THE DREAM VACCINE WHY STOP AT JUST SARS-COV-2? VACCINES IN DEVELOPMENT AIM TO PROTECT AGAINST MANY CORONAVIRUSES AT ONCE - INSTITUTE FOR PROTEIN ...

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THE DREAM VACCINE WHY STOP AT JUST SARS-COV-2? VACCINES IN DEVELOPMENT AIM TO PROTECT AGAINST MANY CORONAVIRUSES AT ONCE - INSTITUTE FOR PROTEIN ...
FEATURES                                                                                                           A pancoronavirus vaccine
                                                                                                                                                                                         might contain a nanoparticle
                                                                                                                                                                                             carrier (gray) that holds
                                                                                                                                                                                            several different versions
                                                                                                                                                                                             of the viral spike protein
                                                                                                                                                                                                        (other colors).

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                                                                                  THE DREAM VACCINE
CREDITS: (ILLUSTRATION) V. ALTOUNIAN/SCIENCE; (DATA) DAVID VEESLER/UW

                                                                                          Why stop at just SARS-CoV-2? Vaccines in development aim
                                                                                                to protect against many coronaviruses at once

                                                                        I
                                                                            n 2017, three leading vaccine research-                 By Jon Cohen                     gave the proposal a low priority score,
                                                                            ers submitted a grant application                                                        dooming its bid for funding. “The signifi-
                                                                            with an ambitious goal. At the time,      drome (MERS), as well as several causes        cance for developing a pan-coronavirus
                                                                            no one had proved a vaccine could         of the common cold and many bat viruses.       vaccine may not be high,” they wrote, ap-
                                                                            stop even a single beta coronavirus—      But these researchers wanted to develop a      parently unconvinced that the viruses pose
                                                                            the notorious viral group then known      vaccine against them all.                      a global threat.
                                                                            to include the lethal agents of severe       Grant reviewers at the National Institute     How things have changed.
                                                                            acute respiratory syndrome (SARS)         of Allergy and Infectious Diseases (NIAID)       As the world nears 3 million deaths from
                                                                            and Middle East respiratory syn-          deemed the plan “outstanding.” But they        the latest coronavirus in the spotlight,

                                                                        SCIENCE sciencemag.org                                                                             16 APRIL 2021 • VOL 372 ISSUE 6539    227
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THE DREAM VACCINE WHY STOP AT JUST SARS-COV-2? VACCINES IN DEVELOPMENT AIM TO PROTECT AGAINST MANY CORONAVIRUSES AT ONCE - INSTITUTE FOR PROTEIN ...
NE WS | F E AT U R E S

SARS-CoV-2, NIAID and other funders have                       cines against beta coronaviruses, a family              10 to 50 years, we may have another out-
had a major change of heart. In November                       that now includes SARS-CoV-2.                           break like SARS-CoV-2,” says structural bio-
2020, the agency solicited applications for                      The threat of another coronavirus pan-                logist Andrew Ward of Scripps Research,
“emergency awards” to pursue pancorona-                        demic now seems very real. Beyond bats,                 one of the scientists who submitted the
virus vaccine development. And in March,                       coronaviruses infect camels, birds, cats,               2017 proposal NIAID rejected.
the Coalition for Epidemic Prepared-                           horses, mink, pigs, rabbits, pangolins, and               The agency has not given out any of its
ness Innovations (CEPI), an international                      other animals from which they could jump                new awards yet, but Ward’s lab is already
nonprofit launched in 2017, announced it                       into human populations with little to no                pursuing a vaccine targeting a subset of
would spend up to $200 million on a new                        immunity, as most researchers suspect                   beta coronaviruses. Some two dozen other
program to accelerate the creation of vac-                     SARS-CoV-2 did. “Chances are, in the next               research groups around the world have

Finding the best shot                                                                               Family matters
Aiming to prevent a future pandemic like COVID-19, scientists are looking                           Coronaviruses are grouped into four genera. They infect many species,
                                                                                                    although most have been found in bats. Of the seven known to infect people,
for ways to immunize people against many, if not all, coronaviruses. Several                        four cause mild colds and three can be lethal.
strategies for these pancoronavirus vaccines focus on spike, the surface                                                                                  Human      Bat
protein common to all members of the viral family.                                                            BETA        MERS-CoV

The crown’s jewel
                                                                                                    SARS-CoV-2
                                                                                                                                                                       ALPHA
Spike initiates an infection when part of

                                                                                                                                                                                                                                                       Downloaded from http://science.sciencemag.org/ on April 15, 2021
its head (S1) binds to a human cellular
receptor and a viral enzyme cleaves                       S1                                                              Sarbecoviruses
spike so its stem (S2) can fuse with the                                                             SARS-CoV
cell. Spike varies between coronaviruses             S2
and the most conserved regions of its
head or stem may serve as a broadly               Viral
protective vaccine.                               membrane                                                                            DELTA
                                                                                                                                                        GAMMA

                                                                                                                                                                                  CREDITS: (GRAPHIC) V. ALTOUNIAN/SCIENCE; (IMAGES) CASALINO ET AL., ACS CENT SCI., 6(10), 1722, (2020); CONSURF SERVER; 7K3J; FEIG LAB/6XDC; PAUL EHRLICH INSTITUTE;
Variable                       Conserved                                                                       RBD

                        N-terminal
                        domain

                                                                                                                                RBD

                                                                                                                                                                                  EUROPEAN MOLECULAR BIOLOGY LAB; MAX PLANCK INSTITUTE OF BIOPHYSICS; D. ELLIS/UW; PDB 6VXX; D. VEESLER/UW
                                                                                                                                                    +

                                                                                                                                                Designed proteins
                                              mRNA

Chimeric spike                                                                                                                                   RBD nanoparticles
A messenger RNA (mRNA)                                                                                                                           Because antibodies to
vaccine that combines                                                                                                                            spike’s receptor-binding
spike gene sequences from                                                                                                                        domain (RBD) may be
SARS-CoV, SARS-CoV-2,                                                                                                                            key to vaccine protection,
and other coronaviruses                                                                                                                          scientists are assembling
can produce a mix of                                                                                                                             RBDs from multiple
protein domains that                            Spi
                                                Spike                                                                                            coronaviruses
may confer broad                                                                                                                                 onto nanoparticles or
immune protection.                                                                                                                               into nanocages.

                                            Spikes

Whole virus                                                                                                                                      Serial vaccines
Vaccinemakers have long                                                                                                                          One pancoronavirus
used inactivated or weakened                                                                                                                     vaccine approach would
viruses. Combining multiple                                                                                                                      deliver a series of different
coronaviruses from one or                                      Viral membrane                                                    Spike head      spike proteins, each in its
more genera could stimulate                                                                                                                      natural trimer configuration
broader immune protection.                                                                                                                       on a carrier particle.

228                                                                                                                                              sciencemag.org SCIENCE

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THE DREAM VACCINE WHY STOP AT JUST SARS-COV-2? VACCINES IN DEVELOPMENT AIM TO PROTECT AGAINST MANY CORONAVIRUSES AT ONCE - INSTITUTE FOR PROTEIN ...
similar pancoronavirus vaccine projects        antibody complexes at atomic resolution—                 SARS-CoV-2 is here doesn’t mean that that’s
underway. Their approaches include novel       an increasingly popular technique called                 going to provide any kind of serious pro-
nanocages arrayed with viral particles,        cryo–electron microscopy (cryo-EM).                      tection against another sarbecovirus from
the cutting-edge messenger RNA (mRNA)             What resembles a telescope view of lunar              coming out of the zoonotic reservoirs,” he
technique at the heart of proven COVID-19      landscapes unfolds across four monitors.                 says. And if a “SARS-CoV-3” jumped into a
vaccines, and cocktails of inactivated vi-     Turner’s trained eye spots the crystallized              person infected with the current pandemic
ruses, the mainstay of past vaccines. A few    spike proteins, clumped together in groups               virus and created something more lethal
teams have even published promising re-        of three called trimers and studded with                 by swapping genetic regions—and corona-
sults from animal tests of early candidates.   antibodies. She points out one of the fan-               viruses frequently recombine—that’s the
   No pancoronavirus vaccine has entered       like structures. “It’s pretty cool,” she says.           making of a Hollywood horror film.
human trials, and how to evaluate a can-       “This is what you want to see.”
didate’s protection against diseases that         The computers over the next few days                  WARD AND OTHERS IN THIS nascent field are
have not yet emerged remains a challenge.      will sort through 1100 different angles of               following the lead of vaccine successes, for
Nor is it clear how such a vaccine might       her sample, migrating the best views into                diseases from polio to human papillomavi-
be used. One possibility: keeping it in re-    software that creates a gorgeous “final                  rus, that depend on combining components
serve until a new human threat emerges.        map” of spike with an attached antibody, at              from multiple forms of a pathogen—up
“We might be able to prime everybody to        a resolution that approaches 3 angstroms,                to 23 forms of a sugar molecule in a shot
get a basic level of immunity” against the     just a tad thicker than a strand of DNA.                 against pneumococcal disease, for exam-
emerging virus, buying time to make a          By creating similar portraits of spikes from             ple—to increase breadth of protection. Al-
more specific vaccine, Ward says.              many different coronaviruses with broadly                though Ward is still at the earliest stages
   Despite the many unknowns, the rapid        neutralizing antibodies bound to them,                   of the design process, trying to identify the

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success of vaccines against SARS-CoV-2         Ward hopes to identify short segments of                 conserved viral targets he wants a vaccine
has sparked optimism. This coronavirus         the protein—so-called epitopes—key to                    to hit, structural biologist Pamela Bjork-
doesn’t seem particularly difficult to foil    that binding for all the pathogens. Those                man at the California Institute of Technol-
with a vaccine, which raises hopes that the    epitopes, Ward believes, are the key to de-              ogy is a few steps further along. Her team
immune system can be trained to outwit         signing a vaccine that can trigger a broad               has recently evaluated candidate pancoro-
its relatives, too. Survivors of SARS years    immune attack on coronaviruses.                          navirus vaccines in mice.
ago provide more encouragement: Some of                                                                    Bjorkman and co-workers chose a por-
their antibodies—an immune memory of                                                                    tion of spike from a range of beta corona-
that viral encounter—can also stymie the            “Compared to flu and HIV,                           viruses: SARS-CoV and SARS-CoV-2, a vi-
infectivity of SARS-CoV-2 in lab dishes.
   NIAID’s Barney Graham, who helped de-
                                                        this is going to be                             rus isolated from a pangolin, and five bat
                                                                                                        viruses. They used each virus’ receptor-
velop Moderna’s mRNA COVID-19 vaccine,
shares the optimism about pancoronavirus
                                                 relatively easy to accomplish.”                        binding domain (RBD), the spike region
                                                                                                        that initiates an infection by docking onto
vaccines. “Compared to flu and HIV, this is                      Barney Graham,                         angiotensin-converting enzyme 2 (ACE2),
going to be relatively easy to accomplish,”     National Institute of Allergy and Infectious Diseases   a protein on human cells. The RBD is the
he predicts.                                                                                            apparent target for most antibodies that
                                                 An ideal pancoronavirus vaccine would                  thwart SARS-CoV-2.
EARLIER THIS YEAR, Hannah Turner, a tech-      protect us from all four of its genera—                     Comparisons of the RNA genes encod-
nician at Scripps Research who works with      alpha, beta, gamma, and delta—but most                   ing the spikes showed the top section of
Ward, took a cold, hard look at a now in-      researchers have more modest goals. “The                 the RBD varied a great deal, but the lower
famous protein: SARS-CoV-2’s spike, which      further you go, the harder it gets” for a vac-           part was conserved across the different vi-
enables the virus to infect cells and is at    cine, says immunologist Dennis Burton of                 ruses. So the investigators fashioned eight
the heart of several successful COVID-19       Scripps Research, who often collaborates                 multimers—small proteins—from the con-
vaccines. All coronaviruses have these         with Ward.                                               served RNA sequences. Then, they fastened
spikes, which create the distinctive crown-      Gamma and delta coronaviruses, mainly                  combinations of them onto the surface of
like appearance that earned them their         found in birds and pigs, are not known to                a nanoparticle built from a bacterial pro-
name, and most pancoronavirus vaccine          infect humans, so vaccine developers have                tein to create various “mosaic” vaccines. In
efforts aim to rouse an immune response        paid them little attention. There’s more in-             theory, a mosaic would produce antibodies
to some part of the spike protein.             terest in alpha coronaviruses because two                that protected against the known viruses—
   On this February morning, Turner mixes      cause colds in humans. But it’s the betas                and because the sequences are conserved,
labmade copies of the SARS-CoV-2 spike         that attract the most effort, and in partic-             the vaccine might protect against distant
with “broadly neutralizing” antibodies         ular the sarbecoviruses, a subset that in-               relatives of those viruses as well.
harvested from COVID-19 patients. These        cludes SARS-CoV-2 and SARS-CoV but not                      Last year, Bjorkman and colleagues in-
antibodies powerfully prevent multiple         the more genetically distinct MERS and its               jected mice with some of their mosaic vac-
variants of SARS-CoV-2, as well as the         relatives. Sarbecoviruses are Ward’s tar-                cines. They report in the 12 February issue
original SARS virus, SARS-CoV, from in-        gets, and Burton is optimistic. “We already              of Science that in lab dishes, antibodies
fecting susceptible cells in test tube stud-   know you can get pretty damn good anti-                  harvested from the mice powerfully neu-
ies. Turner then freezes the spike-antibody    bodies that work against both SARS-CoV                   tralized the infectivity of a wide array of
mixtures with liquid nitrogen and places       and -2,” he says.                                        sarbecoviruses, including ones not used to
the resulting crystals in a $4 million mi-       Ralph Baric of the University of North                 make the vaccine.
croscope the size of three refrigerators. It   Carolina, Chapel Hill, who has studied                      Graham, who worked on pancorona-
begins bombarding the samples with up to       coronaviruses for 35 years, sees this sub-               virus vaccines even before the pandemic,
200 kilovolts of electrons to map the spike-   group as the paramount threat. “That                     reasons that the whole trimer of spike

SCIENCE sciencemag.org                                                                                         16 APRIL 2021 • VOL 372 ISSUE 6539   229
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THE DREAM VACCINE WHY STOP AT JUST SARS-COV-2? VACCINES IN DEVELOPMENT AIM TO PROTECT AGAINST MANY CORONAVIRUSES AT ONCE - INSTITUTE FOR PROTEIN ...
NE WS | F E AT U R E S

might stimulate better or broader immune            Along with calculated strategies, luck       protects mice from the virus as effectively
protection than just the RBDs. His team          can also aid the quest for a pancorona-         as vaccines that feature the full spike.
has taken spike trimers from SARS-CoV-2          virus vaccine. Barton Haynes and his team       The antibodies produced by the vaccine
and two beta coronaviruses that cause hu-        at Duke University, working with Baric’s        also bind to, but do not neutralize, SARS-
man colds and placed them in malleable           group, recently designed a vaccine that         CoV, SARS-CoV-2, and a human cold beta
nanocages, made from two different pro-          contains a SARS-CoV-2 RBD in a ferritin         coronavirus. McLellan’s lab is now conduct-
teins developed by computational biologist       nanoparticle. Intended as a booster dose        ing cryo-EM of antibody-stem conjugates,
Neil King of the University of Washington        for mRNA COVID-19 vaccines, it turned           using S2 from SARS-CoV-2, to develop a
(UW), Seattle. The NIAID group is also           out to be far more versatile. In monkeys,       vaccine for beta coronaviruses. “Our initial
using a second scaffolding: nanoparticles        it worked as intended against SARS-CoV-2.       immunogens target all of S2, but we might
created from ferritin, a blood protein that      But much to the researchers’ surprise, anti-    want to refine that and target smaller por-
normally sequesters and releases iron.           bodies taken from the vaccinated monkeys        tions,” McLellan says.
    In a third strategy, Graham envisions        also neutralized SARS-CoV and two related          Like most developers of a pancorona-
giving people a series of vaccines, each one     bat coronaviruses in lab studies.               virus vaccine, McClellan is trying to rally
containing trimers from a different mem-                                                         antibody-producing B cells. A few groups,
ber of the beta genus, to create a broad                                                         however, hope to also rouse the immune
defense against the viruses. “It’s what we        “Chances are, in the next 10 to                system’s other great army: T cells, which
do right now for influenza, basically, only                                                      protect the body by destroying infected
it is occurring over a lifetime instead of        50 years, we may have another                  cells. On 18 May 2020 in Nature, Vir Bio-
more deliberately in a shorter period of
time,” he says. (The flu shot contains sur-
                                                   outbreak like SARS-CoV-2.”                    technology working with UW structural
                                                                                                 biologist David Veesler described an anti-

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face proteins from three or four strains of             Andrew Ward, Scripps Research            body, isolated from someone who had
that virus, and as it mutates, vaccinemak-                                                       SARS in 2003, that neutralized infectivity
ers change the ingredients annually.)               A clue to this surprisingly broad protec-    of both SARS-CoV and SARS-CoV-2—but
    By arraying spike proteins on nanopar-       tion came when the team isolated an anti-       with help from T cells.
ticles, vaccine developers aim to follow the     body from a person who had recovered               Although the antibody binds to the
style of upscale restaurants, where pre-         from SARS many years ago. It, too, could        RBDs of spike of each virus, it does not
sentation matters nearly as much as the          neutralize a wide range of sarbecoviruses—      block them from attaching to ACE2, cryo-
food on the plate. The goal is to cater to       and it turned out to bind tightly to the        EM showed. The groups instead found it
the tastes of B cells, the immune cells that     same RBD used in their COVID-19 vaccine         may bind to the surface of immune war-
pump out antibodies. The cells identify          booster. A structural analysis of the anti-     riors that educate T cells to destroy already
foreigners using Y-shaped proteins called        body bound to the RBD shows it latches          infected cells. This “vaccinal effect” was
immunoglobulins on their surfaces. (When         onto the domain’s side, not the top region      first described more than 15 years ago in
secreted, the same proteins are antibod-         favored by most vaccine-induced neutral-        cancer research when scientists found that
ies.) B cells respond most strongly when         izing antibodies.                               certain monoclonal antibodies can trigger
each arm attaches to a different epitope.           Because this antibody doesn’t interfere      killer T cells to eliminate tumors.
King says nanocages are ideal for present-       with ones that attach to the top, Haynes           T cells are also central to the vaccine
ing epitopes this way. “We can control           thinks a vaccine designed to trigger it and     quest of Bette Korber, a computational
spacing and geometry [of the viral pieces]       more common neutralizing antibodies             biologist at Los Alamos National Labora-
in a much more precise way than anybody          could provide a one-two punch to multiple       tory. She designs algorithms to scour the
could before,” he says.                          viruses. He expects clinical trials of this     genome sequences of beta coronaviruses,
    The resulting B cell cross-linking primes    idea could begin within 6 months.               looking for regions of viral proteins that
legions of the cells to spit out what re-                                                        can trigger T cell responses, and that vary
searchers have dubbed “superantibodies”          SOME GROUPS HAVE TURNED their sights far        little among the different coronaviruses.
for their remarkably high potency. These         from the RBD, in molecular terms. Spike         Those conserved T cell epitopes, Korber
superantibodies add to a vaccine’s breadth       has both a head, which includes the RBD,        says, might make a good vaccine.
of protection because even when they             and a stem—known as S2—that varies little          She hopes to initially combine this T cell
aren’t a perfect match to a strain, they still   between coronaviruses. “The S2 subunit          approach with a B cell strategy that would
retain some neutralizing activity.               is by far the most conserved portion of         protect against all SARS-CoV-2 variants. It
    Baric’s group is exploring a different       coronavirus spike,” says Jason McLellan,        draws on an analysis of close to 1 million
way to present diverse antigens. Rather          a structural biologist at the University of     sequences of the virus now in databases
than arranging them on scaffolds, the team       Texas, Austin, who co-authored the failed       to understand the “evolutionary space” of
uses mRNA coding for a chimeric protein          grant proposal with Ward.                       the pathogen—what changes could help it
that mixes and matches different parts of           After spike lands on a human cellular re-    evade antibody responses and what muta-
spike from distant human and bat sarbeco-        ceptor, a coronavirus enzyme slices off the     tions it cannot afford.
virus cousins. “Spike is really plastic, so      head, or S1, to expose the stem. That then,          “You need to show the immune system
it’s kind of a modular design,” Baric says.      yes, spikes the cell and initiates the fusion   what it needs to recognize to have breadth,”
“You can move component parts around             that allows the virus to unload its genetic     says Korber, who has applied similar tech-
without any problem.” Four of these mRNA         cargo. Immune responses against S2 can          niques to designing vaccines for HIV, flu, and
spike chimeras solidly protected mice from       derail that key process, even though the        Ebola. Her collaborators plan to convert the
a variety of challenges with human and           stem isn’t always visible enough normally       sequences she selects into mRNA vaccines.
bat sarbecoviruses, Baric, Hayes, and col-       to initiate them.                                  Finally, there’s an old-school approach
leagues reported in a bioRxiv preprint              A few years ago, McLellan developed a        to a pancoronavirus vaccine, one that
posted on 12 March.                              vaccine from the S2 of the MERS virus that      should call into battle both B and T cells.

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                            Structural biologist Andrew Ward studies the nooks and crannies of a coronavirus spike protein for features common to spikes in other members of the virus family.

                            NIAID’s veteran flu researchers Matthew                   few that has the biosecurity needed to grow               protect against the menacing new variants
                            Memoli and Jeffery Taubenberger want to                   and experiment with those coronaviruses.                  of SARS-CoV-2 that keep emerging.
                            combine inactivated versions of represen-                    Another regulation could ease the path.                   Efforts have already begun to develop
                            tative coronaviruses from the four known                  Created by the U.S. Food and Drug Adminis-                second generation COVID-19 vaccines
                            lineages in the beta genus. Vaccines based                tration in the wake of 9/11, when there was               that could protect against those variants.
                            on the entire virus help the immune system                increased worry about engineered viruses                  But Haynes says this is a game of “whack-
                            take “multiple shots at the target,” Memoli               or other biothreats, the “animal rule” says               a-mole” that has no end in sight. “You’re
                            explains, rather than focusing all the re-                a therapy or vaccine can receive approval                 just waiting on the next variant to come
                            sponses on spike or bits of it.                           without an efficacy trial if the study cannot             up.” He and others instead propose that a
                               “Some antigens give you antibodies,                    ethically or practically be done in humans.               pancoronavirus vaccine could do double
                            some antigens may give you more T cell re-                A pancoronavirus vaccine might establish                  duty. If it can handle other members of the
                            sponses, some antigens may do both. Some                  its bona fides under that rule if it works in             coronavirus family tree, it should have no
                            antigens may be better at inducing muco-                  mice or monkey challenge studies against                  problem dealing with variations of SARS-
                            sal immunity than systemic immunity,” he                  a variety of known coronaviruses, appears                 CoV-2, which are minor in comparison.
                            says. “The reality is that the best vaccine is            safe in humans, and is capable of triggering                 “Over time, it may be that the boosting
                            going to deliver antigens that induce all of              broadly neutralizing antibodies or other rel-             will be with a vaccine that is more broadly
                            these responses.”                                         evant immune responses in people.                         protective,” says Luciana Borio, who led
                                                                                         If a pancoronavirus vaccine gets autho-                a White House unit on medical and bio-
                            HOW CAN DEVELOPERS of pancoronavirus                      rized, would countries create stockpiles to               defense preparedness and now works for a
                            vaccines prove their shots protect against a              quickly extinguish an outbreak of a new vi-               venture capital firm, In-Q-Tel, whose portfo-
                            hypothetical SARS-CoV-3? Baric highlights                 rus? Or would they instead plan to rapidly                lio includes biotech companies.
                            one hurdle: “You have to have a good panel                start to produce the vaccine from its blue-                  That might help end the current pan-
PHOTO: JONATHAN L. TORRES

                            of challenge viruses to actually begin to test            print once that fresh threat is seen? Those               demic and forestall the next one. “A
                            these vaccines” in the lab. The U.S. govern-              are issues CEPI’s initiative will explore,                broadly protective vaccine has the goal of
                            ment considers SARS-CoV, MERS, and many                   but there’s a third, simpler option many in               preventing a pandemic from happening,”
                            coronaviruses to be “select agents,” subject-             the field propose: using it in the current                Memoli says. “The issue we have is right
                            ing labs that handle them to greater restric-             pandemic, as the ultimate booster shot to                 now is if a completely new virus appears,
                            tions. Baric notes that his lab is one of the             prevent potentially waning immunity and                   we have nothing.” j

                            SCIENCE sciencemag.org                                                                                                       16 APRIL 2021 • VOL 372 ISSUE 6539      231
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THE DREAM VACCINE WHY STOP AT JUST SARS-COV-2? VACCINES IN DEVELOPMENT AIM TO PROTECT AGAINST MANY CORONAVIRUSES AT ONCE - INSTITUTE FOR PROTEIN ...
The dream vaccine
Jon Cohen

Science 372 (6539), 227-231.
DOI: 10.1126/science.372.6539.227

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