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Notebook Medicine




Vaccine tests and delays

The road to a “safe and effective” coronavirus vaccine—and who will get it first

Federal regulators last week issued new safety guidance for pharmaceutical companies developing coronavirus vaccines. The Food and Drug Administration stated that researchers would need to observe volunteers participating in final-stage vaccine testing for at least two months after giving them their last shot. The two-month period is meant to ensure that volunteers do not develop serious reactions to the vaccines. 

The White House had reportedly resisted the revised rules, which mean U.S. approval of a COVID-19 vaccine before Election Day is technically infeasible. But by reassuring a nervous public about the safety of new vaccines, the new rules and delay might actually encourage more people to get their coronavirus shot.

Mass vaccination would be a crucial turning point in the battle against the coronavirus, so it stands to reason that it should start as soon as we’re sure a given vaccine is safe and effective. But where do we set the goal posts for “safe and effective,” and who should get the vaccine first? 

“Effective” has a relatively simple definition here: If a given vaccine decreases the chance of getting the coronavirus (or getting very sick from it) by 50 percent compared with a placebo shot, the FDA considers it effective. “Safe” is harder to define: What if vaccine-caused health problems only appear in patients later? By definition, the longer researchers follow their test patients, the lower the chance that they’ll miss something with a delayed effect—but the higher the chance that patients will miss out on a vaccine they could have benefited from.

Current trial results are beginning to show the wisdom of taking our time. Oxford and AstraZeneca have paused their ChAdOx1 vaccine trial while researchers evaluate whether a volunteer’s illness resulted from the vaccine. Johnson & Johnson’s vaccine trial is likewise paused, as is Eli Lilly’s monoclonal antibody treatment. These pauses aren’t unprecedented in large trials, since, in a group of thousands of participants, it’s unsurprising one or two might become sick for some reason in any given few months. But the trials serve a valuable function: letting researchers determine whether they’re about to release a dangerous or safe product.

The balancing act between speed and safety, along with disagreement about which is more important, has stoked fears among the public. In a Kaiser Family Foundation poll published Sept. 10, over half of Americans said they would not want to receive a vaccine approved before the election. (Interestingly, despite the Trump White House’s pressure for early approval, Democrats in the poll were more likely to say yes to such a vaccine. Fifty percent of Democrats said they would get it, but only 36 percent of Republicans.)

That’s who’s willing to get it, not who will get access first. Inevitably, all Americans can’t receive the vaccine at the same time. The National Academies of Sciences, Engineering, and Medicine (NAS) has released a draft document discussing who should go first.

The highest priority—what the NAS calls phase 1A—involves high-risk health workers and first responders. Without them, there’s nobody to take care of everyone else. Going second (phase 1B) are people most likely to suffer severe harm from an infection: those already in poor health and older adults in crowded settings. Phase 2 involves teachers, child care workers, the homeless, those in prison, and people with less severe health issues, along with “all older adults.” Phase 3 covers children, young adults, and “workers in industries important to the functioning of society.” Phase 4 covers whoever remains—the equivalent of an airport gate agent’s “All passengers, all rows!”

The NAS doesn’t make laws, but its framework for discussion sets a path for the deliberations that will need to take place in coming months. And amid those phases, there’s good news. As soon as any number of people start receiving the vaccine, the virus will have a harder time finding new people to infect. Deaths should also decline more sharply at the beginning, as those at highest risk go to the head of the line. I will recommend the vaccine for almost everyone, but especially for sick, elderly people, who are at far higher risk than others. 

When it comes out, I encourage you to get it. Until then, please stay safe.

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AP Photo/Bruna Prado

Crowds visit a beach in Rio de Janeiro, Brazil, on Sept. 6 (AP Photo/Bruna Prado)


Will herd immunity end the coronavirus?

Some researchers suggest the threshold for herd immunity is lower than we thought, but ending social distancing measures prematurely would be a mistake

In the COVID-19 debates, one topic manages simultaneously to be the most and least controversial: “herd immunity.” The concept of herd immunity is uncontroversial, and simply states that when enough members of a population develop immunity to a virus, the bug will fizzle out for lack of people to infect. The controversy, though, echoes every child’s favorite road-trip question: Are we almost there yet?

Two developments have raised the question with new vigor. One is in Washington, where Dr. Scott Atlas has become the newest White House adviser on the coronavirus task force. Atlas advocated for herd immunity in his May Senate testimony, saying, “If infection is still prevalent, socializing among these low-risk groups [younger, healthy adults] presents the opportunity for developing widespread immunity and eradicating the threat.” (His recommendations assume viral spread among low-risk groups will remain largely confined to those groups and won’t have serious long-term health consequences.)

The second development was summarized by a recent Washington Post article: Researchers are now questioning where the threshold for coronavirus herd immunity actually lies. So at what point can we argue that we’ve reached herd immunity?

Viruses spread at different rates in different populations. In a March letter to the editor in the Journal of Infection, a Hong Kong–based team attempted to calculate the coronavirus herd immunity threshold for various countries. The authors started with the basic idea that the more easily the virus spreads within a given population, the further that population must be from the immunity threshold. They based this on estimates of Rt, a figure measuring the “effective reproductive number.” (Think of weeds in gardens: They spread freely in general, but they may spread even better—or worse—depending on their circumstances. An Rt value below 1.0 would mean weeds are decreasing.)

The Hong Kong team estimated the U.S. herd immunity threshold was 69.6 percent, assuming no masks or social distancing—meaning about 7 out of 10 Americans would need to get the coronavirus (and survive) in order to stop its spread.

However, a Brazilian team’s new study (not yet peer reviewed) argues that individual variation in susceptibility or exposure could lower the threshold for herd immunity. That’s an interesting hypothesis, and the logic behind it makes sense up to a point. Clearly people who spend much of their time in crowded indoor places, such as the unfortunate folks who “get every cold that goes around,” are at higher risk than others. But—there’s always a “but,” isn’t there?—the Rt already takes that into account: It’s a population-level figure, and it considers those susceptible people along with the happy souls whose immune systems (or introverted lifestyles) mean they seemingly haven’t caught a virus in years.

The Brazilian team argues that under optimal circumstances, herd immunity could require as little as 20 percent of the population to be immune. Wonderful news if true—but is it? And how close can we get to those optimal circumstances? The fact is, we can do things to change effective reproductive number: America’s calculated Rt value, for example, went from an extreme high of 3.8 in some states down to slightly above 1.0 with social distancing, masking, contact tracing, and full-then-partial shutdowns.

We thus end up in another good news, bad news situation. The good news is that being able to change Rt means we can also temporarily, by all working together, get the benefits of herd immunity—reduced case numbers, reduced deaths, sustained reopening—even without having enough people contract SARS-CoV-2 to obtain true herd immunity. This is how distancing, hand-washing, mask-wearing, contact tracing, and staying home have held Taiwan’s population of 23 million people to a total of seven COVID-19 deaths. The Taiwanese are not unusually immune to the coronavirus. They simply worked together to pull Rt down to a level where the virus couldn’t spread.

The bad news comes if we mistake the good news for a get-out-of-jail-free card. The virus hasn’t changed, and the outbreaks at college campuses show just how easily it still spreads. A vaccine should be mass-produced soon—God willing, within the next six months. Observing that Rt is currently low, or that the infection and death figures are more reassuring now, should encourage us to stay the course with measures like masking and social distancing, not abandon them prematurely.

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(Getty Images)


A “silver bullet” for COVID-19?

A Texas doctor claims he’s found a cure for COVID-19, but the evidence is still out

Several readers have written to inform us about Richard Bartlett, a Texas doctor and onetime congressional candidate who says he has discovered a “silver bullet” for COVID-19. His proposed cure? Inhaled steroids.

This would be world-changing news, probably deserving a Nobel Prize, if true. It would save thousands of lives, end the economic and social upheaval caused by preventive measures, and save billions of dollars on hospital treatments.

As the ancient Spartans famously said: “If.”

I can’t say with certainty Dr. Bartlett hasn’t discovered a cure, for the same reason he shouldn’t imply that he has: What he currently has is a hypothesis, one whose evidence is as yet too limited to conclude that the treatment works at all, much less that it works in most or all COVID-19 patients. We simply don’t know. So how could we find out whether it’s a blockbuster—or a bust?

Back in March, we discussed a statistic called the “number needed to treat” (NNT). The NNT is the number of patients we’d need to treat in order to expect a medicine to have the desired effect in one patient. For a perfect treatment that benefits every patient who receives it, the NNT is 1. For many common prescriptions, though—statins for prevention of a heart attack, for instance—the NNT is more in the range of 20 to 100. You’d need to treat 20 to 100 patients in order to benefit just one. 

Many medical conditions and illnesses go away by themselves. Given the relatively high NNT of many treatments, it’s often hard for researchers to tease out whether a new treatment is improving patient outcomes, or whether those patients would have fared equally well without the treatment.

This timeless source of job security for research statisticians brings us back to Dr. Bartlett and his series of patients. According to CBS7, Bartlett says he’s treated “dozens” of COVID-19 patients and all have survived. Since most patients with COVID-19 do survive, it raises the question: Did his patients benefit from the steroids, or were they patients who would have survived anyway?

Answers are on the way: Oxford and the Queensland University of Technology are already investigating this idea with their STOIC (Steroids in COVID-19) clinical trial. Queensland University of Technology elaborates on its origins: Two researchers “had noticed early on in the pandemic that people with asthma and the chronic lung disease COPD were under-represented in the numbers of seriously ill COVID-19 patients.” This struck them as unusual, since you’d normally expect patients with sick lungs not to have an advantage against respiratory viruses. That made them wonder whether those patients’ inhaled steroid treatments might be what was helping them.

In light of the recent discovery that another corticosteroid can help in severe cases of COVID-19—but not in less severe disease—I’m very curious to learn what the STOIC trial will reveal. STOIC aims to reach a conclusion by September. 

In the meantime, let’s not—pardon the pun—jump the gun in our search for a silver bullet.

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