The New York Times - USA (2020-12-01)

D4 N THE NEW YORK TIMES, TUESDAY, DECEMBER 1, 2020

In a 1988 essay on pandemics Joshua Leder-
berg, Nobel laureate and president of the
Rockefeller University, reminded the medi-
cal community that when it comes to infec-
tious disease, the laws of Darwin are as im-
portant as the vaccines of Pasteur.
As medicine battles bacteria and viruses,
those organisms continue to undergo muta-
tions and evolve new characteristics.
Lederberg advised vigilance: “We have
no guarantee that the natural evolutionary
competition of viruses with the human
species will always find ourselves the win-
ner.”
With the emergence of what seem so far
to be safe and effective vaccine candidates,
it appears that humanity may be the winner
again this time around, albeit with a dread-
ful loss of life.
But vaccines won’t put an end to the evo-
lution of this coronavirus, as David A. Ken-
nedy and Andrew F. Read of Pennsylvania
State University, specialists in viral resist-
ance to vaccines, wrote in PLoS Biology re-
cently. Instead, they could even drive new
evolutionary change.
There is always the chance, though small,
the authors write, that the virus could
evolve resistance to a vaccine, what re-
searchers call “viral escape.” They urge
monitoring of vaccine effects and viral re-
sponse, just in case.
“Nothing that we’re saying is suggesting
that we slow down development of vac-
cines,” Dr. Kennedy said. An effective vac-
cine is of utmost importance, he said, “but
let’s make sure that it stays efficacious.”
Vaccine makers could use the results of
nasal swabs taken from volunteers during
trials to look for any genetic changes in the
virus. Test results need not stop or slow
down vaccine rollout, but if recipients of the
vaccine had changes in the virus that those
who received the placebo did not, that
would indicate “the potential for resistance
to evolve,” something researchers ought to
keep monitoring.
There are some reasons to be optimistic
that the coronavirus will not become resist-
ant to vaccines. Several years ago, Dr. Ken-
nedy and Dr. Read presented an analysis of
the difference between resistance to drugs
and vaccines. Neither bacteria nor viruses
evolve resistance to vaccines as easily as
they do to drugs, they wrote. Smallpox vac-
cine never lost its effectiveness, nor did the
vaccines for measles or polio, despite years
of use.
Antibiotics, on the other hand, can
quickly become useless as bacteria and
other pathogens like viruses and fungi
evolve defenses. And resistance builds to
other drugs as well.
The reasons have to do with the very ba-
sic principles of evolution and immunity.
The two key differences are that vaccines
generally act earlier than drugs, and that
the natural immune response they promote
is usually more varied, with more lines of
attack. A drug may be narrowly targeted,
sometimes attacking one metabolic path-
way or biochemical process.
With most drugs, the virus or bacteria
has already been reproducing in the pa-
tient’s body and if one variant is better at
surviving the drug’s attack, it will continue
to grow and perhaps be transmitted to an-
other person. A combination of drugs, as
with H.I.V. treatment, can be more effective
because it unleashes a multipronged attack.
Vaccines, on the other hand, act early, be-
fore the virus begins to proliferate and per-
haps change within a patient’s body. So
there are no new variants, like those forged
in the heat of a drug attack to grow and
spread from the infected person.
Vaccines offer the body’s immune system
a glimpse of the virus, and then the immune

system builds a broad attack. For example,

after a tetanus shot, a person’s immune sys-

tem may produce 100 different antibodies.

Some vaccines, however, do drive viruses

to evolve resistance, Drs. Kennedy and

Read noted in their 2015 article. A vaccine

stopped Marek’s disease, an illness in chick-

ens that is important commercially. But the

virus could still infect the chickens. It rep-

licated and spread without causing disease

and quickly became resistant.

In humans, a type of bacteria that causes

pneumonia bacteria evolved resistance to a

vaccine when the bacteria recombined in

nature with existing strains that were natu-

rally resistant. A vaccine for hepatitis B cre-

ated antibodies targeting only one small

part of one protein — a loop made by nine

amino acids, which is tiny in protein terms.

It did not create a broad attack. A pertussis

vaccine also appeared to drive resistance. It

worked to fend off the disease, but targeted

only a few proteins and was not effective at

stopping infection and transmission of the

virus.

The coronavirus vaccines now in devel-

opment use different ways to get the im-

mune system to respond. Some coronavirus

vaccines under development or in use in

Russia and China use whole virus particles,

inactivated or attenuated, to spark an im-

mune system response.

Many other vaccine candidates, like the

ones from Pfizer and Moderna, now nearing

review by the Food and Drug Administra-

tion for first use as early as this month, are

meant to get the immune system to react to

only a portion of the coronavirus, the so-

called spike protein, which would seem to

offer fewer targets.

But Dr. Kennedy said that was not neces-

sarily a problem. “A vaccine based on just

the spike protein has the potential to gener-

ate a broad immune response,” he said, “be-

cause there are multiple sites on the spike

protein where potent neutralizing antibod-

ies can bind.”

Although these are the first vaccines that

use RNA particles to instruct the cells to

make a viral protein, other vaccines use

parts of the virus, rather than the whole. So

far, Dr. Kennedy said, there was no evidence

to show one type of vaccine would be more

likely to drive resistance. “We have seen

vaccine resistance evolve against many dif-

ferent kinds of vaccines,” he said, “but there

are also plenty of examples for each of these

where resistance has never emerged.”

Resistance can also evolve in ways that

aren’t driven by how a vaccine acts. There

may already be variants of the coronavirus

that are less susceptible to the actions of

vaccines. This concern prompted Denmark

to announce that it would cull all of its mink

because a variant of the virus had appeared

in mink which showed in very preliminary

lab tests that some antibodies were less ef-

fective against it.

The worry has lessened since the Danes

announced the problem, with scientists and

the World Health Organization saying they

saw no evidence yet that the variant would

interfere with any vaccines in development.

But Denmark, after the resignation of a

minister, who announced the cull too soon,

and a legislative debate that appears to be

leading to approval of the cull, still plans to

kill all the mink in the country.

And scientists say that caution in this

kind of situation makes sense. As a virus

jumps from people to animals and back

again, as it has with mink, there are more

opportunities for changes in the virus RNA,

changes that could lead to resistance.

Researchers at the University of Pitts-

burgh have discovered a kind of mutation

that hadn’t been seen in coronaviruses be-

fore and raises fresh concerns about the

evolution of vaccine resistance.

In their search for mutations, re-

searchers have mostly focused on flips of

one genetic letter to another — a kind of mu-

tation known as a substitution. But Paul

Duprex and his colleagues discovered that

the viruses mutating in a chronically in-

fected patient were changing differently:

They were losing sets of genetic letters.

Typically, a mutation that deletes a genet-

ic letter is catastrophic to a virus. Our cells

read genetic letters three at a time to choose

a new building block to add to a growing

protein. A deletion of one genetic letter can

entirely scramble the instructions for a vi-

ral protein, so that it cannot form a func-

tional shape.

But Dr. Duprex and his colleagues found

that the coronaviruses in the patient could

lose genetic letters and yet stay viable. The

secret: The viruses lost genetic letters in

sets of three. Instead of destroying the ge-

netic recipe for a viral protein, the muta-

tions snipped out one or more amino acids.

As much as Dr. Duprex despises the pan-

demic, he finds it hard not to admire the ele-

gance of these mutations. “It’s so cool, it’s

brilliant,” he said.

Having found these deletion mutations in

viruses from one person, Dr. Duprex and his

colleagues wondered how common they

were.

Searching public databases of coronavi-

rus genomes, they discovered that dele-

tions were surprisingly widespread. “It’s

happening independently in different parts

of the world,” Dr. Duprex said.

All the deletions, it turns out, only arise in

one region, the spike protein. Dr. Duprex

and his colleagues found that deletions in

the spike gene didn’t prevent the coronavi-

rus from infecting cells.

Dr. Duprex and his colleagues posted

their study online Nov. 19. It has not yet

been published in a peer-reviewed journal.

The researchers are now infecting animals

with deletion-mutant viruses to better un-

derstand the risk they may pose to vac-

cines.

“Well, this paper does nothing to reduce

the anxiety!” Dr. Read said in an email.

“This is early data strongly suggesting the

virus has the potential to escape human im-

munity.”

But Drs. Read and Kennedy argue that vi-

ral evolution won’t necessarily doom vac-

cines. Vaccine makers just need to stay

aware of it, and devise new vaccines if nec-

essary.

And there are numerous varieties of vac-

cines in development. The first two ap-

proaching approval in the United States

both use a significant chunk of viral RNA to

train the immune system. Other vaccines

that are in development use the whole vi-

rus. And different vaccines deliver the virus

or part of it in different ways, all of which

could prompt a different immune response.

The Evolution of the Virus Will Continue

Vigilance is required because,

over time, it could become

resistant to vaccines.

A scanning electron micrograph of an apoptotic cell heavily infected with coronavirus particles.

NIAID

One researcher admires

the elegance of the

genetic mutations.

By JAMES GORMAN and CARL ZIMMER

PHASE 1 PHASE 2 PHASE 3 LIMITED APPROVED

38 17 13 6 0

Tracking Coronavirus Vaccines and Treatments

Researchers are testing 55 coronavirus vaccines in humans and at least 87 more in

animals. Last week California-based City of Hope announced a Phase 1 clinical trial, and

AstraZeneca and the University of Oxford reported promising early Phase 3 trial results.

Follow updates at nytimes.com/vaccinetracker and nytimes.com/treatmenttracker.

THE NEW YORK TIMES

Vaccines in large

safety trials

Vaccines testing

safety and dosage

Vaccines in larger

efficacy tests

Approved for

early or limited use

Approved for

full use

Last month, Farah Khemili popped a win-
tergreen breath mint in her mouth and no-
ticed a strange sensation: a bottom tooth
wiggling against her tongue.
Ms. Khemili, 43, of Voorheesville, N.Y.,
had never lost an adult tooth. She touched
the tooth to confirm it was loose, initially
thinking the problem might be the mint. The
next day, the tooth flew out of her mouth and
into her hand. There was neither blood nor
pain.
Ms. Khemili survived a bout with
Covid-19 this spring, and has joined an on-
line support group as she has endured a
slew of symptoms experienced by many
other “long haulers”: brain fog, muscle
aches and nerve pain.
There’s no rigorous evidence yet that the
infection can lead to tooth loss or related
problems. But among members of her sup-
port group, she found others who also de-
scribed teeth falling out, as well as sensitive
gums and teeth turning gray or chipping.
She and other survivors unnerved by
Covid’s well-documented effects on the cir-
culatory system, as well as symptoms such
as swollen toes and hair loss, suspect a con-
nection to tooth loss as well. But some den-
tists, citing a lack of data, are skeptical that
Covid-19 alone could cause dental symp-
toms.
“It’s extremely rare that teeth will lit-
erally fall out of their sockets,” said Dr. Da-
vid Okano, a periodontist at the University
of Utah in Salt Lake City.
But existing dental problems may wors-

en as a result of Covid-19, he added, espe-

cially as patients recover from the acute in-

fections and contend with its long-term ef-

fects.

And some experts say that doctors and

dentists need to be open to such possibili-

ties, especially because more than 47 per-

cent of adults 30 years or older have some

form of periodontal disease, including infec-

tions and inflammation of the gums and

bone that surround teeth, according to a

2012 report from the Centers for Disease

Control and Prevention.

“We are now beginning to examine some

of the bewildering and sometimes disabling

symptoms that patients are suffering

months after they’ve recovered from

Covid,” including these accounts of dental

issues and teeth loss, said Dr. William W. Li,

president and medical director of the Angio-

genesis Foundation, a nonprofit that stud-

ies the health and disease of blood vessels.

While Ms. Khemili had become more dili-

gent about her dental care, she had a his-

tory of dental issues before contracting the

coronavirus. When she went to the dentist

the day after her tooth came out, he found

that her gums were not infected but she had

significant bone loss from when she used to

smoke. He referred Ms. Khemili to a spe-

cialist to handle a reconstruction. The den-

tal procedure is likely to cost her just shy of

$50,000.

The same day Ms. Khemili’s tooth fell out,

her partner went on Survivor Corp, a Face-

book page for people who have lived

through Covid-19. There, he found that Di-

ana Berrent, the page’s founder, was report-

ing that her 12-year-old son had lost one of

his adult teeth, months after he had a mild

case of Covid-19. (Unlike Ms. Khemili, Ms.

Berrent’s son had normal and healthy teeth

with no underlying disease, according to his

orthodontist.)

Others in the Facebook group have

posted about teeth falling out without bleed-

ing. One woman lost a tooth while eating ice

cream. Eileen Luciano of Edison, N.J., had a

top molar pop out in early November when

she was flossing.

“That was the last thing that I thought

would happen, that my teeth would fall out,”

Ms. Luciano said.

Teeth falling out without any blood is un-

usual, Dr. Li said, and provides a clue that

there might be something going on with the

blood vessels in the gums.

The new coronavirus wreaks havoc by

binding to the ACE2 protein, which is ubiq-

uitous in the human body. Not only is it

found in the lungs, but also on nerve and en-

dothelial cells. Therefore, Dr. Li says, it’s

possible that the virus has damaged the

blood vessels that keep the teeth alive in

Covid-19 survivors; that also may explain

why those who have lost their teeth feel no

pain.

It’s also possible that the widespread im-

mune response, known as a cytokine storm,

may be manifesting in the mouth.

“If a Covid long hauler’s reaction is in the

mouth, it’s a defense mechanism against

the virus,” said Dr. Michael Scherer, a

prosthodontist in Sonora, Calif. Other in-

flammatory health conditions, such as car-

diovascular disease and diabetes, he said,

also correlate with gum disease in the same

patients.

“Gum disease is very sensitive to hyper-

inflammatory reactions, and Covid long

haulers certainly fall into that category,” Dr.

Scherer said.

Dentists haven’t seen many of these

cases, and some dismiss these individual

claims. But physicians like Dr. Li say

Covid-19’s surprises require that the profes-

sion be on the lookout for unexpected con-

sequences of the disease.

“Patients may be bringing in new find-

ings,” he said, and physicians and dentists

need to cooperate on understanding the ef-

fects of long-term Covid-19 on teeth.

For now, Ms. Khemili hopes her story

may serve as a cautionary tale. If people

aren’t taking the proper precautions to pro-

tect themselves from the coronavirus, “they

could be looking at something like this.”

Their Teeth Fell Out. Was Covid-19 the Culprit?

The coronavirus may

aggravate previous dental

problems, some experts say.

Some Covid-19 survivors say

loose teeth have fallen out

without bleeding. Others claim

that their gums are more

sensitive, or that their teeth

are turning gray or chipping.

BEN HASTY/MEDIANEWS GROUP/READING EAGLE, VIA GETTY IMAGES

By WUDAN YAN

CORONAVIRUS IN DEPTH