Vaccine Chaos Is Looming

The COVID-19 vaccines furthest along in clinical trials are the fastest to
make, but they are also the hardest to deploy.
Sarah Zhang <> 2:36 PM ET
[image: Illustration of a syringe that has been tangled into a knot]Getty /
The Atlantic

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On the day that a COVID-19 vaccine is approved, a vast logistics operation
will need to awaken. Millions of doses must travel hundreds of miles from
manufacturers to hospitals, doctor’s offices, and pharmacies, which in turn
must store, track, and eventually get the vaccines to people all across the
country. The Centers for Disease Control and Prevention, along with state
and local health departments, coordinates this process. These agencies
distributed flu vaccines during the 2009 H1N1 pandemic this way, and they
manage childhood vaccines every day. But the COVID-19 vaccine will be a
whole new challenge.

“The COVID situation is significantly different and more complex than
anything that we have had to deal with in the past,” says Kris Ehresmann
an infectious-disease director at the Minnesota Department of Health.

Read: A vaccine reality check

The two leading vaccine candidates in the U.S.—one developed by Moderna,
the other by a collaboration between Pfizer and the German company
BioNTech—have progressed so quickly to clinical trials precisely because
they are the fastest to make and manufacture. They rely on a novel vaccine
technology whose advantage is speed, but whose downside is extreme physical
fragility. These vaccines have to be frozen—in Pfizer/BioNTech’s case, at
an ultracold –94 degrees Fahrenheit, colder than most freezers—which will
limit how and where they can be shipped. The ways these vaccines are
formulated (without added preservatives) and packaged (in vials that hold
doses for multiple people) also make them easier to develop and manufacture
quickly but harder to administer on the ground.

In other words, speed is coming at the expense of convenience. “For this
first generation of vaccines, we won’t trade off safety. We don’t want to
trade off effectiveness,” says Kelly Moore
<>, the
associate director of immunization education at the Immunization Action
Coalition. So instead, the U.S. is planning for a vaccine that requires
brutally complicated logistics. Public-health departments in states,
territories, and major cities are currently drawing up vaccine plans
for the end of October. It’s still unclear whether these vaccines are safe
and effective—and it’s extremely unlikely that data will be available by
the end of October. But the departments are getting ready. Many are already
stretched thin by the ongoing pandemic, and they are now helping plan, as
Moore puts it, “the largest, most complex vaccination program ever
attempted in history.”

The leading vaccine candidates both deploy a new, long-promised technology.
Their core is a piece of mRNA, genetic material that in this case encodes
for the spike protein—the bit of the coronavirus that helps it enter human
cells. The vaccine induces cells to take up the mRNA and make the spike
protein and, hopefully, stimulates an immune response.

By using mRNA, vaccine makers do not need to produce viral proteins or grow
viruses, methods that are used in more traditional vaccines and that add
time to the manufacturing process. This is why Moderna and Pfizer/BioNTech
have been able to get their vaccines into clinical trials so quickly.
Moderna went from a genetic sequence of the coronavirus to the first shot
in an arm in a record 63 days

To get a naked strand of mRNA inside a cell, scientists have learned to
encase it in a package called a lipid nanoparticle. mRNA itself is an
inherently unstable molecule, but it’s the lipid nanoparticles that are
most sensitive to heat. If you get the vaccine cold enough, “there’s a
temperature at which lipids and the lipid structure stop moving,
essentially. And you have to be below that for it to be stable,” says Drew
Weissman <>,
who studies mRNA vaccines at the University of Pennsylvania and whose lab works
with BioNTech
Keep the vaccine at too high a temperature for too long, and these lipid
nanoparticles simply degrade. Moderna’s and Pfizer/BioNTech’s vaccines have
to be shipped frozen at –4 degrees and –94 degrees Fahrenheit,
respectively. Once thawed, Moderna’s vaccine can then last for 14 days at
normal fridge temperatures; Pfizer’s, for five days.

Read: America is running low on a crucial resource for COVID-19 vaccines

The freezer temperature required by Moderna’s vaccine makes it difficult to
ship; the ultracold temperature required by Pfizer and BioNTech’s vaccine
is nearly impossible to maintain outside of a large hospital or academic
center with specialized freezers. For this reason, Pfizer has devised
“thermal shippers” that, unopened, can keep the vaccines frozen for up to
10 days;once opened for the first time, they have to be replenished with
dry ice within 24 hours then every five days. These shippers are supposed
to be opened no more than twice a day to take out vials, and must be closed
within one minute. The real catch, though, is that these shippers hold, at
a minimum, 975 doses of the COVID-19 vaccine.

A large hospital in a city could deal with that volume, but in rural areas,
a 975-dose shipment will need to be broken up into smaller ones—all while
making sure the vials stay ultracold. “The other potential would be only
shipping that vaccine to our more urban areas,” says Molly Howell, North
Dakota’s immunization program manager, “but then we’re leaving out a lot of
people who are health-care workers in rural areas or at high risk in rural
areas.” To get the vaccine out to those places, her department is looking
into buying frozen-transport coolers and potentially a dry-ice machine. If
North Dakota is allocated, for example, 2,000 doses, the state will have to
open the thermal shipper, repackage smaller allotments in dry ice, and
physically drive them to rural clinics across the state. The vaccines are
too precious to risk shipping conventionally.

Read: What if the vaccine works only half the time?

The storage and handling requirements for these vaccines are especially
stringent, but they’re also especially uncertain. In time, it may turn out
that these mRNA vaccines can be stored at higher temperatures or can be
reformulated to be stored at higher temperatures, as other vaccines have
been. Scientists are actively trying to create more stable lipid
nanoparticles <>, and
Pfizer says it is working on a freeze-dried version of its vaccine that can
be kept in normal freezers. These incremental improvements in storage are a
normal part of the vaccine-development process, but they take time. For
example, Kathleen Neuzil
<>, a vaccine
researcher at the University of Maryland School of Medicine, points out
that the flu vaccine FluMist initially needed to be frozen but can now
be stored
at normal fridge temperatures
(Neuzil is also an investigator on the Pfizer/BioNTech-vaccine trial
In the August CDC meeting
where Pfizer unveiled the thermal shipper, a CDC official interjected to
tell stakeholders not to go out and buy freezers in anticipation of a
vaccine. The agency was exploring other storage solutions, and the
requirements could change.

And in fact, between that August meeting and the publication of the CDC’s
vaccine-distribution playbook
in September, the number of days Pfizer and BioNTech’s vaccine could be
stored at fridge temperature increased from one to five. The vaccine is so
new that even its manufacturer is still figuring out its minimum storage

It sounds absurdly simple, but how the mRNA vaccines are packaged also
imposes logistical challenges. Currently, they’re in multidose vials that
have to be used or discarded within six hours of opening. Moderna’s vaccine
comes in 10-dose vials; Pfizer and BioNTech’s, in five-dose vials. Unused
doses can degrade over time at high temperatures and, more dangerous, can
become contaminated with bacteria
because the vaccines lack preservatives. Both the multidose vials and the
lack of preservatives help get a vaccine out faster, says Moore: Experts
have been worrying about a shortage of glass for vaccine vials, and
preservatives add complexity that can slow down vaccine development.

Vaccine providers in the U.S. are unaccustomed to giving multidose,
unpreserved vaccines, though. Administering them will require scheduling
appointments with extra care in order to minimize waste, but also
discarding unused doses if needed for safety. When multidose vaccines are
used outside the U.S., according to Moore, who chairs a World Health
Organization immunization committee
some waste is built into the vaccination program. “It’s okay to open a vial
for one baby,” she says, because a program that doesn’t waste any doses is
probably erring on the side of turning people away. But this mindset might
seem counterintuitive, especially while COVID-19 vaccines remain scarce.

Lastly, both Moderna’s and Pfizer/BioNTech’s vaccines require two doses per
person over time, and the second dose has to come from the same
manufacturer as the first dose. It also has to be administered 28 days, for
Moderna’s, or 21 days, for Pfizer and BioNTech’s, after the first dose—in
both cases longer than the vaccines can be stored in the fridge. All of
this means that having the right number of vaccines for the right people
will require extensive and careful record keeping.

Read: How we survive the winter

Individual states maintain electronic immunization registries that track
which residents have gotten which vaccines. What needs to be reported to
the registries varies state by state
<>; many
vaccine providers, such as pharmacies and pediatrician’s offices, directly
connect their records to the registry. But doctors who don’t routinely give
vaccinations, such as those who see adults, might not be connected, which
could mean manually inputting the data for every patient into the
immunization registry. New connections to the system can also take weeks or
months to establish, because of the complexity of electronic health
records, Moore says.

The CDC is rolling out a new Vaccine Administration Management System
(VAMS) to supplement existing state registries, and it is expected to offer
features such as scheduling and supply management. But VAMS has also added
confusion, says Rebecca Coyle, the executive director of the American
Immunization Registry Association. One issue is that VAMS requires
collecting identifiable information that some states are not allowed to
share from their existing immunization registries. If that’s not
reconciled, vaccine providers might have to spend hours manually inputting
patient data into the new system. “There’s a lot of clarification that
still needs to happen,” Coyle says. “The clock has started with states to
finalize their response plans, and yet there are giant chunks of
information that are missing.”

The two-dose requirement for these vaccines also runs up against the
problem of human nature: People forget. They can’t get off work. They can’t
find child care. They might even move. “That’s just normal human behavior
outside of COVID,” says Azra Behlim, a senior director at the
health-care-services firm Vizient. The CDC is planning to send physical
vaccination-record cards for each patient along with vaccine supplies when
states order their doses. It is also encouraging public-health departments
and hospitals to send reminders about a second dose. This is important
because even a full course of a vaccine may offer only partial protection
against COVID-19
and one dose is likely to offer even less.

If a vaccine is fast-tracked through an emergency use authorization rather
than formally licensed by the Food and Drug Administration, that too could
create bureaucratic hurdles. For example, Medicare doesn’t
cover the costs of emergency-use drugs. So while the government intends to
pay the cost of the vaccine and of supplies like syringes, hospitals would
be on the hook for storage, scheduling, record keeping, and paying staff to
actually give the injections. “Hospitals are not happy about that—at all,”
Behlim says. A fix will likely have to come from Congress.

Another worry for hospitals: having to juggle multiple vaccines that are
not interchangeable, especially after more become available in the future.
“What they’re concerned about is: I get a vaccine now in November, and then
another manufacturer launches in January, and then another manufacturer in
March, and three more launch in May,” Behlim says. Immunization registries
can record who got which vaccine, but hospitals and clinics will still have
to decide which ones to stock and how much of each. One vaccine might be
more effective, but another one easier to store. A third might be most
effective in older people, while a fourth could have the advantage of
requiring only a single dose. The more vaccines there are on the market,
the harder vaccine management becomes.

In fact, with dozens of vaccines
currently in clinical trials, the U.S. will very likely have multiple
COVID-19 vaccines from multiple manufacturers next year. Two other vaccines
are just behind Moderna’s and Pfizer/BioNTech’s mRNA vaccines, in Phase III
clinical trials in the U.S. One of those is made by AstraZeneca and the
other by Johnson & Johnson; both insert the genetic code for the
coronavirus spike protein into a harmless virus.

These vaccines take slightly longer to manufacture, because they require
growing viruses, and they are also a relatively new technology. But they do
not have to be frozen, and Johnson & Johnson’s can be given in just a
single dose. Close behind these two are more traditional vaccines that use
proteins purified from the virus, which will likely have traditional
storage requirements. Of course, clinical trials still need to be completed
before scientists will know whether any of these vaccines are safe and
effective. “Which vaccine or vaccines will prove the safest and the most
effective and the most deployable? I think we don’t know yet. And that’s
why having redundancy is good,” says Dan Barouch, a vaccine researcher at
Harvard. (His lab is a collaborator on Johnson & Johnson’s vaccine

In the short run, speed is of the essence. But in the long run, these other
characteristics—safety, effectiveness, and ease of use—will determine which
vaccines get widely distributed. Julie Swann
<>, who studies supply chains at
North Carolina State University and who worked with the CDC during the 2009
flu pandemic, says she’s disappointed that the U.S. has put its weight
behind these mRNA vaccines, which rely on new technology and whose handling
imposes extra requirements on states and vaccine providers. It will be even
harder to use them in developing countries. “There’s no way we can use this
in some countries around the world,” she says.

The good news is that more deployable vaccines
are moving fast through the pipeline too. The race to *a *vaccine has
dominated hopes for an end to the pandemic. But the first COVID-19 vaccine
may not ultimately be the most important COVID-19 vaccine.