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The mRNA Vaccines Are Looking Better and Better

theatlantic.com/health/archive/2021/04/mrna-vaccines-johnson-blood-clots/618594/

April 14, 2021

Health
Concerns about blood clots with Johnson & Johnson underscore just how lucky Americans
are to have the Pfizer and Moderna shots.

Sarah Zhang

April 14, 2021

Katie Martin / The Atlantic

A year ago, when the United States decided to go big on vaccines, it bet on nearly every
horse, investing in a spectrum of technologies. The safest bets, in a way, repurposed the
technology behind existing vaccines, such as protein-based ones for tetanus or hepatitis B.
The medium bets were on vaccines made by Johnson & Johnson and AstraZeneca, which use
adenovirus vectors, a technology that had been tested before but not deployed on a large
scale. The long shots were based on the use of mRNA, the newest and most unproven
technology.

The protein-based vaccines have moved too slowly to matter so far. J&J’s and AstraZeneca’s
vaccines are effective at preventing COVID-19—but a small number of recipients have
developed a rare type of blood clot that appears to be linked to the adenovirus technology

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and may ultimately limit those shots’ use. Meanwhile, with more than 180 million doses
administered in the U.S, the mRNA vaccines have proved astonishingly effective and
extremely safe. The unusual blood clots have not appeared with Pfizer’s or Moderna’s mRNA
technology. A year later, the risky bet definitely looks like a good one.

The U.S. has ordered enough mRNA vaccines to inoculate its entire population. In that
context, the CDC and FDA’s call to pause the J&J rollout this week is a blow to the American
inoculation campaign, but hardly a devastating one. (J&J’s vaccine accounts for less than 5
percent of doses administered so far, and AstraZeneca’s has not yet been authorized in the
U.S.) But the rest of the world has been banking on the J&J and AstraZeneca vaccines, which
are both cheaper and easier to distribute because they don’t require the same cold storage as
mRNA vaccines. If the blood-clot risk is real, the divide between the mRNA-vaccine haves
and have-nots will only grow. The U.S. will be fine; the rest of the world will face difficult
questions about balancing the risks and benefits of an affordable, good-but-not-best vaccine
against a disease that has killed nearly 3 million people.

Read: What’s the use of a pretty good vaccine?

The blood-clot events with the AstraZeneca and J&J vaccines are so rare—appearing in one
in 100,000 to one in 1 million vaccine recipients—that they would not have shown up in
clinical trials, even ones conducted within more leisurely, non-pandemic timelines. (The
COVID-19 vaccine trials, which generally included tens of thousands of participants each,
were actually unusually large because researchers wanted data as quickly as possible.) “It’s
true with all new medications of any sort. You only find rare events when things are rolled
out to very vast numbers of people,” says John Grabenstein, the associate director of
scientific communication for the Immunization Action Coalition, who used to work on
vaccines for the pharmaceutical giant Merck. “One-in-a-million events are just barely
measurable.” That faint signal is especially difficult to see against a noisy background: Some
people get blood clots for reasons unrelated to the vaccine, too.

In Europe, the strange nature of these blood clots tipped doctors off to a possible link to
AstraZeneca’s vaccine. The patients with clots also had low numbers of platelets, which are
tiny blood cells that help with clotting. Normally, someone with a low platelet count cannot
form clots and bleeds as a result. But in these people, who had all recently gotten an
AstraZeneca shot, an immune reaction may have set off uncontrolled clotting that bound up
all their platelets.

Some scientists now hypothesize that the immune reaction is triggered by some part of the
adenovirus-vector technology. If that’s true, these blood clots might show up as a rare side
effect with other adenovirus-vector vaccines. But they clearly are very infrequent. The
AstraZeneca and J&J coronavirus vaccines are the first adenovirus-vector shots to even be
deployed widely enough in the U.S. and Europe for such rare events to emerge, but vaccines

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including Russia’s Sputnik V, China’s CanSino, and J&J’s Ebola vaccine also use the
technology.

Read: 3 different futures for the Johnson & Johnson vaccine

mRNA vaccines are similarly new, but they have so far racked up a good safety record. So
many doses have been administered that these unusual blood clots—or any serious one-in-
a-million event—would very likely have shown up by now. Back in December, experts quickly
noticed and warned the public about a handful of severe allergic reactions to the Pfizer-
BioNTech and Moderna vaccines, which is why vaccination sites now monitor recipients for
15 to 30 minutes after the jab. In addition, doctors have picked up on a possible one-in-
a-million risk of a bleeding disorder called immune thrombocytopenia, which happens when
the immune system attacks platelets after vaccination. (It’s a rare but documented side effect
of some other vaccines, such as the one against measles.) These patients do have low platelet
counts, but they do not have the accompanying blood clots that seem unique to adenovirus-
vector vaccines.

Immune thrombocytopenia is easily diagnosed and treated, James Bussel, a pediatrics

professor at Weill Cornell Medicine who studies the condition, told me in an email. But the
unusual combination of blood clots and low platelets is trickier. For example, one standard
treatment for clots is a blood thinner called heparin, but the drug can, in very rare cases,
cause the exact combination of low platelets and blood clots that doctors are concerned
about. Experts now fear that heparin might make the potential vaccine reaction even worse.
This combined condition also seems to be more dangerous than immune thrombocytopenia,
but the prognosis may improve as more doctors learn how to treat it.

U.S. officials expect the J&J pause to last no more than a few days, as experts review the
safety data and potentially revise recommendations. After a similar pause and review of the
AstraZeneca data in Europe, several countries restricted that vaccine to older residents.
(Most of the 86 blood-clot cases observed with the AstraZeneca vaccine in Europe were in
women under 60, as were all six cases observed with the J&J vaccine in the U.S.) The U.K.
now recommends that people younger than 30 be offered a different vaccine if possible.

Read: The differences between the vaccines matter

The recommendations take into account individual risk: For older people at high risk of
severe COVID-19 complications, the benefits of the vaccine clearly outweigh the risks of a
blood clot. But for young people at lower risk from the coronavirus, the benefits are not so
clear. For regulators, that balance also depends on whether a country has any other vaccines
available and the severity of its local COVID-19 outbreak. The European Union and the U.K.
do not have as many mRNA vaccines as the U.S., and less wealthy nations have even less
supply. Ultimately, every country will have to do its own benefit-risk calculation.

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The U.S.’s recommendations may end up diverging from other countries’, but they may also
influence them. Sean O’Leary, a pediatrician at the University of Colorado and a liaison to
the CDC’s Advisory Committee on Immunization Practices, notes two historical examples.
Although the United States has discontinued use of the oral polio vaccine—which is more
effective and easier to administer than the shot, but also carries a one in 2.5 million risk of
paralysis after infection with the live virus in the oral vaccine—the World Health
Organization continues to recommend it in countries where polio is endemic. But when the
U.S. in 1999 stopped using a vaccine against rotavirus because of rare reports of intestinal
blockage, the rest of the world fell in line, despite the fact that the virus was killing about half
a million kids worldwide each year. “The decision was made, essentially, if it’s not good
enough for you, it’s not good enough for us,” O’Leary says. Eventually, two newer rotavirus
vaccines with a lower risk of complications were developed. They are now used in the U.S.
and around the world.

With rotavirus, the vaccine conundrum became moot as new alternatives became available.
With COVID-19, those alternatives already exist in the form of mRNA vaccines. There was no
guarantee that the mRNA shots would be ready so quickly, or turn out to be so good and so
safe. That they did is a great stroke of luck. But in the near future, the Pfizer and Moderna
vaccines’ limited supply, high price, and distribution challenges will make them functionally
unavailable to much of the world. The U.S. can afford, literally, to vaccinate most of its
population with Pfizer’s and Moderna’s vaccines. Most other countries cannot.

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