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Operation Warp Speed: Are we rushing COVID-19 vaccine development?

Recently, President Trump introduced Operation Warp Speed, promising a coronavirus vaccine by the end of the year. Even pro-vaccine advocates—especially pro-vaccine advocates—worry that we’re moving too fast.

I write about vaccines a lot, mainly antivaccine nonsense, and have been doing so ever since I first started this blog, as hard as it is to believe, over 15 years ago. While regular people, namely those who don’t pay much attention to antivaccine pseudoscience and the conspiracy theories of the antivaccine movement, might have thought that the COVID-19 pandemic might prod antivaxxers to change their views and become more amenable to vaccines, those of us who’ve been following the antivaccine movement for a long time knew better. Indeed, what actually happened is far from any sort of epiphany on the part of antivaxxers, in which they realize that the only escape from coronavirus is a vaccine. In fact, antivaxxers have not only doubled down, but they’ve teamed up with COVID-19 deniers, who downplay the severity of the threat from the pandemic, and conspiracy theorists, who posit claims such as the claim that SARS-CoV-2 was the product of a laboratory, that 5G made people susceptible to the virus, that those who get the flu vaccine are more likely to become seriously ill from coronavirus, or even that glyphosate and e-cigs are to blame for COVID-19. This should come as no surprise, though, because at the heart of antivaccine views are conspiracy theories, and COVID-19 is a magnet for conspiracy theories. One of these is the belief on the part of antivaxxers that COVID-19 is being exaggerated in order to impose forced vaccination. Unsurprisingly, antivaxxers have already launched a pre-emptive disinformation war against an as-yet nonexistent coronavirus vaccine, and the hype over coronavirus vaccine development efforts, such as the Moderna vaccine, is a

All of this is one major reason why, as huge a proponent of vaccines as I am, I’m a bit concerned about a COVID-19 vaccine. It’s not because I doubt that a vaccine is possible, but rather because the incredible rush towards a vaccine is naturally concerning. I mean, President Trump dubbed the US effort to develop a vaccine “Operation Warp Speed,” for crying out loud!

Witness:

When Donald Trump launched Operation Warp Speed last week, he borrowed language from Star Trek to describe the drive for a Covid-19 vaccine. “That means big and it means fast,” the US president said, promising an effort “moving on at record, record, record speed.”

His hope that a coronavirus vaccine might be ready “prior to the end of the year” was even quicker than the optimistic—but often repeated—timeline for a vaccine to be ready in 12 to 18 months.

The race for a vaccine appeared to be picking up pace this week when Moderna, a Boston-based biotech company, unveiled early positive results for its potential vaccine in a small trial—and AstraZeneca said it could have the first doses of another vaccine delivered by October if trials are successful.

As I’ve mentioned before (and, as explained by blog bud Skeptical Raptor), even the 12-18 month timeline for a coronavirus vaccine to be approved is extremely optimistic. Were a vaccine to be approved within that timeline, it would be a world record in terms of speed, and pushing it to be even faster could well be an utter disaster.

As for that Moderna vaccine trial, I don’t know why I didn’t comment at the time, but the breathless hype, both in the press and even by some pro-vaccine advocates who should know better, over that trial far exceeds anything merited by it. For one thing, the trial has not yet been published in the peer-reviewed literature; its results were, rather, announced by press release. The trial itself was only a very early phase I safety trial involving only eight subjects. If you want to know the real reason for the press release, here it is:

The company’s stock, along with the Dow Jones industrial average, soared on the report that eight participants who received low and medium doses of Moderna’s vaccine had blood levels of virus-fighting antibodies that were similar or greater than those in recovered covid-19 patients. That suggests, but doesn’t prove, that it triggers some level of immunity.

Moderna’s vaccine is an interesting one in that it is not a typical attenuated live virus vaccine or a vaccine consisting of key peptide antigens to provoke an immune response. Instead, it consists of messenger RNA (mRNA). For those not familiar with the biology, the DNA in your genome is translated into mRNA, which is then used as a template for the ribosomes to produce protein according to the nucleotide sequence of the mRNA. Of course, the process is a lot more complicated than that. For many genes, there are longer mRNA precursors that are cut up and then spliced together to form the final mRNA, but this description is correct, at least as far as the essence of the process goes: DNA to mRNA to protein. The Moderna vaccine uses mRNA, which is taken up by cells and turned into proteins, in order to provoke an immune response. It’s an interesting technique, although mRNA is notoriously difficult to work with because, unlike DNA, it is very unstable and breaks down easily.

Perusing the Moderna website, I find a paucity of detail over how, exactly, the mRNA is delivered to cells. The video on the site indicates that the vaccine is injected intramuscularly, which implies that it’s likely the skeletal muscle cells that are taking up the RNA and making protein. This is plausible to me, because during graduate school I worked in a laboratory in which one of the projects (not mine, a project carried out by another graduate student) involved injecting naked plasmid DNA into skeletal muscle and proving that it was taken up and that the reporter gene expression was regulated by the various regulatory elements as expected. The idea, of course, was as a precursor to gene therapy. Personally, given my experience, I’m not sure why injecting mRNA would be superior to just injecting plasmid DNA, given how unstable and difficult to work with RNA is in general compared to DNA, but there you go. I understand that the mRNA is chemically modified, but even so.

The hype and spin are incredibly strong, too. For instance, it turns out that a story hit the news a couple of days ago about a man named Ian Haydon, a 29-year-old man from Seattle who took part in the Moderna vaccine trial. The headline says it all: He experienced a severe reaction to Moderna’s Covid-19 vaccine candidate. He’s still a believer. My reaction was: Ugh. Headlines like this veer into the realm of propaganda more than anything else, portraying a man who had a significant reaction to the vaccine, who, despite that, still believes in it. The story itself isn’t as bad (although it is a bit more boosterish than I would like and made me a bit uncomfortable), but, damn, that headline!

Haydon’s been all over the media, too:

Haydon has spoken about the vaccine on CNN and CNBC. He even said he’d volunteer to be exposed to the novel coronavirus, SARS-CoV-2, if researchers want to test to see if the vaccine was actually effective. But up until now he has left out a key detail: He is, apparently, one of three people in the trial who had a systemic adverse reaction to the vaccine.

Twelve hours after receiving his second dose, he developed a fever of more than 103 degrees, sought medical attention, and, after being released from an urgent care facility, fainted in his home. He recovered within a day.

He has not brought up the side effects previously, he said, out of “an abundance of caution.” “I understand that sharing the story, it’s going to be frightening to some people,” he said. “I hope that it doesn’t fuel any sort of general antagonism towards vaccines in general or towards even this vaccine.”

Also:

In the 45-person Moderna study, four participants experienced what are known as “Grade 3” adverse events — side effects that are severe or medically significant but not immediately life-threatening. Neither the company nor the National Institute of Allergy and Infectious Diseases, which is running the trial, have previously detailed the nature of those incidents, but Moderna did disclose that three, likely including Haydon, received the highest dose of the vaccine that was tested, and had reactions that involved their whole bodies. A fourth received a lower dose and had a rash at the injection site.

Funny, isn’t it, how the original news stories about the trial left out the bit about the significant adverse events.

A couple of days ago, bioethicist Arthur Caplan and colleagues published an article in JAMA warning of the potential adverse consequences of too much speed:

There is grim historical precedent for allowing expediency to rule vaccine development. In 1955, the inactivated polio vaccine developed by Jonas Salk was declared “safe, potent, and effective” following the largest public health experiment in the nation’s history, involving more than a million schoolchildren. Within weeks, however, the miracle vaccine intended to end the scourge of polio stood accused of causing it. Years in development, the Salk vaccine had been rigorously tested in preparation for the massive trials. But the very success of these trials led to an understandable outcry for the immediate, but premature, public release of the vaccine. Five pharmaceutical companies were given Salk’s formula and left to produce the vaccine without significant oversight. As speed took precedence over caution, serious mistakes went unreported. One company, Cutter Laboratories, distributed a vaccine so contaminated with live poliovirus that 70 000 children who received that vaccine developed muscle weakness, 164 were permanently paralyzed, and 10 died. Not surprisingly, that incident forced the federal government to directly intervene. The legacy of this event is a regulatory landscape in which vaccines undergo thousands of tests to ensure their safety and effectiveness.

Caplan continues:

COVID-19 has created intense concern and uncertainty in the US and throughout the world. There are immense public and political pressures to develop a new vaccine, a process that typically takes years, not months. But as history warns, these pressures must not supplant rigorous scientific practice. Proceeding stepwise through the phases of clinical trials is the ethical standard for investigations involving human research participants. Adherence to the scientific method is the only way to safeguard against a SARS-CoV-2 vaccine that is ineffective, or worse, carries unacceptable adverse effects.

Failing to abide by standards of safety and scientific rigor during the COVID-19 crisis will fuel the argument that physicians and scientists cannot be trusted. Vaccination rates, which are declining due to widespread concern about visiting clinicians’ offices, could further decrease. The US could see resurgences of many vaccine-preventable illnesses, and inevitably, massive increases in avoidable deaths and irreversible outcomes.

I could go on and on and on, but I’ll wrap it up. Here’s what I fear. Currently, everyone is so desperate for a coronavirus vaccine—for obvious (and understandable) reasons. Thousands upon thousands of people are getting sick, some very seriously so, and many are dying, with the death toll in the US alone recently having surpassed 100,000, and that death toll occurred even with extreme measures to enforce social distancing, in which many states have more or less shut down their economies for two months and counting, resulting in unemployment levels not seen since the Great Depression. The pressure for a vaccine is understandable, hence hype like Operation Warp Speed.

As Caplan notes, there is, however, hope that bad outcomes like the Cutter incident and other historical precedents (the problems with the the 1976 swine flu vaccination campaign) will not come to pass. These include increased regulatory oversight, technological advances and real-time dissemination of reports of adverse events, and improved understanding of the immune system and vaccines. Will they be enough? Who knows? The pressure to produce a vaccine is there, and it’s getting more intense, not less.

Here’s the thing, though. We need to get this right. In particular, an op-ed by Shibo Jiang published in Nature on March 16 (which now seems like ancient history) was eerily prescient over Operation Warp Speed. He started out by noting:

Around the world, I am seeing efforts to support ‘quick-fix’ programmes aimed at developing vaccines and therapeutics against COVID-19. Groups in the United States and China are already planning to test vaccines in healthy human volunteers. Make no mistake, it’s essential that we work as hard and fast as possible to develop drugs and vaccines that are widely available across the world. But it is important not to cut corners.

And then concluded:

Testing vaccines and medicines without taking the time to fully understand safety risks could bring unwarranted setbacks during the current pandemic, and into the future. The public’s willingness to back quarantines and other public-health measures to slow spread tends to correlate with how much people trust the government’s health advice. A rush into potentially risky vaccines and therapies will betray that trust and discourage work to develop better assessments. Despite the genuine need for urgency, the old saying holds: measure twice, cut once.

It’s not hard to imagine that when promising vaccine candidates emerge President Trump, hyping “Operation Warp Speed,” in a frenzied effort to demonstrate leadership and produce good news, pressuring the FDA to approve a vaccine that has serious side effects. One can’t help but note that an ex-Moderna executive and board member is currently in charge of Operation Warp Speed. Large clinical studies for a new vaccine for a new disease take months or years to carry out, particularly for a vaccine, in which a large population needs to be vaccinated and compared to a population receiving a placebo. One can imagine the disaster that would occur if a vaccine were deployed and then the reports of serious adverse events—or even deaths—started rolling in. Even under ideal conditions, after large clinical trials show safety, Arthur Allen notes:

Vaccinating 20,000 people in a trial can reveal whether a vaccine is clearly dangerous to a general population. But when 200 million receive the same vaccine, less common side effects could still affect thousands. Botched batches of polio vaccines released after Salk’s trial permanently paralyzed 200 people and killed 10. Early vaccines against measles caused tens of thousands of cases of grave illness in the 1960s.

Maurice Hilleman, the vaccine pioneer who developed successful vaccines against measles, mumps, hepatitis A and B and other diseases, once said he never breathed a sigh of relief “until the first 3 million doses” had been delivered.

Unexpected problems naturally bedevil quick rollouts, as this one will almost certainly be as the nation searches for a way to check a pandemic that is killing tens of thousands of Americans and paralyzing the economy. But as Gregory Poland, the leader of Mayo Clinic’s vaccine research, told me, “There is an irresolvable tension of speed versus safety.”

No one questions that I am about as pro-vaccine as they come, but I’m worried that, with Operation Warp Speed, we’re moving too fast and corners will be cut. There’s already too much fear of vaccines, to the point that only around half of Americans right now would get a coronavirus vaccine. (If I am satisfied with the clinical trials, I’ll be as close to the front of the line as I can manage to get such a vaccine.) As I said before, we need to get this right.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

76 replies on “Operation Warp Speed: Are we rushing COVID-19 vaccine development?”

Everyone is rushing, even potential study participants. I am a physician, and since I am no longer working, I would like to contribute in some way. I am a pathologist, so I do not have the skill set necessary to participate in the care of critically ill patients. I have tried to offer to enroll in a couple of vaccine trials, and I have gotten nothing but automated emails.

Everyone needs to calm down. As a society, we will survive this. We need to let the experts do their jobs as only they know how.

I concur. The beauty is the new techniques being brought to vaccine development that are much “cleaner” than prior vaccines (in that no refrigeration is required and no carriers are necessary). The hope is to find a fast way to do this, as it would be a game changer. But the problem is that the immune system is incredibly complicated; pathogens are incredibly clever in avoiding the immune system; and some immune reactions are detrimental rather than helpful. And there may be unintended consequences from some of these newer techniques. Unfortunately at this point, it means slow and steady, rather than all speed ahead, and the torpedoes be damned.

I am also worried. As fast as possible, as you say, but not cutting safety testing. In one viewpoint article authors reminded us of the rush to make a fly vaccine during the 1976 swine flu scare, and the negative results. https://jamanetwork.com/journals/jama/fullarticle/2766651

I have heard that the adverse events for the Moderna high dose were flu like symptoms and they led to a decision not to use the high dose version.

I’ve only watched a few episodes of “The Apprentice”, but what struck me was that Donal Trump would give contestants projects that were difficult if not impossible to do well in the time given, and very few of these projects came off well (which was why people watched along with seeing someone get “fired” every week). Operation Warp Speed feels like another unrealistic Apprentice-like project that’s been put out to those who do vaccine research. I hope there’s a winner (ie a successful vaccine) but that the winner is truly justified through hard science and not by Trump deciding who won based on his judgement.

I told Trump that he should instead name the project “Operation Impulse Power”, but that guy never listens. 🙁

Moderna jumping into this is a little concerning to me. They aren’t about vaccines, they are about mRNA and, unfortunately, they are about searching for a nail to hit with their wonderful new mRNA technology hammer. In my opinion, that means they have not only the normal vaccine challenges to answer, but also the challenges involved with bending their totally new technology into the task of vaccination, which they’ve never done before. If you look at the therapeutics they’re actually ready to offer, of which none are approved, you’ll see they aren’t vaccines. Setting up an appropriate immune response is not merely about having the protein present. Of course several people in 45 had adverse events!

It’s a pandemic, so naturally Moderna jumped into it. But, their purpose is to improve the optics on the potential of their technology as much as taking a wild swing at solving the problem. Give me the reliable, tested pipeline of an actual vaccine manufacturer over this… their expertise would be better. Worse if Moderna screws it up by cutting corners and gives the cranks a legitimate reason to be afraid of another new technology.

That seems like a huge percentage of adverse events for a phase one trial. Scale it to millions and that’s a lot of people alone at home fainting with a dangerous fever.

Isn’t part of Phase I figuring out the right dose? Maximum tolerated and minimum responsive (since you’re not looking at actual efficacy) doses?

Yes it is. It’s called dose escalation. My point was more about how Moderna’s first announcement was that eight subjects formed neutralizing antibodies while it neglected to mention that there were any adverse events at all.

It seems that the only way to truly accelerate vaccine development considerably is to do a vaccine challenge trial. This basically requires that you deliberately infect people with SARS-CoV-2, first in a dose-escalation group, and second, in a placebo group. It could accelerate vaccine development by as much as a year, but, needless to say, it is fraught with ethical risks even if you could get enough volunteers willing to risk their lives on the chance of finding out whether a candidate vaccine actually works or not. It could go many ways. The vaccine could actually work, and in that case 1% of the dose-escalation and placebo groups might die. The vaccine could do nothing, in which case about 1% of all the people in the trial will probably die. The vaccine could have serious side effects, meaning 1% of the dose-escalation and placebo groups might die, and likely much more than 1% of the treatment group. With 1500 participants, approximately ten deaths in the first case, around fifteen deaths in the second case, and probably significantly more than fifteen in the third. If I were the scientist in charge of this trial, even if the vaccine actually did work, writing letters to family of the ten or so people who died and telling them their sacrifice was not in vain and they’d saved the world would still be painful. So much worse would it be if the vaccine candidate failed, and the chances of that are actually quite high, given the track record of experiments with other coronavirus vaccines like for the original SARS.

Ohh, it would not cost that many $hillbucks$. Just come on down to where I’m at, set up a canopy in the beerstore parking lot next to the “come see how our car wax kills coronavirus” kiosk, and offer patrons a case of coors to get a jab.

Get a face recognition app and lpcr app on some inexpensive android phone and pay the guy that sits by the ice machine all day, everyday $3 an hour to log the comings and goings of the study participants.

This way, the researcher does not need experience qualms of unethicalness with the challenge part of the study because none of these… persons … wear masks.

— pussy lib
— I’m not going to live in fear
— the face is the likeness of god
— I’m not going to be forced to breath my own germs
— if someone comes into my shop with a mask, I’ll treat is a robbery in progress
— The day I see Trump in a MAGA mask, I’m going to pound this baby pangolin. In a sexual way.

The subjects are reliable, checking in consistantly at regular intervals. If they are all checking in after a couple months then your vaccine is safe and effective.

If, however, a not insignificant number of the subjects fail to check in after the specified amount of time has passed, all it means is that they quit drinking or got shot dead by their baby momma after getting caught with Nikki or Carl. Again.

no, wait..

@ Tim

I like your sense of humour. It’s hard to make me laugh. Thanks.

Somehow, where you lives seems to be a lot different to the filthily healthy mentality of the swiss tax haven where my heart lies and that I can’t help but think of as the epitome of human progress, civility, political rationality and courteous racism. But when I read about the US, I’m fascinated and mildly enthralled by the “I’m entitled to do what I want no matter how stupid” mentality. Freedom indeed includes the freedom to be and act stupid, and that should defended at almost all costs. Almost…

“Freedom indeed includes the freedom to be and act stupid, and that should defended at almost all costs. Almost…”

I’d say that being and acting stupid can be defended up until the point where it begins to affect other people. That’s the basic principle I think.

@ Anonymous Coward

“I’d say that being and acting stupid can be defended up until the point where it begins to affect other people. That’s the basic principle I think.”

Could be.

There are however a few minor details to get straight: some people have a tendency to claim implicitly that they are “affected” and sometimes do get a free pass by society. For instance, I do not believe relatives should be given a free pass by society when it comes to assessing whether or not they feel “affected” by every minute healthcare related aspect of someone else’s life. Moreover, what is considered “healthcare related” can sometimes be pretty intrusive.

Who one fucks shouldn’t be considered as affecting relatives as being healthcare related. It nevertheless is. Same goes for academic choices, professional choices, drinking habits, eating habits, choices of social acquaintances and even one’s personal thoughts or philosophical orientation. All these aspects, I’ve witnessed them being considered “health related” aspects of one’s life where society have given relatives a free pass in assessing whether or not they have a right to feel “affected” by eventual or alleged stupidity.

Well, some relatives more than others…

Medicine should not be turned into a parallel criminal procedure code where rules are both incoherent and unspoken and where relatives can act discretionarily as judge, jury and executioners on the grounds that they are allegedly “affected”… That nonetheless can and does happen. Hopefully rarely.

Instead of volunteers you could conscript prisoners, or best of all – political enemies. I would love to conscript the entire reporting and editorial staff of WaPo, NYT, CNN, and NBC, including their executives, for a vaccine challenge study.

I am not in a relevant profession, but when reading initial news reports, my first question was, why did they only test this on eight people? Then I found out that it was tested on many more, at various doses, but that only eight were reported. The remaining 37 who received some version of the vaccine were… unreported. Why did Moderna fail to report results for them? My first uninformed response is to guess that they did not show a positive result and that the report was cherry-picking results to boost Moderna’s stock price. And now to read that some people had serious reactions makes me even less optimistic about this vaccine. I’m glad other countries are also working on vaccine development. With all the misinformation flooding out of Washington, D.C., and even Dr. Fauci saying nice things about remedesivir—before the evidence supports it—I hesitate before believing anything coming from our federal agencies, too.
Now the states are re-opening, people are violating social distancing requirements, and wearing masks is considered “unmanly” I fear a resurgence even before the first wave subsides.

My mistake—there are evidently 105 people in the trial, per clinicaltrials.gov. In any case, it seems there were a lot more than eight people being tested, so why were eight results reported with great fanfare, while the rest were not?

Because those eight have antibodies.

It’s very fuzzy but it appears those eight were all in the two lowest dose groups. It’s likely the cycle of injection and testing has results being ready at different times. Of course selective reporting is an age old way to lie.

It seems that their people might have taken courses at the Didier Raoult School of Scientific Data Manipulation.

Something I read somewhere (can’t remember, or I’d link) said that the testing for neutralizing antibodies has to be done in a Level 3(?) lab which means it takes longer to do. Whether this is really an issue or Moderna is jumping the gun is hard to say. Since phase 1 trials are generally about preliminary safety evaluation I wouldn’t attach a huge significance to lack of the data, though I would have thought they’d be very keen to extract as much useful data as possible.

From the photos I’ve seen in our local newspaper, the blood processing is done in a BSL II or maybe modified II (same as working with HIV). Now, that’s blood processing, which you have to do to get at antibodies, not working with the virus, which I would expect to be BSL III, because it’s airborne.

But large scale antibody screening does take a lot of time and expertise, even if you’ve got a fancy ELISA robot (which is bigger than a king-sized bed; none of this Theranos BS).

When I first heard of Moderna I checked their web site. As of that date (maybe six weeks ago), they did not have anything listed that had reached phase 3. Not super encouraging.

Then there’s the timing of the press release, coming just days before corporate officers sold large blocks of stock (https://www.latimes.com/business/story/2020-05-26/moderna-execs-stock-sales). While the sales were claimed to have been scheduled in advance, the all too convenient press release doesn’t pass the smell test. Maybe it’s a small company suddenly in the spotlight not knowing proper behavior. Then again, with the ex-exec cozied up with Trump, maybe not.

I hope it works, but I won’t be first in line unless there’s solid evidence they’ve done a proper job.

A political commenter was once a participant in Trump’s show: she is Black ( Tara Dardell/ Dowdell? sp?) and said that she was filmed and presented selectively – whenever she did well and solved the problems involved, they didn’t document it or include it but every failure or misstep was filmed and portrayed in the final cut.

Since you brought up the issue of using mRNA over pDNA:

Not an immunologist but my understanding is that mRNA might actually offer some advantages over plasmid DNA in terms of potency and safety. Once the mRNA reaches the cytosol it can be translated by ribosomes whereas a plasmid would have to take the extra step of entering the nucleus for transcription first. The fact that RNA degrades much more easily also means that it would not persist as long, potentially shortening unintended side effects. Furthermore, RNA cannot integrate into the genome which would be another safety issue. For plasmid DNA it is at least possible under certain circumstances even if you do not use a viral vector. Another issue I can think of is that with a plasmid you never just introduce the gene of interest but also features that are needed during the production process. With the mRNA it is just the ORF of the gene of interest plus 5′ and 3′ UTR. Chances are slim that other proteins than the intended one are produced. In terms of cost, I am not sure. Chemical synthesis is more costly for RNA than for DNA but I would assume that this is out of the question for fragments as large as a whole mRNA. They probably use enzymatic approaches and in this case the gap is probably not that large.

I have applied for a job at CureVac in the past (was never invited for an interview though). That’s another company with an mRNA platform and several mRNA-based vaccines in development, now including – of course – a SARS-CoV2 vaccine. From what I remember the intended target cells are not skeletal muscle cells but rather dendritic cells and macrophages. They would take up the mRNA and translate it into protein, fragments of which would then be presented on MHC I to T lymphocytes. In their case the RNA backbone is not even chemically modified to make it more stable. The 5′ cap and polyA tail already offer some protection and apparently they add protamine to form complexes which are protected from degradation and neutralize the negative charge of RNA for easier uptake. I suppose different companies use different approaches, though. In general modifications to the RNA backbone are widely established.

I realize that this sounds a bit like I am promoting this stuff but I just wanted to share a bit of information about the questions you asked. I actually share all of your concerns about rushing the development, testing and approval phases. The safety of the product should be the highest priority. In addition to endangering people, if we screw this up the effect on vaccine acceptance could be catastrophic. Apparently, people are already avoiding doctor’s visits and delaying necessary vaccinations because they are afraid that they might come into contact with COVID-19 patients in the waiting room. Not to sound overly pessimistic but this might just be another disaster in the making.

Yeah, the instability of the mRNA is a plus in this context. Theoretically, it would get into the cytosol, make a little protein, then get broken down pretty quickly.

Oooh I wish I hadn’t left my last conference notes at work, because at least one of the talks I went to was about the debate between plasmid DNA and mRNA, where I think (I might have two things conflated) that this researcher’s solution to the fragile mRNA was to embed it in these fossil-like micro structures that would slowly release the mRNA over time but protect it from degradation.

I think they were working on spine repair, and it was 100% not ready for human use at all.

Once the mRNA reaches the cytosol it can be translated by ribosomes whereas a plasmid would have to take the extra step of entering the nucleus for transcription first. The fact that RNA degrades much more easily also means that it would not persist as long, potentially shortening unintended side effects. Furthermore, RNA cannot integrate into the genome

…They would take up the mRNA and translate it into protein, fragments of which would then be presented on MHC I to T lymphocytes.

Thx. I’m still clueless. How does this work for conveying immunity?

Perhaps somebody could give me a fleshed out version of this two page immunology for dummies:

Once inside, the cells of the immune system cannot ‘see’ the virus and therefore do not know that the host cell is infected. To overcome this, cells employ a system that allows them to show other cells what is inside them – they use molecules called class I major histocompatibility complex proteins (or MHC class I, for short) to display pieces of protein from inside the cell upon the cell surface. If the cell is infected with a virus, these pieces of peptide will include fragments of proteins made by the virus.

A special cell of the immune system called a T cell circulates looking for infections. One type of T cell is called a cytotoxic T cell because it kills cells that are infected with viruses with toxic mediators.

https://www.immunology.org/public-information/bitesized-immunology/pathogens-and-disease/immune-responses-viruses

Ok. So, normally(?), a cell is invaded with virus and being forced to replicate it — it signals out and T-cell scouts on reconnaissance get the memo and then others spread out doing search and destroy and are like, “sorry bud, you gotta take one for the team.” Cell says, “please mercy me now, I’m incubating chest bursters.”

What is the mRNA part? Is it that the virus gets in (and must get in to trigger the process), does handshaking with the zerox parts in the cell juice but gets delivered a faulty print? Does the new mRNA bugger up the virus so it does not replicate? Or does the new mRNA put those protein markers out for the t-cells (possibly getting triggered by aforementioned handshaking) in advance.

Furthermore, RNA cannot integrate into the genome

If this is like a computer microcode patch that is only for some small subsystem, what happens to that patch of muscle? It just keeps doing its’ thing or start conflicting with some other system that it is not used to it doing that thing?

How can it spread to the rest of the body? It does not? That local spot of intramuscular injection is kinda like a nuwave OxyPure machine or a training station for the t’s.

For immediate effect, would not a better delivery mechanism be like a nebulizer to coat the lungs with the (as yet to be determined safe) stuff? Or would that trigger assured mercy delivered by the t’s to all the exposed cells, eventually but the new cells are normal?

It is just.. It is not supposed to get into the genome and maybe even if it does it means fuckall (I hear we have all kinds of viral stuff that got incorporated over, like, 6000 years since man has existed. Even that mitochondria might have used to have been things that cells regularly dined on until one day…).

I suppose, if it stays local to the injection and does start causing problems, then that area can be irradiated, cut out, or have its’ twitter account suspended in some other way. So, there is that.

Does this help? I’m afraid that my PPI has yet to be preauthorized, so I feel like my esophagus is on fire and that’s all I’ve got.

Well, not so much. Thx, anyways. What is the ‘Golgi apparatus’ supposed to be? The cameraman? I hate shaky cam and jump cuts.

@ Tim

Cell says, “please mercy-kill me now, I’m incubating chest bursters.”

You got that part right. I think your confusion is because we are talking simultaneously about at least three different biological activities, which happen to be all involved at some point in the “acquiring an immune reaction” process.
OK, trying to unpack. In reverse chronological order:

1 – there is the response from the immune cells to the presence of a virus-infected cell. Either the cell itself shows some signals, and/or some of the proteins produced for making new viruses go by themselves on the cell surface (as part of the mechanism of an enveloped virus for making new enveloped viruses – it’s fascinating in its simplicity)

2 – there is the process of making proteins (and other bits) on-command for the virus. Try to picture virus replication as some extremely intrusive customer at a fast-food joint. Virus drives in, forcefully enter the kitchen to drop its order, and then the kitchen starts mass-producing more virion particles
Different types of viruses – RNA, DNA – will insert their ‘order’ in a different part of the kitchen; e.g. many DNA and some RNA viruses have their ‘order’ going to the manager’s office – the nucleus – instead of just bothering the kitchen’s staff.

3 – and then there are the ‘normal’ cellular processes for making legit proteins and stuff
To use your software simile, the nucleus of a cell is a library, a repository of instructions/programs. Picture old-fashion computers using magnetic tape reels, except the tapes are DNA molecules. In order to make something in the cell, this library will make copies of the relevant parts in the form of one or more messenger RNA molecules and send these copies into the cytoplasm.
Now, picture this mRNA as one of these old-fashion punch cards. A weird molecular assembly in the cytoplasm called ribosome will catch one of these cards, and literally follow its instructions to assemble a preliminary version of a specific protein. Things in the cytoplasm called organelles (think of them as a chain of car workshops – tuning, accessorizing, painting…) will then pick-up in turn these nascent proteins and keep modifying them. The Golgi is one such workshop, specialized in accessorizing (sugars, lipids, maybe a red stripe to make the protein run faster…).

Fhew. OK, now, let’s pick all of this back the other way.

viruses, as stated above in 2, forcefully hijack the cell’s processes. They endeavor to have their mRNA/punch cards floating in the cell cytoplasm, the ribosomes eventually pick them up, and the cell dutifully makes viral proteins. One of the produced viral protein has the job of making more viral genetic material (DNA or RNA, as appropriate)
Some viruses will do this by first having their DNA/tape reel either floating around or fully incorporated in the nucleus’ library. It’s a signature of herpes-type viruses. Some of these viruses actually ‘forget’ to go on the next step, i.e. making more virion particles. They stay dormant in the cell DNA library for years, or in some cases forever.
mRNA vaccines, as I understand them, are just a punch card carrying the information of selected viral proteins. Manage to get them inside a cell, and again the ribosomes will pick them and start the process of making the encoded viral proteins. The cells ‘infected’ with this mRNA will put these proteins on their surface and hopefully trigger an immune reaction. But it’s one-shot – the mRNA itself is not replicated, the ‘infected’ cell will not spread the infection.

@Athaic

The Golgi is one such workshop, specialized in accessorizing (sugars, lipids, maybe a red stripe to make the protein run faster…).

Lol. And thx. I got through some of Narad’s link when combined with the wikipedia page on ‘antigen’. Just out of curiosity, what do the square, circle, and triangle mean? And their relative positions? Just staring at them, it is vaguely remaniscant of the ‘particle zoo’ in the Standard Model.

This new way of doing things would still need adjuvants?? I guess “Haydon’s” arm could be hurting just because it did work and a whole bunch of dentritic (nerve?) cells got offed afterward — yet to be seen for actual virus.

Perhaps fever and what not comes from step 6 where the new protein sometimes escapes.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076378/figure/pharmaceutics-12-00102-f001/?report=objectonly

Maybe I should get that book (6’th edition) that Joel keeps hawking.

About your adjuvant question: RNA itself can actually be used as an adjuvant (in principle, I am not sure if it has ever been used in a real vaccine that was administered to people). Apologies for the wall of text:

Maybe think of it this way. One of the reasons to use an adjuvant is to “trick” the immune system into thinking that there is actual danger. Just a defined and highly purified antigen isn’t enough. The dendritic cells (not nerve cells by the way) and macrophages serve as a messenger and their role is to activate cells of the adaptive immune system (not only). They take up pathogens and carry parts of them to lymph nodes where they present these parts (antigens) to T cells and B cells. If the T and B cells recognize these antigens, they become active and play their role. In the case of T cells, this mostly means either recruiting more immune cells to the site of infection to clear up the danger, killing virus-infected cells, or activating B cells. It depends on the subtype of T cell and also on the type of infection. B cells become plasma cells and produce antibodies. Antibodies inactivate viruses by covering the proteins that they use to enter cells. They also clump up pathogens and make them “tasty” for macrophages (their name means “large eaters” after all). And they recruit other so-called complement proteins that are floating around to form a pore in the membrane of a pathogen, effectively killing it. The beauty is that the T and B cells that are activated, and by extension also the antibodies that are produced, are specific for the part of the pathogen that was presented to them by the dendritic cells. There is a huge number of different T and B cells that can all recognize different antigens but only those that recognize the antigen that the dendritic cell is showing around are activated. That is part of what makes the adaptive immune system adaptive.

But before all this can happen, the dendritic cells and macrophages need an extra push to make the effort and and search out the T and B cells to begin with. They cannot determine on their own whether the antigen that they have taken up belongs to a pathogen. They need a signal to know that something dangerous is going on. For this purpose they have a set of receptors that recognize molecules that a lot of pathogens have in common or that are released if cells undergo uncontrolled cell death. That is one reason that adjuvants are included in highly purified vaccines. You provide an extra signal that pushes dendritic cells to seek out T cells. The purified antigen alone would not be enough.

RNA outside of cells is such a danger signal, it usually does not belong there. It means that a viral infection is going on or that cells are dying and releasing RNA. So if you use RNA in a vaccine you technically provide both the adjuvant and the blueprint for the antigen that you want to immunize against. However, I don’t know if this is really enough. You might still have to add extra adjuvants. They also serve other purposes such as a slow release of antigen over time for an extended stimulation with minimal amount of antigen.

One disclaimer at the end. It’s a useful analogy sometimes to describe cells as if they could think or want something. But it can be misleading too. So please take what I have written with a grain of salt.

@Julian

You might still have to add extra adjuvants.

Hmm. Perhaps it could be a sort of bi-phasic treatment? That is, give the mRNA, as one does, and let it get all settled in before adding an adjuvent siren. Maybe that would cut down on all the friendly fire.

It’s a useful analogy sometimes to describe cells as if they could think or want something.

I’m not sure I want to go on living with this new knowledge of such violence of mindless, unthinking things in my body nonchalantly slurping up the remains of their murdered comrades. That is some interoffice rivalry, right there. 🔪

I’m sorry, I don’t mean to be the karen here. But I’m going to have a word with my immune system’s manager after what I witnessed in that video. That is not acceptable. No more. I’m going to get my engineers to…

Whereas American anti-vaxxers were all on board with Trump when he hinted at his anti-vaxx views before and after the election, that he is, like them, a conspiracy theorist, and most recently has jumped on the COVID-19 vaccine bandwagon and into bed with Big Pharma does the anti-vaxxer:

a) Abandon Trump
b) Become pro-vaccine
c) Triple down on the cognitive dissonance and remain both pro-Trump and anti-vaxx
d) Stock up on guns and rations and hide in a bunker until it all blows over
e) Die from home made natural remedies
f) Blow a neural fuse and go insane(r)
g) All of the above (see ‘c’)

2 weeks ago Trump said he would mobilize the military to make sure Americans got the COVID-19 vaccines. That prolly was the last straw and if there are any AVers that still support him it’s for other reasons. Ironically if Trump rushes an unproperly vetted vaccine to market he might wind up being the best thing to happen to AVers since Wakefield .

Yes, but freedom-loving Americans are still on board because big-T promises to take reproductive rights away from women, and will appoint judges who are willing to champion right-wing causes.

Some of the usual suspects in the anti-vaccine arena, particularly the vaccine causes autism crowd, seemed to have significantly cooled on Trump in recent months. It seems to have dawned on them that Trump doesn’t care about them, only himself.

Some of the others for whom anti-vaccination was just another part of their anti-science, anti-government belief system are still “locked and loaded” behind Trump and waiting for him to drain the swamp.

Mobilize the military? We might well end up with a crash program.
The basic premise of the crash program: If you get nine women pregnant you can get a baby in one month.

Currently, the Trump administration is on a rampage about any regulations on businesses thaty might impede restarting the economy. It almost sounds as if Trump wants to take us back to the days of laissez faire capitatlism. He’s hardly going to want to enforce or even encourage pesky safty regulations on vaccines. As long as he can announce it by November, he’s not going to care whether it’s safe or even if it works.

Another problem associated with rushing forward is the undermining of public trust. A poll released today (AP-NORAC poll) counted ~50% of Americans unwilling to take a coronavirus vaccine, with higher refusal rates among minorities. If a new vaccine is associated with profiteering, and if there’s highly visible debate about the quality of the data, that number may climb higher.

I know from personal experience (lol) that injecting naked DNA intramuscularly does a perfectly good job of activating the cellular immune system and making antigen-specific T cells. In mice (of course). What I have no idea about is if those T cells actually do anything.
I was working with little bits of HIV DNA and I could totally get a mouse to produce T cells to env or pol or tat or rev, easy peasy. But because it was a mouse system and HIV, who knows if those T cells would have done anything, because HIV doesn’t infect mice (lucky them).

So I’m very curious if the mRNA vaccines get presented correctly and the memory T cells and B cells are actually capable of activation, or if they just sit on their metaphorical butts.

(If ever there were evidence against intelligent design, it’s the immune system. Seriously, it’s just so freaking convoluted!)

I got an impression from reading something on the website of a British group working on a vaccine that they were planning on using a non-pathogenic virus as a vector to get mRNA into cells. It was all rather hand-wavy and not at all clear. They referred to whatever the vector was by a cryptic alphanumeric string and it wasn’t even really clear to me they were working on an mRNA vaccine. Presumably myocytes don’t make a habit of just slurping up random strings of nucleic acids floating around in the extracellular compartment, so using a virus as a vector would seem to me as plausible.

Ar5?Av5? Something like that?

I just hope we don’t have someone insisting on trying an adenovirus as a vector again; too many people already mount a perfectly good immune response to adenovirus, which makes it a crap vector.

trying an adenovirus as a vector again

I remember dimly (maybe a post by Derek Lowe, or maybe in the comments under) that adenovirus is tried, but is quite a challenge because as you said, plenty of people will simply neutralize a well-known virus before it had a chance at delivering its payload.

Athaic: Yup! My first science job was manufacturing andeo-virus based treatments, one a prototypes HIV vaccine (didn’t work) and the other a gene therapy for rheumatoid arthritis (didn’t work and a patient died).

I’m kind of over adenovirus and adeno-associated virus, but they’re still popular.

I’ve been reading so many things on COVID my brain has glazed over and I’m not paying adequate attention. I think it was the Oxford site where I saw reference to the vector virus and Narad’s link makes it clear that they are using an adenovirus.

@ Aarno Syvänen
Wouldn’t that turn people into chimanzees?

I can see the anti-vaxxers all over it.

Yes, now that my aged brainz haz been poked enough times I do recall that it was the chimpanzee virus.

What are the implications of using any virus as a vector in this fashion? Presumably most humans would not already have antibodies against a virus that infects chimpanzees, but it would seem to me that this method would likely preclude booster doses. I would think that antibodies against the vector virus, resulting in it being killed off promptly if administered again later, unless somehow the vector simply didn’t get replicated by the human host (thereby limiting how much of the mRNA payload could be presented) and was very rapidly and non-specifically eliminated from the extra-cellular compartment after the initial dose.

This is all so depressing! I have had some vaccines as a child, which I obviously had no control over, but as an adult have chosen only to have them prior to travelling, but not for other reasons, e.g. flu shots. I have done my best to listen to both sides of the vax arguments but really just get more confused. I want to believe vaccines are thoroughly tested, and it seems some are, but there are so many other things going on as well, e.g. politics, financial conflicts of interest, etc. I share your concerns about Moderna (not sure, but I heard they haven’t produced any successful vaccines) but it doesn’t matter who it is, if they don’t get it right it certainly won’t help science, not to mention the people it will actually harm. It will take a lot to convince me any hurried solution is safe.

“If a new vaccine is associated with profiteering”

I have scant concern about the makers of a Covid-19 vaccine reaping a solid profit, if their product is effective and safe (like other vaccines currently in use).

My point regarding “profiteering” was that if the developer appears to be making an “excessive profit” (whatever the definition of excessive is), that perception will further undermine the acceptability of the vaccine in the minds of those predisposed to be distrustful. The critical issue is whether enough of the population will accept being vacinated to generate herd immunity.

stumbled on this site…always surprised how many people are just so completely full of $hit!!!
Like this BS Orac crap, what a transparent pharma shill.

All the usual claptrap, same old pharma talking points, same logical fallacies, same lack of scientific understanding, nothing ever changes…

Get a life, stop campaigning to hurt others, INFORMED CONSENT is no threat to you you moron.

I can’t help but notice you haven’t pointed to anything incorrect in this post.

Which is, actually, pretty critical of pharma.

Maybe you should reread it?

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