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

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.