next, can be defeated.

COVID19 update, June 27, 2020: The Economist on how COVID-19 changed the office; reduced hospital fatality rates in the UK; initial infection rates may have been 80 times higher than reported

(1) The Economist has a video on how COVID-19 is changing the office building as we know it. Working from home used to be the exception — companies insisted that you show up in the office even for work that can be done from home very well

Now COVID-19 has forced companies to make a virtue of necessity — and it turns out this works pretty well. The video claims that 47% of all existing jobs in Switzerland can be done from home, with somewhat lower percentages for other developed economies, but much lower percentages for developing countries.

And guess what: considering how expensive office space in premium locations is (downtown Hong Kong, with about $250/mo/square meter, probably takes the case), companies can save a ton of money by letting WFH-feasible jobs be done from home and downsizing their office locations.

This will have a ripple effect: a WSJ journalist interviewed in the video claims that every Manhattan office job created employment for 5 people in the service industry (bars and restaurants, custodial,…) 

Of course, one man’s meat is another man’s poison, so it is quite possible that the lost jobs catering to downtown office worker may be partly or even wholly offset by other jobs created elsewhere — as people working from home will want to upgrade their housing arrangements, or will have more disposable income to spend on family amenities.

I would not say that COVID-19 will bring the end of the Dilbert cube farm as we know it: simply that it triggered a transformation that was waiting to happen, only delayed by managerial inertia.

(2) There are reports from various countries that hospital mortality rates have dropped considerably from the peak of the infection. The Daily Telegraph reports that mortality of COVID19 patients admitted to English hospitals has dropped fourfold, from 6% in April (the peak of the epidemic there) to 1.5% now. A number of explanations are proffered:

  • Doctors have gotten better at managing the disease and mitigating its severity
  • Hospitals have enough capacity now that milder cases can now be admitted that would have been sent home earlier: as these mild cases almost invariably recover, this drives down the statistics
  • The most vulnerable older people either have already died or recovered, or we have simply gotten better at shielding the elderly from infection. 
  • [not in the article] the better, sunnier weather reduces vitamin D deficiency

(2b) [Hat tip: Erik W.]

An epidemiological study from Penn State U. suggests that the initial COVID19 infection rate in the US may have been about 80 times the officially reported one. The paper can be read directly here:

http://doi.org/10.1126/scitranslmed.abc1126

Quoting from the abstract:

Detection of SARS-CoV-2 infections to date has relied heavily on RT-PCR testing. However, limited test availability, high false-negative rates, and the existence of asymptomatic or sub-clinical infections have resulted in an under-counting of the true prevalence of SARS-CoV-2. Here, we show how influenza-like illness (ILI) outpatient surveillance data can be used to estimate the prevalence of SARS-CoV-2. We found a surge of non-influenza ILI above the seasonal average in March 2020 and showed that this surge correlated with COVID-19 case counts across states. If 1/3 of patients infected with SARS-CoV-2 in the US sought care, this ILI surge would have corresponded to more than 8.7 million new SARS-CoV-2 infections across the US during the three-week period from March 8 to March 28, 2020. Combining excess ILI counts with the date of onset of community transmission in the US, we also show that the early epidemic in the US was unlikely to have been doubling slower than every 4 days. Together these results suggest a conceptual model for the COVID-19 epidemic in the US characterized by rapid spread across the US with over 80% infected patients remaining undetected.

Note that a “Dunkelziffer” of 80:1 is in the 50:1  – 85:1 range the [much-maligned] original version of the Santa Clara serological study (Ioannides et al.) had.

(3) “Covid toes” may actually not be a COVID-19 symptom or sequel after all, but simply result from lack of physical activity , reports UPI.

The “symptom” mirrors that of a condition called Chilblains, or perniosis, a painful inflammation of the small blood vessels in the skin that occurs after repeated exposure to cold air, they said.

(4) [Hat tip: Jeff Duntemann] A retired anesthesiologist on masks:

To protect yourself, you need an N95 respirator mask that is properly fitted.  Then you need to re-sterilize it every four hours using UV light or properly dispose of it and start over with a new one.  That is too expensive for most people.

The outside world is the safest place you can be.  The state of Florida has zero cases of COVID-19 that can be traced to outside transmission.  During the day, solar UV kills all viruses very quickly, and there’s always enough air movement to disperse aerosols, making them non-infective.  It has become clear that virtually all cases have been spread in closed spaces with prolonged (>10 minute) exposure.  And as the studies I’ve cited show, other than N95s, masks are no help there.  For that matter, six-foot spacing doesn’t help, either, since the aerosols that transmit the virus aren’t adequately dispersed.

COVID19 update, June 9, 2020: Matt Ridley on parallels with the 1890 flu epidemic; 57% infected in Bergamo, Italy; corroboration of different susceptibilities between blood groups

(1) (H/t: masgramondou). Matt Ridley tells the story of the 1890 Russian flu epidemic 

The killer came from the east in winter: fever, cough, sore throat, aching muscles, headache and sometimes death. It spread quickly to all parts of the globe, from city to city, using new transport networks. In many cities, the streets were empty and shops and schools deserted. A million died. The Russian influenza pandemic of 1889-90 may hold clues to what happens next — not least because the latest thinking is that it, too, may have been caused by a new coronavirus.

In addition to the new diseases of S[ARS], M[ERS], and C[COVID]-19, there are four other coronaviruses that infect people. They all cause common colds and are responsible for about one in five such sniffles, the rest being rhinoviruses and adenoviruses. As far as we can tell from their genes, two of these coronaviruses came from African bats (one of them bizarrely via alpacas or camels), and two from Asian rodents, one of the[se] via cattle.

It sounds very  familiar… (Note that at the time, not everybody even believed in bacteria — and the first virus was only discovered eight years later by Martinus Beijerinck.)

Genetic analysis by the Belgian virologist, Prof. Marc van Ranst at the University of Leuven, suggests OC43, one of the four common cold coronaviruses diverged away from a pneumonia virus in cattle around 1890. Matt Ridley describes the hypothesis that OC43 was the pathogen of the 1890 Russian Flu, then gradually evolved away to a much more contagious, but infinitely less harmful, form.

 

 

The first case is thought to have been in Bukhara, in central Asia in the spring of 1889, but by October, Constantinople and St Petersburg were affected. In December, military hospitals in the Russian capital were overcrowded, factories and workshops closed for lack of workers and ‘whole districts of the city were abandoned by the population’, according to one report. The symptoms were said to include headache, fever, aching bones, facial rash and swollen hands. The illness lasted for five or six days but sometimes left the patient exhausted for weeks.

The virus reached Paris in November. By the turn of the year, with hospitals full, patients were housed in military barracks and tents in the city’s parks. […] In Vienna the schools closed early for Christmas and stayed closed till late January. In Berlin, it was reported that many post-office staff were affected. In London so many lawyers fell ill that the courts were closed for a while. One day in January at St Bartholomew’s Hospital in the City of London, Dr Samuel West found more than 1,000 people crowded into the casualty ward, most of them men.[Sounds familiar?] […]

According to a modern analysis, the death rate peaked in the week ending 1 December 1889 in St Petersburg, 22 December in Germany, 5 January 1890 in Paris, and 12 January in the US. [The basic reproductive number] R0 has been estimated at 2.1 and the case fatality rate was somewhere between 0.1 per cent and 0.28 per cent: similar figures to today’s pandemic.

Contemporary newspaper reports say that like today’s epidemic, the Russian flu appeared to attack adults more than children, and in some schools the teachers were all affected but not the pupils. Like today’s virus, it was, intriguingly, reported to affect men much more badly than women. Newspapers were filled with statistics of mortality, anecdotes and reassuring editorials.

By March 1890 the pandemic was fading in most places, just as common colds and flu do in spring today. The seasonal pattern displayed by colds and flus is so striking that it cannot be a coincidence that today’s pandemic was also in retreat by May all around the world, irrespective of the policies in place. By the northern summer of 1890 the virus was ensconced in the southern hemisphere, having reached Australia in March. It returned to Europe the following winter and for several years after.

If OC43 was the cause of the 1889-90 pandemic — far from proven, of course — and given that it is the cause of perhaps one in ten colds today, then it has evolved towards lower virulence. It is easy to see how this occurs with respiratory viruses, which are transmitted by people chatting and shaking hands. Mutations that affect the severity of the virus also tend to have an impact on whether people pass it on: if it sends you to bed feeling rotten, you will not give it to so many people. In the inevitable struggle for survival, the milder strains will gradually displace their nastier ones. This is why so many cold viruses affect us but so few kill us, except maybe when new to our species.

Perhaps, too, a degree of immune response in the population helps moderate the effects of the virus, even if not achieving full and permanent immunity. Some cross–immunity seems to exist today, whereby those who have had coronavirus colds do not catch, or do not suffer severely from, Covid-19.

 

(2) Die Welt reports that in the Italian city of Bergamo (classical music lovers may think of Debussy’s Suite Bergamasque) no fewer than 57% of 10,000 tested subjects had antibodies for COVID19. (This is most definitely in 1st-order ‘herd immunity’ territory.) Among a similar-sized (10,400) sample of healthcare workers, “only” 30% had antibodies (which is in the 2nd-order herd immunity range).

In a summary of the state of the epidemic so far, the German daily quotes virologist Prof. Christian Droste, who in an interview in Der Spiegel states that with our present state of knowledge, it is time to shorten the 2-week quarantine in case of exposure to just one week.

(3) A German-Norwegian collaboration, reports Die Welt, found confirmation of earlier indications that blood groups have an effect on disease progression. A+ are worst off (oh joy ;)), while O imparts a degree of protection.

Dass die Blutgruppe Krankheitsverläufe beeinflussen kann, ist grundsätzlich nichts Neues. So gibt es schon seit Längerem Hinweise darauf, dass Blutgruppe 0 auch vor schweren Malaria-Verläufen schützen kann, dafür aber anfälliger für Magen- und Darminfektionen macht, während Träger der Blutgruppen A, B oder AB besser gegen die Pest gewappnet sind.

[That blood groups can influence disease progression is fundamentally nothing new. There have for long been indications that blood group O can also protect for severe malaria [!!], but makes one more susceptible for gastro-intestinal infections, while carriers of blood groups A, B, or AB are more resistant to the plague.

Preprint: https://www.medrxiv.org/content/10.1101/2020.05.31.20114991v1.full.pdf+html

Laut Blutspendedienst des Bayerischen Roten Kreuzes haben 37 Prozent der Bevölkerung die Blutgruppe A Rhesus Positiv und 35 Prozent die Blutgruppe 0 Rhesus Positiv.

[According to the blood donation service of the Bavarian Red Cross, 37% of the [German] population have blood group A+ and 35% O+.]

(4) A new Nature paper “Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe”

http://doi.org/10.1038/s41586-020-2405-7

(This is a “postprint”, i.e., accepted version after peer review, but without copy-editing by the publishers and corrections in proof.) I will probably devote tomorrow’s edition to discussing this paper. (The hoary sketch comes to mind: “Why are you spraying pesticides on an organic garden?” 

“Those aren’t pesticides, that’s a powder against elephants.”

“But there aren’t any bleeding elephants here!”

“Yeah, good stuff, huh?”)

 

(5) Apropos of nothing:

“Liberty is for science what air is for an animal: when deprived of liberty, [science] dies of suffocation as surely as a bird deprived of oxygen. […]

Thought must never submit —

neither to dogma,

nor to party,

nor to passion,

nor to special interest,

nor to a preconceived idea,

nor to anything but the facts themselves —

for when thought submits,

that means it ceases to be.”

—Henri Poincaré, Le libre examen en matière scientifique (1909)

COVID19 update, June 4, 2020: is the virus a picky eater; co-authors of influential Lancet hydroxychloroquine study retract paper

(1) Somebody quipped to me the other week: “the virus is a picky eater”. Now, Prof. Karl Friston of UC London, a well-known neuroscientist and computational modeler who is a member of “the independent SAGE committee” is interviewed here on UnHerd.

Now, from the unlikely source of a prominent member of the “Independent SAGE committee”, the group set up by Sir David King to challenge government scientific advice and accused by some of being populated with Left-wing activists, comes a claim that the true portion of people who are not even susceptible to Covid-19 may be as high as 80%.

 

A written essay is here. His thesis: 

Theories abound as to which factors best explain the huge disparities between countries in the portion of the population that seems resistant or immune — everything from levels of vitamin D to ethnic-genetic and social and geographical differences may come into play — but Professor Friston makes clear that it does not primarily seem to be a function of government coronavirus policy. “Solving that — understanding that source of variation in terms of this non-susceptibility — is going to be the key to understanding the enormous variation between countries,” he said.

Controversial? We link, you decide.

(2) The Washington Examiner reports that the influential The Lancet paper, which claimed hydroxychloroquine was more harmful than helpful in the treatment of COVID19 based on dodgy Surgisphere data, has now been retracted by 3 of the 4 authors (the 4th is the CEO of Surgisphere). Here is the original retraction notice:

https://www.thelancet.com/lancet/article/s0140673620313246

After publication of our Lancet Article,1 several concerns
were raised with respect to the veracity of the data
and analyses conducted by Surgisphere Corporation
and its founder and our co-author, Sapan Desai, in
our publication. We launched an independent third-
party peer review of Surgisphere with the consent of
Sapan Desai to evaluate the origination of the database
elements, to confirm the completeness of the database,
and to replicate the analyses presented in the paper.

Our independent peer reviewers informed us that
Surgisphere would not transfer the full dataset, client
contracts, and the full ISO audit report to their servers
for analysis as such transfer would violate client
agreements and confidentiality requirements. As such,
our reviewers were not able to conduct an independent
and private peer review and therefore notified us of their
withdrawal from the peer-review process.

We always aspire to perform our research in accordance
with the highest ethical and professional guidelines. We
can never forget the responsibility we have as researchers
to scrupulously ensure that we rely on data sources that
adhere to our high standards. Based on this development,
we can no longer vouch for the veracity of the primary
data sources. Due to this unfortunate development, the
authors request that the paper be retracted.

We all entered this collaboration to contribute
in good faith and at a time of great need during
the COVID-19 pandemic. We deeply apologise to
you, the editors, and the journal readership for any
embarrassment or inconvenience that this may have
caused.

The accompanying statement by the Lancet editorial board:

Statement from The Lancet
Today, three of the authors of the paper, “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis”, have retracted their study. They were unable to complete an independent audit of the data underpinning their analysis. As a result, they have concluded that they “can no longer vouch for the veracity of the primary data sources.” The Lancet takes issues of scientific integrity extremely seriously, and there are many outstanding questions about Surgisphere and the data that were allegedly included in this study. Following guidelines from the Committee on Publication Ethics (COPE) and International Committee of Medical Journal Editors (ICMJE), institutional reviews of Surgisphere’s research collaborations are urgently needed.

(3) Elsewhere in the Lancet is an article with a “meta-analysis” of other studies (in plain English: a study in which the raw data of several original lstudies are combined into a larger dataset and the statistical analysis repeated in order to achieve greater productive power than the individual studies)  on the effectiveness of distancing, face masks, and eye protection, in both  healthcare and non-healthcare (community) settings.

https://doi.org/10.1016/S0140-6736(20)31142-9

From the summary (paragraphing and emphasis mine):

Our search identified 172 observational studies across 16 countries and six continents, with no randomised controlled trials and 44 relevant comparative studies in health-care and non-health-care settings (n=25 697 patients).

Transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 m (n=10 736, pooled adjusted odds ratio [aOR] 0·18, 95% CI 0·09 to 0·38; risk difference [RD] –10·2%, 95% CI –11·5 to –7·5; moderate certainty); protection was increased as distance was lengthened (change in relative risk [RR] 2·02 per m; p_interaction=0·041; moderate certainty).

Face mask use could result in a large reduction in risk of infection (n=2647; aOR 0·15, 95% CI 0·07 to 0·34, RD –14·3%, –15·9 to –10·7; low certainty), with stronger associations with N95 or similar respirators compared with disposable surgical masks or similar (eg, reusable 12–16-layer cotton masks; p =0·090; posterior probability >95%, low certainty).

Eye protection also was associated interaction with less infection (n=3713; aOR 0·22, 95% CI 0·12 to 0·39, RD –10·6%, 95% CI –12·5 to –7·7; low certainty).

Unadjusted studies and subgroup and sensitivity analyses showed similar findings.

 

ADDENDUM: “WHO frustrated by China’s info delays as coronavirus started to spread, report finds”. Is this damage control/reputation management on the part of the WHO, or the genuine expression of frustration by the technical levels of the organization? More about this tomorrow, G-d willing.

COVID19 update, Shavuot edition: Singapore research finds 50% of sample has pre-existing immunity

Breaking news (via Instapundit): Prof. Francois Balloux from UCLondon highlights preprint from Singapore: https://doi.org/10.1101/2020.05.26.115832

Recent preprint reporting that 24/24 (100%) people form Singapore infected by SARS-1 in 2003 have pre-existing T-cell immunity against #SARSCoV2, but more surprisingly 9/18 (50%) with no exposure to SARS-1 also possess T-cells targeting #SARSCoV2.

One take[-]home message is that infection with coronaviruses induces strong and long-lasting T-cell (cross-)immunity. T-cell immunity is likely a far more important for our immune response to #SARSCoV2 infection than antibodies, in line with other recent reports.

What remains unresolved is which virus caused T-cell immunity in the people with no prior exposure to SARS-1 in 2003. We know of seven coronaviruses infecting humans: #SARSCoV2, SARS-1, MERS and four causing ‘common colds’ (OC43, HKU1, 229E and NL63). [NB: most common colds are caused by rhinoviruses, which are a different family]

Intriguingly, none of the known viruses in circulation in humans looks like a good candidate for the T-cell immunity to #SARSCoV2 in those with no prior exposure to SARS-1. This might suggest that other yet unknown coronaviruses could have been in circulation in humans.

No surprise that having had SARS 1.0 would protect you against SARS 2.0, but nice to know. But that half of a random sample would have immunity owing to previous exposure to a common cold-level virus… If confirmed on a larger sample, this could be yuge. Put this together with the 2nd-order correction for the herd immunity threshold, and acquiring herd immunity could take a lot less doing than previously assumed…

Developing…

Happy Shavuot to my fellow Jews!

UPDATE 1: Dr. Anthony Fauci no longer considers 2nd wave inevitable.

“We don’t have to accept that as an inevitability. Particularly[…] when people start thinking about the fall. I want people to really appreciate that, it could happen, but it is not inevitable.”

COVID19 update, May 23, 2020: CDC dramatically revises fatality rates downward; important new immunity data and “cross-reactivity”

 

(1) Pardon my French, but this is a big [bleep]ing deal. Via Matt Margolis, here are revised CDC best estimates for COVID-19 epidemiological parameters (Table 1, “Scenario 5”). Parameter values are based on data received by CDC prior to 4/29/2020

Their R0=2.5 (remember, R-naught is the reproductive number absent any intervention). Percent asymptotic infections is 35%. 

Age cohort  Fatality  Hospit.  of which ICU 

Under 50 0.05% 1.7% 21.9% 

50-64 0.2% 4.5% 29.2%

Over 65 1.3% 7.4% 26.8%

Overall 0.4%  3.4% N/A 


Also according to the report, about three-quarter of patients in the ICU need mechanical ventilation of some sort, regardless of age group.

Now wait a second, you say. According to worldometers, the cumulative documented infections on April 29 were 1,064,194, with 61,655 deaths. That’s an overt case fatality rate (CFR) of 5.79% — while now CDC is talking a CFR of 0.4% CFR, and an infection fatality rate of 0.26% [that is, 0.4%*(100%-35%)]. How come?

Well, “overt” or “documented” is the operative word here. These number imply a Dunkelziffer/undocumented infection rate of about 22 times the known infection rate. (This ratio is actually within the uncertainty band of the revised Santa Clara County community sampling study. (Bendavid, Ioannides et al. from Stanford).

As I reported here on May 5, German virologist Hendrik Streeck, from his whole-community testing of the hard-hit German town of Gangelt, inferred an IFR of “0.36%, but possibly as low as 0.24%”. He at the time suggested the ratio between the overt CFR and 0.36% as a guesstimate for the Dunkelziffer. It increasingly looks like Streeck, Ioannides, and the CDC are all on the same page to within overlapping uncertainties.

 

Back in March, the single biggest “known unknown” the decision makers had was precisely the Dunkelziffer. Would they have decided on hard lockdowns based on a 0.26% IFR? Chances are, many countries would have hewn a course closer to Sweden’s. But decisions made “in the fog of war”, as a member of our local ad hoc planning commission described it, are easy to second-guess with 20:20 hindsight. Back then, our own commission applied case fatality rates by age cohort reported from China to our much “younger” population pyramid, and arrived at an “if we do nothing” back-of-envelope upper limit 20,000 dead before herd immunity would be reached. Based on  what we know with benefit of hindsight, it would probably have been more in the 3,000-8,000 range. As of today, after a strict but comparatively brief lockdown and a phased reopening, we have fewer than 300 dead out of a population of 9.15 million. So it is possible that the lockdown saved thousands of lives here — but it could be that our thankfully small mortality is thanks as much to our sunny climate and comparatively outdoors lifestyle as to any human intervention.

What we can tell now, however, is that extended lockdowns have long outlived any epidemiological purpose they ever might have had. At this point, their collateral mortality will well exceed any residual epidemiological benefit they might still have. Besides, in the states and countries that have reopened, the sky isn’t falling.

(2) This new paper in the top-tier journal CELL https://doi.org/10.1016/j.cell.2020.05.015 (h/t: LittleOldLady) and this press release about it, in layperson-friendly languagee (h/t: Jeff Duntemann) have some very hopeful  news about COVID19 and immunity. But the big shocker to me was buried further down:

The teams also looked at the T cell response in blood samples that had been collected between 2015 and 2018, before SARS-CoV-2 started circulating. Many of these individuals had significant T cell reactivity against SARS-CoV-2, although they had never been exposed to SARS-CoV-2. But everybody has almost certainly seen at least three of the four common cold coronaviruses, which could explain the observed crossreactivity.

It is still unclear, though, whether the observed crossreactivity provides at least some level of preexisting immunity to SARS-CoV-2 and therefore could explain why some people or geographical locations are hit harder by COVID-19.

“Given the severity of the ongoing COVID-19 pandemic, any degree of cross-reactive coronavirus immunity could have a very substantial impact on the overall course of the pandemic and is a key detail to consider for epidemiologists as they try to scope out how severely COVID-19 will affect communities in the coming months,” says Crotty.

 

Most common colds are caused by rhinoviruses, but actual coronaviruses account for a minority of them. “Cross-reactivity” is immunology-speak for where exposure to one antigen results in at least a partial immune response to related antigens. What Edward Jenner achieved — inoculating people with the relatively innocuous cow pox and thus giving them immunity to the far more dangerous smallpox — is an example of strong cross-reactivity. [*] Hmm, could be be seeing inoculation with common-cold coronaviruses?

Staying on the immunity topic, reader Cathe Smith drew my attention to this recent paper in NATURE Communications: https://doi.org/10.1038/s41467-020-16505-0 Let me just give a teaser:

To address the urgent need for a medical countermeasure to prevent the further dissemination of SARS-CoV-2 we have employed a synthetic DNA-based vaccine approach. Synthetic DNA vaccines are amenable to accelerated developmental timelines due to the ability to quickly design multiple candidates for preclinical testing, scalable manufacturing of large quantities of the drug product, and the possibility to leverage established regulatory pathways to the clinic. Synthetic DNA is temperature-stable and cold-chain free, important features for delivery to resource-limited settings7. Specifically for the development of a COVID-19 vaccine candidate, we leveraged prior experiences in developing vaccine approaches to SARS-CoV8, and our own experience in developing a MERS-CoV vaccine (INO-4700)9,10, as well as taking advantage of our vaccine design and manufacturing pathway previously utilized for the Zika vaccine candidate, GLS-570011, which was advanced to the clinic in under 7 months. INO-4700 and GLS-5700 vaccines are currently in clinical testing.

 

 

 

[*] Cross-reactivity is not limited to pathogens. People who have an allergic reaction to a given antibiotic (e.g. a penicillin), and who are switched to a different antibiotic (e.g., a cephalosporin) may sometimes develop a cross-reaction to the latter (which is from a different “branch” of the same chemical family, beta-lactams).

ADDENDUM: New CDC report on transmission: easily from person to person, less easily via fomites (intermediate objects), unlikely via pets. John Campbell clarifies.

 

And via Dr. Seheult, an analysis piece in THE LANCET Diabetes and Endocrinology about vitamin D and COVID19. 

https://doi.org/10.1016/S2213-8587(20)30183-2

Moneygrafs:

A growing body of circumstantial evidence now also specifically links outcomes of COVID-19 and vitamin D status. SARS-CoV-2, the virus responsible for COVID-19, emerged and started its spread in the Northern hemisphere at the end of 2019 (winter), when levels of 25-hydroxyvitamin D are at their nadir. Also, nations in the northern hemisphere have borne much of the burden of cases and mortality. In a cross-sectional analysis across Europe, COVID-19 mortality was significantly associated with vitamin D status in different populations. The low mortality rates in Nordic countries are exceptions to the trend towards poorer outcomes in more northerly latitudes, but populations in these countries are relatively vitamin D sufficient owing to widespread fortification of foods. Italy and Spain are also exceptions, but prevalence of vitamin D deficiency in these populations is surprisingly common. Additionally, black and minority ethnic people—who are more likely to have vitamin D deficiency because they have darker skin—seem to be worse affected than white people by COVID-19. For example, data from the UK Office for National Statistics shows that black people in England and Wales are more than four times more likely to die from COVID-19 than are white people.

[…]
Rose Anne Kenny (Trinity College Dublin, University of Dublin, Ireland) led the cross-sectional study into mortality and vitamin D status and is the lead investigator of the Irish Longitudinal Study on Ageing (TILDA). She is adamant that the recommendations from all public health bodies should be for the population to take vitamin D supplements during this pandemic. “The circumstantial evidence is very strong”, she proclaims regarding the potential effect on COVID-19 outcomes. Adding, “we don’t have randomised controlled trial evidence, but how long do you want to wait in the context of such a crisis? We know vitamin D is important for musculoskeletal function, so people should be taking it anyway”. Kenny recommends that, at the very least, vitamin D supplements are given to care home residents unless there is an extremely good reason not to do so.
Adrian Martineau (Institute of Population Health Sciences, Barts and The London, Queen Mary University of London, UK), lead author of the 2017 meta-analysis has joined with colleagues from universities around the UK to launch COVIDENCE UK, a study to investigate how diet and lifestyle factors might influence transmission of SARS-CoV-2, severity of COVID-19 symptoms, speed of recovery, and any long-term effects. They aim to recruit at least 12 000 people and to obtain interim results by the summer. Despite his enthusiasm for the study, Martineau is pragmatic: “At best vitamin D deficiency will only be one of many factors involved in determining outcome of COVID-19, but it’s a problem that could be corrected safely and cheaply; there is no downside to speak of, and good reason to think there might be a benefit”.
 

And now Dr. Anthony Fauci has warned that staying closed for too long could cause irreparable damage.

COVID19 update, May 15, 2020: interview about German meat processing plants; Santa Clara County immunology study redux

(1) Die Welt (in German) interviewed a Polish guest worker at a German meat processing plant on condition of anonymity. (The interview was conducted in Polish.)
My summary in bullet points:

  • almost all line workers are Polish, Romanian, and Bulgarian guest workers hired via subcontractors. No German wants to do that work [and definitely not at that salary]
  • we get paid net EUR 6.50 to 9.50 per hour, depending on position. We typically work 12 hours a day, 6 days a week. No bonuses for overtime or weekend work—don’t understand my work contract so I don’t know if I’m entitled. [I’m reminded of the Israeli situation where direct employees of a large enterprise — especially long-standing ones — have lavish benefits, but outsourced subcontractor employees often have none at all.]
  • we work as many hours as we can so we can send more money home
  • we typically live 2 or even 4 to a room in houses or apartments, typically arranged via the subcontractor. I paid EUR 150/mo. for effectively half a room; meanwhile I learned two bits of German so I was able to rent a place for just myself. We kept our place clean, but some of the Bulgarians and Romanians are withheld EUR 250/mo. from their wages for 4-to-a-room pigsties.
  • [He claims] some of the Romanians and Bulgarians can’t read or write in any language, and are hence taken advantage of by the middlemen.
  • “we could never in our lives keep 1.5m/5ft distance on the assembly line.” (Title of the article.) “Our stations are 60cm/2ft apart.” They would have to make the line 2.5 times as long for the same productivity.
  • Contrary to claims in the media, general hygiene in the plant is good; otherwise, there are disinfectant stations at toilets, cloakrooms, entrances.
  • we get fresh cloaks every day, with an RFID tracking chip inside. We ourselves have to carry RFID on our persons. Cloak not returned on end of shift — 30 Euro docked from pay
  • masks are mandatory inside now; they used to be optional, but most were wearing them anyhow
  • German foremen are generally polite and reasonable, since previous incidents of brutality led to walkouts
  • Poland just exempted cross-border commuters from 14-day quarantine, so I’m looking forward to visiting my family for the first time in 8 weeks.

(2) (Hat tip: Cedar Sanderson). Interview with Prof. John Ioannides about the revised version of the Santa Clara County [read: Silicon Valley] immunity study [below: Bendavid et al.]. You can read the paper for yourself here (note the “v2” for Version Two at the end of the URL: the original is still available by substituting “v1”. These kinds of preprint servers keep full version history to avoid “Oceania has always been at war with Eastasia” rewriting of history):
https://www.medrxiv.org/content/10.1101/2020.04.14.20062463v2

I think pretty much every serious epidemiologist assumes there is a substantial “Dunkelziffer”/stealth infection rate — the debate is about how big. Truly asymptomatic infection proportions? 22% was reported by German virologist Prof. Hendrik Streeck on his all-community test in a German village; Ref.8 of Bendavid et al. reaches 17.9±2.4% from Diamond Princess data. But this excludes “eh, just a seasonal cough/cold” minimally symptomatic cases, which I suspect are the majority of the Dunkelziffer.

In the current manuscript, they arrive at 1.2% seroprevalence after weighing test performance, and 2.8% (95CI 1.3-4.7%) after adjusting for population demographics.


These prevalence point estimates imply that 54,000 (95CI 25,000 to 91,000 using weighted prevalence; 23,000 with 95CI 14,000-35,000 using unweighted prevalence) people were infected in Santa Clara County by early April, many more than the approximately 1,000 confirmed cases at the time of the survey.

In plain English: the original manuscript claimed there were 50 to 85 “stealth” infections for every documented one, while in the revised version, it may be as low as 14 or as high as 91. OK, let’s apply a simple “Streeck sanity check” here: he proposed using the ratio between the reported case fatality rate (CFR) and his whole-population IFR (infection fatality rate) of about 0.36±0.12% as a crude estimate of how many “stealth” infections are out there for every documented one. From Worldometers data today, I get a 4.1% apparent CFR for California, and 5.6% CFR for Santa Clara County. 5.6 divided by 0.36 leads to about 16:1, though it could be as high as 24:1, consistent with Ioannides’s “unweighted prevalence” data and at the lower end of the 95% confidence interval for weighted prevalence.

(3) Via Erik Wingren, nutritionist Dr. Rhonda Patrick on the wildly popular Joe Rogan Show, speaking on how to boost one’s immune system against infections in general (and thus also COVID19). A commenter summatized the segment as “vitamin D, sauna, sauna,…” Here is a more useful table of contents of the 3-hour podcast.

(4) Israel Hayom, lying around in our condo complex’s lobby, had a headline where outgoing Economics minister Moshe Kaḥlon was quoted as saying: “We sacrificed the economy on the altar of health”. It reminds me of the debate in the US about who is right, Anthony Fauci MD or Senator Rand Paul (R-KY; himself an MD ophthalmologist and a COVID19 survivor). My personal answer: both. They just emphasize opposite scales of the balance. There is no perfect solution here—only a trade-off between different sources of mortality, and the best you can do is try to minimize their sum. Because make no mistake: even the now-disgraced Neil Ferguson (he of the “2 million dead” model that ) acknowledged that continued hard lockdown would engender collateral mortality exceeding any reduction in COVID19 mortality.

(5) Lagniappe: Roger Seheult MD on glutathione deficiency, which brings us back to our previous items on N-acetylcysteine, a.k.a. “NAC”.

ADDENDUM: Israel Institute for Biological Research files for patents on 8 SARS-nCoV-2 antibodies

Antibody tests of two Snohomish County, WA residents push back COVID19 timeline in the USA to probably mid-December.

Marta Hernandez on the ChiCom propaganda machine being turned up to 11. But Peter Zeihan has an interesting out-of-the-box theory about that.

COVID19 update, April 23, 2020: community immunity testing results from Belgium; non-COVID19 hospital care; India

(1) DE STANDAARD (in Dutch) reports on a new immunity study in Belgium. Researchers from the University of Antwerp collected residual blood samples of 3,686 patients that had originally been taken for other purposes (e.g., to check for anemia) and checked those for COVID19 antibodies. The samples were collected on March 30.

The Antverpian team found that about 3% of the samples had antibodies — if their sample were truly representative, that would imply about 300,000 people had antibodies for COVID19 around March 30. 

Let’s work with this a bit, shall we? According to worldometers, on that date (March 30) Belgium had 11,899 documented cases. This implies a Dunkelziffer/“dark number” (De Standaard uses this English term) to documented cases ratio of about 25:1.

As of April 22, Belgium had 41,889 documented cases — if we (dubiously) assume that the “dark number” ratio is constant, then about 10.6% of the population may have antibodies at present. 

How much would you need for herd immunity? The herd immunity threshold %HI depends in a very simple way on the effective reproductive number R of the virus: 

%HI = 100% * (1 – 1/R)

If R≤1 then the epidemic will die out anyway and %HI is zero. For R=1.1 just 9% would already be enough, while for R0=1.5 you’d need 33%, for R=2 you’d need 50%, and for R=2.5 you’d need 60%.  (Corollary: if Belgium does have about 10-11% with antibodies, it doesn’t need to keep R below 1.0 with social distancing measures, but can let things slide a little higher. As the percentage of immune residents grows, further relaxation is possible.)

(2) At Sarah Hoyt’s blog, a guest post by “Scarlett Doc” called “Healthcare Charlie Foxtrot” about the current situation in US hospitals for non-COVID19 care. These are the fruits of rigid edicts by domineering, not-too-bright bureaucrats: entire hospitals sitting on their hands waiting for the COVID19storm to hit (which is largely confined to NYC and a few other hotspots), while myriad non-COVID19 patients go untended. There are even hospitals furloughing most of their medical staff. The article is aptly illustrated with a picture of a dumpster fire. Read and weep.

It gets bad enough even without meddlesome middlebrow bureaucrats with Messiah complexes. German hospitals by and large continued normal operations. Yet DIE WELT (in German) reports on how internal medicine wards in German hospitals see such a drop in admissions for their “big 3” emergencies (heart attacks, strokes, and appendicitis) that it is making doctors suspicious. https://www.welt.de/vermischtes/article207436223/Corona-Deutlich-weniger-Patienten-in-der-Kardiologie-Aerzte-werden-stutzig.html 

“It cannot be that we suddenly have 30% fewer strokes than usual because of corona” says one — so they suspect patients are staying away when they shouldn’t, out of fear of contracting COVID19. “In 2018 there were 210,000 heart attacks and about 300,000 strokes in Germany. That these numbers have suddenly contracted because of the Corona-epidemic, nobody in the medical community believes.”

(3) (Hat tip: Alex W.) Quartz India wonders why the remarkably low toll in India. A young population pyramid is a plus, but against that stand two minuses: multigenerational families and high incidence of chronic diseases even among fairly young people. Then again, the weather being very hot and humid (bad for the virus), universal BCG vaccination, and broad (hydroxy)chloroquine use in areas where malaria is endemic could all be factors. (Incidentally, monsoon season in India is flu season there, so we could see a surge then.)

Related, however, a recent preprint claims that the BCG differential is “an illusion created by testing”: https://www.medrxiv.org/content/10.1101/2020.04.18.20071142v1

(4) Finally, could the serine protease nafamostat (an anticoagulant that also has some antiviral properties) be a drug candidate for COVID19? A Japanese group shows in vitro evidence in this preprint: https://www.biorxiv.org/content/10.1101/2020.04.22.054981v1

UPDATE: Matt Ridley, popular science writer and member of the House of Lords, gives a layman-friendly overview of COVID19 drug candidates in the special 10,000th issue of The Spectator.