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$1.28 billion border wall contract goes to company with history of fraud and sex crimes

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Tucson.com reports that the United States government gave a $1.28 billion border wall contract to Fisher Sand and Gravel, a private company run by Tommy Fisher.

Fisher Industries seems well-suited for a president like Trump. From Wikipedia:

Tommy Fisher has appeared on local and conservative TV and radio and is a donor to several charities and the Republican Party.[3][4] Senator Cramer suggested Fisher's Fox News appearances are what attracted Trump to the company.

The High Plains Reader has documented environmental violations and tax evasion by the company, including 169 citations and paying $1 million in air quality violation fines in Maricopa County, Arizona over the past 10 years. In 2009 Michael Fisher, then-owner of Fisher, pled guilty to nine counts of felony tax fraud[5] being sentenced to 37 months in prison and over $300,000 in restitution. The comptroller also pled guilty to one count of conspiracy to defraud the United States in 2009. Another former head of the company, David William Fisher, pled guilty in 2005 to child pornography and was sentenced to 10 years in prison.[1] He was released on April 30, 2010.[6]

By the way, illegal border crossings have been declining for the last 20 years. "In 2017, border-crossing apprehensions were at their lowest point since 1971." (NY Times)

Image: YouTube/Fisher Industries

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petrilli
14 days ago
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Impeached Trump sure loves a corrupt business.
Arlington, VA
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Trump Brings in the Infantry for His War on Blue America

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Updated at 10:47 a.m. ET on May 14, 2020.

Even during the shared national challenge of the coronavirus outbreak, President Donald Trump is escalating his attacks on the institutions of blue America. And a growing number of other Republicans are joining him.

Trump has long provoked questions about whether he respects the legitimacy of small-d democratic institutions. But in the crucible of the outbreak, he has grown more explicit than ever about rejecting the legitimacy of institutions controlled by big-d Democrats.

His recent targeting includes flatly blocking testimony to the House of Representatives by administration officials on the pandemic, asserting sweeping immunity from subpoenas at the Supreme Court, encouraging defiance from business owners and protesters against social-distancing orders from Democratic officials, insisting that blue states must adopt conservative policies to receive any further federal aid, and cheering on Attorney General William Barr as he hints at possible prosecution of officials from Barack Obama’s presidency.

So far, congressional Republicans have been way more likely to applaud than question any of these initiatives. And they all come as Republican governors intent on rapidly reopening their economy have moved aggressively to override the decisions of Democratic mayors and county executives.

“What we’re having is a wedge that is being driven deeper and deeper between the federal government and some of the states, and, in the states, between Republican governors and Democratic mayors and Democratic cities,” says Donald Kettl, a public-policy professor at the University of Texas at Austin, and the author of The Divided States of America. “It is a deep, profound, and growing chasm that is almost unprecedented in American history.”

This multifront assault could mark an ominous new stage in the nation’s political polarization and separation. The tension between Washington Republicans and Democratic-run state and local governments “is as bad as I’ve seen it in my lifetime, and [if there is a second term] it is going to be worse just because of the aggressive nature of this presidency,” says Kasim Reed, the former Democratic mayor of Atlanta.

Long before the outbreak started, Trump pursued a broad array of policies meant to pressure or punish Democratic-run local governments, such as ending the federal deductibility of state and local taxes in the 2017 tax bill and seeking to revoke the authority California has wielded under the Clean Air Act since the 1970s to set its own air-pollution standards.

Trump revealed volumes about his mindset at a recent White House event, when he was asked about providing more federal aid to states buckling under the lost revenue and increased cost of grappling with the coronavirus. Trump said he might be open to considering such assistance, if it were narrowly tied to costs directly linked to the outbreak. But then he added: “We’d want certain things, also, including sanctuary-city adjustments.”

The most telling word in that sentence is the pronoun we. It suggests the existence of an American community from which blue states are distinct and separate—and to which blue states must provide concessions if they are to receive help from the federal government. Leaving aside the reality that many Republican-run states are facing financial difficulties as great as the Democratic-run ones, Trump’s formulation shows how little obligation he feels to represent the places where fewer of his own voters live. Instead, he portrays those places almost as foreign supplicants seeking aid from his America. “This president is seeing himself as the president of red America, where blue America is pushed aside and is not even legitimate,” Kettl says.

Trump isn’t the only Republican who has resisted providing financial aid to state and local governments run by Democrats. Senate Majority Leader Mitch McConnell has portrayed granting more federal assistance as a “blue-state bailout,” and suggested instead that states should declare bankruptcy (though he’s edged slightly away from his initial remarks). On Tuesday, the conservative House Republican Study Committee charged that blue states and cities “have historically demonstrated a lack of respect for federal law and constitutional rights, and more recently a penchant for overly restrictive shutdown orders.” Helping “these jurisdictions,” the group continued, “would only serve to condone these actions and encourage economically oppressive restrictions on American people and businesses.” Trump has similarly argued that in granting any further aid, the federal government should require states and cities to cut taxes; indemnify businesses from coronavirus-related lawsuits; end sanctuary-city policies in locales that don’t readily cooperate with immigration authorities; and adopt other conservative priorities.

He’s pressured Democratic leaders in other ways, too. Standing at the White House podium, he famously acknowledged that he had told Vice President Mike Pence not to return calls for help from governors who have criticized him. He’s repeatedly encouraged the “liberate” protesters, primarily targeting Democratic governors. In the past few days, he’s loudly trumpeted his support for a beauty-parlor operator in Dallas and the Tesla founder Elon Musk, who each reopened their business in explicit defiance of local stay-at-home orders. Barr has also threatened to sue states that impose what the administration considers excessive restrictions.

The parallel to Trump’s pressure on Democratic governors has been systematic moves by Republican governors to supersede the stay-at-home policies of the big blue cities in their state. In Georgia, Governor Brian Kemp ordered the reopening of Atlanta businesses despite the fervent public objections of Mayor Keisha Lance Bottoms. In Texas, Governor Greg Abbott not only undermined local lockdown orders in Dallas, Houston, and other major cities; he also explicitly overruled the incarceration of the defiant beauty-parlor owner and invalidated a policy in Houston’s home county authorizing fines for people who do not wear masks in public.

Reed, the former Atlanta mayor, says these state interventions offer only a “more extreme” version of the frequent moves over recent years by Republican state governments to overturn regulations and laws in Democratic-run cities. The governors feel particular urgency to invalidate stay-at-home orders for a simple reason, he says: Most states have grown so financially dependent on their largest cities that they cannot revive economically unless the cities participate.

“What the current environment shows is that Republicans need Democratic cities to drive the economy,” he says. “By overruling what would be a traditional conservative philosophy of local control, they are really trying to achieve the financial interest for the state and for President Trump.” House Democrats pursuing a new round of state and local aid, Reed says, must recognize those diverging interests. They must “ensure that the next round of support flows directly to cities,” not through governors, some of whom might use the money to pressure local leaders.

While the conflict between Trump and Democratic-controlled institutions has heightened primarily around the COVID-19 response, the outbreak hasn’t slowed his offensive on other fronts. At the Supreme Court this week, Trump’s attorneys argued that he and his accounting firm should be immune to subpoenas from the Manhattan district attorney and a House investigative committee, in part because they have partisan motives. Efforts to obtain that information should be suspect, his attorneys wrote in one brief, because it “became a priority of the Democratic Party both before and after the 2018 elections.”

Trump’s announcement last week that he would not allow Anthony Fauci or other administration experts to testify before Congress—because “the House is a bunch of Trump haters”—followed the similar defiance he displayed during the impeachment inquiry. In some ways, Trump’s new blockade is even more remarkable because it seeks to sideline the House during a crisis affecting all corners of the country.

“It’s just a stunning denial of the most basic responsibility that he has to respect and respond to a coordinate branch of government,” says Democratic Representative David Price of North Carolina, who studied Congress as a political scientist before he was elected to the body in 1986. “And the fact that we kind of stammer around and are not entirely sure how to respond to that is because it’s so stunning. There is no precedent I know of.”

Most sweepingly, Barr’s decision to drop charges against Michael Flynn, the former Trump national-security aide who admitted to lying to federal investigators, marked another step in the attorney general’s long campaign to discredit the investigation of possible collusion between Russia and the 2016 Trump campaign. Barr has systematically worked to shift the focus from the Trump campaign’s actions to the decisions by Obama law-enforcement officials to investigate those actions. It is as if Barr is unraveling the Mueller investigation and weaving the threads into a new design.

Barr has hinted at future prosecutions of Obama officials, and Trump seems to have that prospect in mind with his repeated allegations that Obama broke the law. Just this morning, Trump raised the stakes even further by calling on the Senate to demand Obama’s testimony under oath on the Russia investigation’s origins, which he called once again “the biggest political crime and scandal” in the country’s history.

None of this has raised much alarm among congressional Republicans. Representative Tom Cole of Oklahoma, the ranking Republican on the House subcommittee that had hoped to hear from Fauci, did object to Trump blocking the testimony, but his was a lone voice. (“One would think there would be some Republican cooperation in asserting institutional prerogatives,” Price said. “Maybe there will be, but I haven’t seen it so far.”) Former Senate Judiciary Committee Chairman Chuck Grassley of Iowa has openly encouraged Barr’s moves to investigate the Russia investigators. “I think there are more shoes to drop, and I think there will be prosecutions,” Grassley insisted on Fox News earlier this month.

Barr has assembled copious legal theories to support each element of his campaign. But what binds it together is the delegitimization of any oversight of the president, especially from institutions controlled by members of the opposite party. “This whole pattern of events is a systematic effort to cut off all meaningful checks and balances,” Donald B. Ayer, the former deputy attorney general under George H. W. Bush, told me. “If you look at each piece in isolation, then you misunderstand what is going on.”

Even this effort to block oversight is only one piece of the larger whole—that is, how Trump is more overtly governing of, by, and for the places and constituencies he views as part of his base. The coronavirus crisis was so staggering that it compelled Trump to respond, however belatedly and belligerently, to the urgent public-health needs in both blue and red states. But his persistent sparring with local leaders over that response—and the relentless advance even during the crisis of his other efforts to undermine Democrats—underscores how committed Trump remains to a long-term project of eroding blue America’s ability to resist his direction or even to set its own course.

Throughout his presidency, Trump has seemed to view himself less as the leader of a unified republic than as the factional champion of a nation within a nation—one that, in his telling, constitutes the “real” America. Imagine for a moment that in 1860, the U.S. had elected as its president not Abraham Lincoln, but Jefferson Davis, and Davis had then used the instruments of national power to strengthen the South in its sectional struggle with the North.

That may be the clearest analogy to understand Trump’s zero-sum approach to governing: He is using the tools of national authority to advance the priorities of red America while weakening blue America’s capacity to impede them. From the office that symbolizes national unity, Trump is pursuing a form of secession from common purpose. Even the nation’s most wrenching crisis since the Depression and World War II hasn’t deterred him from that course. That may be the best portent of how forcefully Trump would execute his fundamentally separatist vision if enough voters grant him four more years to do so.

We want to hear what you think about this article. Submit a letter to the editor or write to <a href="mailto:letters@theatlantic.com">letters@theatlantic.com</a>.

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petrilli
22 days ago
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Trump is doing his best to drive the entire republic over a cliff. The comparison with Jefferson Davis is apt.
Arlington, VA
duerig
22 days ago
The gravest threat to the republic right now is Trump. The second gravest threat is the aftermath of him being removed from office. I hope President Biden can live up to this historic challenge.
acdha
22 days ago
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Washington, DC
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This Japanese Man Paints a Picture of Every Meal He Eats

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Itsuo Kobayashi

Itsuo Kobayashi

Itsuo Kobayashi

For 32 years, Itsuo Kobayashi has been painting top-down pictures of the meals he eats. The paintings are accompanied by descriptions of each meal. Kobayashi worked as a chef for years until he suffered an illness that left his movement impaired, causing him to double-down on his art.

Tags: art   food   Itsuo Kobayashi
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petrilli
29 days ago
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This is amazing.
Arlington, VA
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2 public comments
cinebot
30 days ago
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i like this
toronto.
cjheinz
31 days ago
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Wow. Just wow.

Entrepreneurs are seeing mini-empires of Airbnb properties collapse

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People who launched mini-empires of Airbnb rental properties are experiencing extreme financial hardship as a result of the coronavirus pandemic, reports The Wall Street Journal. These are people who bought or leased residential property with the sole intention to list them on Airbnb. In March alone Airbnb lost $1.5 billion in canceled bookings.

From The Wall Street Journal:

Smaller players have spent hundreds of thousands of dollars each buying homes for short-term rentals. Jennifer Kelleher-Hazlett of Clawson, Mich., spent about $380,000 to buy two Michigan properties in 2018. She said she and her husband cashed out their financial investments and borrowed $100,000 from employers to furnish them.

The 47-year-old expected to net up to $7,000 a month from Airbnb after mortgage payments, supplementing her income as a part-time pharmacist and her husband’s as a schoolteacher. Before the virus struck, the couple was considering buying more homes. Now, they can’t make mortgage payments because no one is booking, she said. “We’re either borrowing more or defaulting.”

Photo by Kyle Glenn on Unsplash Read the rest

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petrilli
36 days ago
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I have a hard time having any sympathy.
Arlington, VA
denubis
36 days ago
Risk, it turns out, is a thing on all investments...
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Coronavirus Vaccine Prospects

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Time for another look at the coronavirus vaccine front, since we have several recent news items. Word has come from GSK and Sanofi that they are going to collaborate on vaccine development, which brings together two of the more experienced large organizations in the field. It looks like Sanofi is bringing the spike protein and GSK is bringing the adjuvant (more on what that means below). Their press release says that they plan to go into human patients late this year and to have everything ready for regulatory filing in the second half of 2021. For its part, Pfizer has announced that they’re pushing up their schedule with BioNTech and possibly starting human trials in August, which probably puts them on a similar timeline for eventual filing.

“But that’s next year!” will be the reaction of many who are hoping for a vaccine ASAP, and I can understand why. The thing is, that would be absolutely unprecedented speed, way past the current record set by the Ebola vaccine, which took about five years. More typical development times are ten years or more. But hold that thought while you peruse another news item today from J&J. They have an even more aggressive timeline proposed for their own vaccine work: they have already announced that they have a candidate, and they say that they plan first-in-human trials in September. Data will be available from those in December, and in January 2021 they say that they will have the first batches of vaccine ready for an FDA Emergency Use Authorization. Now that is shooting for the world record on both the scientific and regulatory fronts.

So let’s talk vaccine development, because everything is going to have to work perfectly for any such timetable to be realized. Here’s a good overview of the coronavirus vaccine world in Nature Reviews Drug Discovery. The official WHO list is here, and at BioCentury they have constantly updated open-access summaries of the vaccines and other therapies that are in the clinic and the ones that are still preclinical. They have also just published this excellent overview of the vaccine issues; I recommend reading that one after you’ve picked up some background from this post.

NRDD counts 115 (!) vaccine programs, of which 37 are unconfirmed (no further information available on them) and 78 are definitely real. Of those 78, five of them are in the clinic, although that number will be climbing rapidly. You have Moderna’s mRNA1273, which as the name tells you is an mRNA candidate, and  Inovio’s INO4800, which is a DNA plasmid, There are two cellular candidates from Shenzhen Geno-Immune Medical Institute: LV-SMENP-DC, a dendritic cell vaccine  that’s been modified with lentivirus vectors to express viral proteins, and an artificial antigen-presenting cell (aAPC) vaccine along the same lines. And finally there’s a more traditional protein-fragment vaccine, Ad5-nCoV from CanSino.

Let’s go into what all those mean. You will note the diversity of approaches in that list, and that’s not even the whole spread. When you go back into the preclinical candidates, you have in addition “virus-like particles”, viral vectors, both replicating and non-replicating, live attenuated viruses, inactivated viruses, and more. From this you may deduce correctly that there are a lot of ways to set off the immune response. What are the differences between them?

Types of Vaccines

For starters, “Live attenuated virus” is just what it sounds like, although as always there’s room to argue about whether the word “live” should ever be used when talking about viruses at all. At any rate, this would be a real infectious virus that just doesn’t give you much of a disease but does give you immunity to the wild-type virus. The smallpox, chickenpox, rotavirus, and MMR vaccines are all of this type, and they can be very effective – in fact the most effective vaccines are mostly of this type. The protection comes on more quickly and completely, with less need for booster shots and with longer-lasting effects. The tricky part is developing one of those attenuated viruses in the range where it produces effective immunity on infection but is definitely not effective at putting people in the hospital. There is a process of getting milder with time that happens with many viruses in general as they co-exist with their hosts, and the idea here is to speed that up in the lab by passaging the virus through human cells again and again and letting it mutate. Ideally, you want a strain that has ended up with a very long path to mutating back to virulence, of course!

The next class are the inactivated virus types. In that case, even if you think virii are alive (I don’t), these are dead, having run down the curtain and joined the bleedin’ choir invisible. This was originally done by exposing pathogen preparations to high temperatures, but now is often done by through nasty denaturing disinfectants like formalin or beta-propiolactone, things that alter the proteins enough to keep the virus from working, but perhaps not so much that they don’t set off the right immune response. That’s a bit of an art form, of course, and this generally has to be tried a number of times in order to get a reproducible immune response and a reproducible way to manufacture the inactive virus. As you would imagine administering a pile of disabled protein pieces in this manner is often not as effective as the live-virus approach above, which makes the human cells crank out viral proteins on their own. You’re into big ol’ injection plus booster shot territory for the most part. The hepatitis A vaccine and the seasonal flu vaccine are of this type.

Yet another common sort of vaccine uses just a particular protein, protein fragment or subunit piece of a pathogen. (For some bacterial diseases, you can also try to raise antibodies to some protein toxin that the bacteria produce, rather than to the bacteria themselves). The key is to pick one that provokes a strong immune response, and since there are a lot of possibilities, working through them can be a process all its own. The good part is that you can then produce the protein recombinantly and in quantity, once you’ve narrowed down. There are other possibilities, of course – this could be a glycoprotein, or even just a piece of polysaccharide from an organism’s outer coating, since those can be quite distinctive. The tricky part here is getting enough response – the immune system can be very sensitive to pathogen attack, but these pathogen pieces can be less effective in triggering antibody production, and generally need adjuvants to work well (see below!) Vaccines of this class include the ones for shingles, hepatitis B, HPV, meningococcus, and more.

A more recent approach is a DNA vaccine. This uses a circular DNA plasmid, coding for some antigen protein, which has been engineered with strong promoter signals and stop signals at both ends of the sequence. The plan is that this will be taken up by cells, where the DNA may well then be transcribed into RNA and that then translated into protein, which sets off the immune response. A nice feature, as with the attenuated-virus technique, is that you’re taking advantage of all the cellular machinery to make your antigen proteins for you, so they come out folded correctly and with the necessary post-translational modifications already done for you. If you want to really stack the deck for protein production, you can take a known virus (which doesn’t have to be related to the pathogen you’re vaccinating against) and re-engineer its nucleic acid payload to deliver just the piece you want. In that case, you’re back into the “live attenuated virus” technique, but by sort of cobbling one together from different parts. This may sound pretty similar to gene therapy, which also generally uses viral vectors, and if so your intuition is right on target – the two fields have had a lot to teach each other. There is no human vaccine yet that uses any DNA technique, although there is a Zika DNA vaccine for horses. Some candidates have been tried, but haven’t elicited enough of a response. Another tricky part is stability of the DNA plasmid, both on storage and on injection, but these problems have had a lot of money poured into them from the gene therapy end, and the situation has improved over the years. Overall, though, I would say that a DNA vaccine for SARS-CoV2 would be a real come-from-behind story.

Similary, the mRNA vaccine idea has had a great deal of work put into it in recent years. That’s conceptually similar to the DNA vaccine idea, only you’re jumping in at the messenger RNA stage. I wrote a bit about it in the CureVac post – basically, the immunogenicity was noticed as an unexpected side effect in experiments giving mRNA to animals, and people have gradually taken it from there. As with the DNA vaccines, you can actually get two kinds of immune response – the innate immune system can recognize foreign nucleic acid sequences floating around as a sign of infection, and the adaptive immune system can generate antibodies to the resulting proteins. One of the challenges has been getting a bit less of the innate response and a bit more of the adaptive one (which is what counts for the long-term immunity that you want from a vaccine). The mention the other day of younger recovering Covid-19 patient who don’t seem to have developed antibodies is an example of that very problem: a really robust innate response could clear the virus in an infected person, but leave them without much long-term immunity.

mRNA has some potential advantages over DNA, and (perhaps) over all the virus and protein techniques laid out above. It’s pretty much the most stripped-down vector that you can imagine, so you don’t run into so much immune-response-to-the-vector trouble, which can be a problem on repeat dosing with other vaccine technologies, and it can’t possibly be inserted into the genome. A big problem over the years has been getting the mRNA species to last long enough on dosing, to be taken up into the cells efficiently, and to be well translated into protein once that happened. The first link in the preceding paragraph has a great deal of information on this, with links to yet more reviews, and I won’t even try to summarize it all. But there have been extensive modifications made to the RNA sequences themselves and to the formulations that they’re dosed in (a lot of this by pretty brutal trial-and-error work), and the technique might be ready for prime time. We don’t quite know that yet, though. The DNA vaccines have been around longer and (as mentioned) haven’t produced a human therapy yet. Are the mRNA ones better, or is it that we just don’t know about the disappointments to come? We’re going to find out more quickly than we had planned.

Adjuvants

There’s another key vaccination technique that I haven’t mentioned, and it applies to all of the techniques above: adjuvants. Obviously, the big thing you want from a vaccination is a robust, long-lasting immune response, and it turns out that various additives can provoke just that. These are all about that balance between the innate and adaptive immune response mentioned above; the idea is to get the best carryover from the immediate innate mechanisms to drive the antibody-centric adaptive ones. See this post for a quick immune-system primer, and there are of course many other places to learn about this – the key here is the handoff to the antigen-presenting cells and the helper T cells.

The adjuvant field started out, frankly, as about the closest thing to voodoo that you’ll find in infectious disease treatment. Antibodies were generated by injecting horses and extracting their plasma, and a veterinarian (Gaston Ramon) noticed in the 1920s that the yields were higher from animals that had developed a strong reaction at the original injection site. He started experimenting with additives to induce such reactions, including things like tapioca starch. In the same era, Alexander Glenny was formulating various diphtheria vaccines and noticed that the ones that included aluminum salts were much more effective. No one really knew the details of how these things did what they did, but aluminum salts are still very common in vaccines nearly a century later. We’ve learned more about what’s going on – in the 1990s, the first new adjuvants in decades began to show up, and more have been added. For example, the GSK shingles vaccine (Shingrix) has lipoproteins from Salmonella bacteria added to it along with terpene glycosides from the Chilean soap-bark tree, which seems to be an especially powerful combination. I can tell you that the reaction at the site of injection for that one is very impressive, especially on the second shot! GSK’s expertise in this field is in fact what they’re bringing to the collaboration with Sanofi mentioned in the first paragraph, and they’re collaborated with many others as well.

Developing a Covid-19 Vaccine: Efficacy

OK, back to the broad picture of developing a coronavirus vaccine: the question is, which of all these possible techniques is the most effective and safe? That we are only going to find out, in the end, by dosing people. Lots of people. With therapies targeting the immune system, there is in the end no other way to know, because of the complexities of the human immune response and its wide variation in the human population. Rushing the process is going to take a vast amount of effort, and some of the steps are going to have to be done on a scale never before attempted. There’s another point that can’t be ignored, either: if we want this done as quickly as we would like, there are going to have to be some shortcuts.

To that point, one reason that the Moderna vaccine got off the mark so quickly is that the mRNA route can be intrinsically faster, but a bigger reason is the step of seeing how well it works in animals was entirely skipped, a very unusual step indeed. That’s partly because it’s still unclear which animal model will be the most informative. We have a bit of a head start thanks to the work that’s been done on the earlier human coronavirus pathogens for SARS and MERS, but you may recall Monday’s post talking about how SARS and the nCoV-19 virus do show real differences in various tests (there are many lines of evidence for that). We can expect those differences to carry over to the animal models as well. One approach that I know that people are taking is to breed animals that have been engineered with the human form of the ACE2 protein which seems crucial for viral entry – one way or another, we should be able to find a small animal (mouse, hamster, etc.) that can be useful, but will it be found in time to actually be useful? My guess is that several other clinical vaccine candidates will end up going the same route as Moderna’s, and skip past animal efficacy entirely. Believe me, that’s a shortcut, and there will be others.

Fortunately, testing for vaccine efficacy can be (fairly) straightforward, and it involves many of the same issues that are being frantically beaten on for antibody testing: does a vaccinated patient develop antibodies? How many? Are they the right kinds to neutralize the virus? And how long do they last? Those first three are the subject of a huge amount of work right now, and although it’s nerve-wracking at the moment I have no doubt that these are questions that can be and will be resolved. We’re going to have a lot to think about with what endpoints we’ll be measuring for efficacy, to be sure – surrogate ones will be faster, but will regulatory agencies want to see more patient-focused clinical endpoints as well?

Here is a review from the dear, long-gone days of 2016 of the standard development process for a new preventative vaccine. Take a look at the lengthy, detailed, overlapping, interlocking system of trials that such vaccines have undergone in the past, and reflect that we’re not going to be able to do all of that if we want a vaccine on the timelines stated at the beginning of this post. Ideally, you want want to study these efficacy questions in Phase II trials in different populations (age, gender, pre-existing health conditions and range of medications being taken), all with different dosing schedules, and carefully tune things up for bigger Phase III runs. We’ll be able to deal with some of that by running a lot of simultaneous trials instead of doing things more sequentially, but that’s not going to cover every issue. Not by a long shot. Remember, there are at least 78 of these things under development right now – there will be fierce attrition, and only a few (low single digits) will make it deep into the process, but it’s still a fearsome process to get all this organized.

And some things cannot be accelerated by any means known to humanity. The last point above, how long immunity lasts, is a big question for both people naturally infected by SARS-Cov2 and for those given a vaccine, and unfortunately there is no way to answer that one other than time, which is in short supply these days. The field provides many examples of vaccines whose protection has not held up as well as expected as the years went on. My guess is that we may end up with a first-round vaccine that doesn’t last as long as it might, but will provide enough immunity to do the job and provide cover for us to collect more data on an optimized candidate.

Developing a Covid-19 Vaccine: Safety

But that takes us to the second question for any new therapy: safety, and its balance with efficacy. This is an especially fraught question with any therapy that’s targeting the immune response, because the downsides are gigantic: a runaway immune reaction can disable someone for life or even kill them within minutes where they stand. Guillain-Barré syndrome is an example: your body reacts to an antigen (a viral infection or a vaccination) by deciding that the myelin sheaths around your nerves are also the enemy, and starts destroying them. Very bad news, and although most people recover, a few die. Roughly estimated, even a seasonal flu vaccine might kill about one out of every ten million recipients though such a reaction – we give it to everyone possible, though, because far more people will die if we don’t. The 1976 swine flu debacle shows what can happen, both in perception and in reality, when you get this balance wrong. But you can’t avoid the problem: the huge person-to-person variation in everyone’s immune system means that these severe events can never be ruled out at some low level if you’re dosing enough people.

Now you see the exact bind that vaccine development has always been in, because the whole point is to treat millions, even billions of people who are not currently sick, to protect them against disease while not doing more harm along the way by setting off the body’s fiercest and most alarming biological responses. I have no doubt that the companies and regulatory agencies involved will be doing everything they can to address safety issues, but if you’re looking at a vaccine getting an EUA early next year, well. . .

Developing a Covid-19 Vaccine: Logistics

Another big problem is going to be manufacturing and distribution. Many readers will have heard about the difficulties that sometimes occur during the flu-vaccine production process, leading to shortages. Depending on what vaccine technology comes out on top, manufacturing enough doses in a reproducible fashion could be quite challenging – space and finger fatigue don’t permit going into all the details, but they are many and complex. Keep in mind as well that many vaccines need “cold chain” distribution and storage, which is always a layer of complexity. What if an eventual vaccine needs more than one round of administration, as many of the adjuvant-formulated ones do? Keeping track of that and following up on it is yet another issue.

My guess is that scale-up and manufacturing could well be the biggest chance for the timelines mentioned earlier to blow up, so there is going to be a massive effort to front-load the work on these problems  – this is why, for example, Bill Gates has already indicated willingness to fund factories for up to seven vaccines up front. The live-virus, attenuated virus, recombinant protein, and nucleic acid vaccines will all involve completely different production methods and formulations, and since we don’t know which way we’ll be going, this would seem the only way to address the issue. Pfizer and others have already said that they’re going to be working on production even before the efficacy data come in, which needless to say is not the usual business practice. I think we’ll get vaccine efficacy, one way or another, although it sure won’t be characterized as thoroughly as it normally would. And I think we’re already agreeing to cut corners on safety, whether anyone says so in as many words or not. But producing the vaccine on scale could be a bigger issue yet, and as the process goes on, that’s where I would keep an eye out for trouble.

It is a tightrope, folks, and we’re going to be trying to run across it. Watch closely; with any luck we will never see anything quite like this again.

 

 

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petrilli
51 days ago
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The amount of work going on right now to find a vaccine is awe inspiring.
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acdha
50 days ago
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Washington, DC
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Ikea's founder was a Nazi, and never stopped praising the Nazi leader he called "Best Brother"

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Ingvar Kamprad founded Ikea and invented some of the modern tax-evasion playbook, while amassing billions; despite this, he is lionized both in Sweden and abroad for his quirky frugality and the ubiquity of his stores and their products.

But Kamprad was also a member and patron of the Swedish Nazi party, enlisting at 17 years old in 1943, as Member No. 4,014 of Swedish Socialist Unity (Sweden's Nazis). He was an active recruiter to the Nazi cause and brought in several friends to join the party. There's no record of Kamprad ever leaving the Swedish Nazis, and as an adult, he fell in with Per Engdahl and his Swedish fascist organization, the New Swedish Movement. He hosted fascist meetings in his home, published one of Engdahl's books, and had Engdahl give a speech at his wedding in 1951, and in correspondence, Kamprad and Engdahl called one another "BB" for "best brother."

Engdahl was instrumental in smuggling Nazi war criminals out of Europe, and he knit together the post-WWII pan-European fascist network that encompassed fascists in the UK, Belgium, the Netherlands, France, Germany, Hungary, Italy, Denmark and Norway. He gathered the leaders of these movements together for a meeting in Malmo, and dubbed the outcome of this meeting the "Malmo Movement," AKA "Europäische Soziale Bewegung." The Movement published a Holocaust denial journal called Nation Europe, and Engdahl published a book that was the central text of the movement, called "The Renewal of the West" which Kamprad praised in a 1951 letter to Engdahl.

When all this came to light through Elisabeth Åsbrink's 2011 book "Och i Wienerwald står träden kvar," and Ikea headed off the negative publicity by making its largest-ever charitable donation, $51m for the UN High Commission on Refugees.

Åsbrink interviewed Kamprad in 2010 and asked him about Engdahl, and Kamprad reiterated his support for his Nazi "Best Brother," saying, "There’s no contradiction as far as I’m concerned. Per Engdahl was a great man, and I’ll maintain that as long as I live."

When did Kamprad leave the Swedish Nazi Party? No one has so far managed to find out the answer to that question. On the other hand, we know that his involvement in Per Engdahl’s fascist organization, the New Swedish Movement, continued after the end of the war. He invited comrades from the movement to his home in Elmtaryd and was regarded as their benefactor. There are letters where he is asked to donate or thanked for the latest contribution. Kamprad also acted as publisher for one of the fascist leader Per Engdahl’s books. The two had become close friends and called each other “BB”: best brother. Engdahl was invited to Kamprad’s first wedding in 1951, a quiet affair in a church outside Stockholm, at which he gave a beautiful speech.

On the Far Right Past of Ingvar Kamprad, Founder of Ikea [Elisabeth Åsbrink/Lithub]

(Image: Ardfern, CC BY-SA)

(via Kottke)

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petrilli
239 days ago
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