[From building up defenses in the nose to slowing down a virus’s
ability to make copies of itself, scientists are rolling out a raft of
creative approaches to fighting infection]
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WHAT NEXT-GEN COVID-19 VACCINES MIGHT LOOK LIKE  
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Bob Holmes
November 3, 2022
Knowable Magazine
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_ From building up defenses in the nose to slowing down a virus’s
ability to make copies of itself, scientists are rolling out a raft of
creative approaches to fighting infection _

Vaccine developers are working on several new types of Covid
vaccines, including nasal vaccines, that they expect to be more
effective against a wider range of variants, credit: Knowable Magazine


 

Nearly two years after the advent of vaccines against Covid-19, the
pandemic is still, frustratingly, with us. The vaccines have done an
excellent job at their primary mission, preventing severe disease or
death. But they haven’t been as effective at keeping people from
catching and spreading the virus — partly because SARS-CoV-2 has
become more contagious, and partly because it is evolving to dodge the
vaccines.

That’s why experts are excited about a crop of novel vaccines now
under development. All require more testing before they’re ready for
use in people. But if they perform as hoped, some of them will be much
better at stopping the virus from spreading. Others could provide
lasting immunity toward many different strains of the virus — and
possibly toward a wider range of coronaviruses, perhaps including some
found in animals that are likely candidates for the next emerging
disease. Still others could make vaccinations more convenient — and
improve vaccination rates — by delivering multiple boosters in a
single injection.

Here’s what’s on the vaccine horizon:

Live-attenuated vaccines

One way to build a more effective vaccine is to give the immune system
more to chew on. The Covid vaccines currently in use train the immune
system to recognize and attack just a single part of the virus: the
spike protein on the virus’s surface. That has proved problematic,
because the spike protein mutates easily, and newer variants aren’t
attacked as forcibly by an immune system trained to recognize older
forms of the protein.

Using the whole, live virus — weakened so it can no longer cause
disease — may work better. “A live vaccine mimics the virus.
It’s like you’ve had Covid, but you don’t get sick,” says
Robert Coleman, a virologist and CEO of Codagenix
[[link removed]], a biotech company in Farmingdale, New York.
“Not only are you making antibodies to the spike but to all the
other proteins of the virus, and you’re making immune cells that
recognize the proteins.”

Such live-attenuated vaccines have been around for many years, and
include the familiar, highly effective chickenpox, smallpox and
measles/mumps/rubella vaccines. But until now, the only way to produce
a weakened virus has been to laboriously infect cultured cells,
generation after generation, selecting the least pathogenic viral
lineages each time. That’s time-consuming and runs a slight risk
that the virus could later mutate back to a more aggressive form,
which is a rare complication seen with the old oral polio vaccine.

Codagenix avoids that labor and risk by exploiting a quirk of the
genetic code. The genome of every organism, including viruses, uses
three-letter “words,” or codons, to specify which amino acid to
add next when building a protein. Usually, several different codons
can specify the same amino acid — and cells such as our own are more
adept at using some codon sequences than others.

Codagenix takes advantage of this by deliberately swapping in
less-favored codons at 283 different spots in the viral genome. Each
individual change has only a tiny effect, but together they slow viral
replication to less than 10 percent of normal — enough that the
host’s immune system can keep the virus from causing disease.
“It’s death by a thousand cuts,” Coleman says.

Yet the weakened virus produces exactly the same proteins as wild
SARS-CoV-2, thus generating a protective immune response. And with 283
different changes to reverse, Coleman says, the chance that the virus
could revert to a more pathogenic form is nearly nil.

In early-stage human trials that measured the ability to trigger
antibodies and immune cells, the Codagenix live-attenuated vaccine,
given as nasal drops, produced a strong response with good safety.
And, promisingly, volunteers who received the vaccine in mid-2021 —
before the emergence of the Omicron variant — produced immune cells
that recognized and attacked Omicron, even though they had never been
exposed to it. This suggests that the Codagenix vaccine produces a
more broadly protective immune response
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other vaccines, presumably because it offers more points for the
immune system to recognize, says Coleman.

The company has just begun the final stage of testing, a phase 3
clinical trial in up to 20,000 people, and vaccine experts such as
Jerome Kim, director general of the International Vaccine Institute in
Seoul, South Korea, are watching with interest. If all goes well, the
vaccine should be ready for market sometime next year, Coleman says.

Needle-free vaccines

Most people dislike getting a needle in their arm, so the idea of
getting a vaccine in a puff of nasal spray sounds attractive right
away. But intranasal vaccines have an even bigger advantage. It turns
out that they may also be better at preventing respiratory viruses
from spreading between people.

That’s because presenting a vaccine to the soft, moist tissues of
the nose and airways — the mucosa — induces a different kind of
immune response, one that’s concentrated not in the bloodstream but
in the mucosal tissues themselves, where the virus that causes Covid
enters the body. Immunologists don’t fully understand this mucosal
immune response yet, but they hope that by gathering defenses at the
virus’s point of attack, the body may neutralize the virus before it
can cause an infection, rather than just reducing an infection’s
severity.

“If you’re at a nightclub, you have security guards inside that
keep people in order, but you also have bouncers outside to keep
unruly people from entering in the first place,” says Jen Gommerman
[[link removed]], an
immunologist at the University of Toronto who studies mucosal
immunity.

The mucosal immune response — the bouncers — seems to involve a
two-pronged approach. Immune cells (B cells, T cells and others)
trained to recognize an invader concentrate in mucosal tissue where
they can defend the perimeter. But in addition, some of the B cells
secrete an unusual class of antibody, known as IgA, into the mucus
layer on the surface of the airways where they can act like bouncers.

The more familiar antibodies that dominate in the blood — the inside
guards, known as IgG — are roughly Y-shaped, with each arm of the Y
able to grab onto a recognition point, or antigen, on the virus. An
IgA, in contrast, comes in pairs stuck together at the base of the Y.
“It looks like a dog bone,” says Gommerman. “Instead of two
binding sites, it’s got four.” That’s one reason IgA should be
better able to latch onto viral antigens before the virus enters cells
of the body, she says.

Ordinary vaccines given through a needle aren’t good at producing
mucosal immunity — but natural infections are. In one recent study,
for example, researchers compared 10 people who were recovering from
natural Covid infections and 19 volunteers who had received standard
intramuscular vaccines. The former group had significantly more
anti-Covid IgA antibodies in their airways
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scientists found, though the study did not show that this translated
into better protection.

That sounds promising, but nasal vaccines face formidable technical
challenges. The mucosal tissues of the airways are built to repel
invaders. A nasal vaccine would have to penetrate the slimy mucus
layer lining the airways before it could enter the body, while
intramuscular vaccines bypass those defenses with a needle.

One solution is to use live viruses in the vaccine, as Codagenix does,
since they have evolved to evade host defenses. But live-attenuated
vaccines can be risky for people with weakened immune systems.

Another way around the mucosal defense problem could be to use a nasal
vaccine as a booster after initial doses of standard intramuscular
vaccines. The shots in the arm don’t produce a strong mucosal
response themselves, but they would prime the immune system to respond
vigorously to even tiny quantities of the booster that get past the
mucus, says Akiko Iwasaki [[link removed]],
an immunologist at Yale University who wrote about  mucosal immunity
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the 2016  _Annual Review of Immunology_.

Iwasaki’s team has tested this in mice, using a single injected
priming dose of mRNA vaccine (the familiar Pfizer vaccine in standard
use today). Then they followed it up with a nasal booster consisting
of SARS-CoV-2 spike protein, instead of an injected second dose. The
approach generated high levels of mucosal antibodies and immune cells
[[link removed]], her group
found, whereas two intramuscular doses of the Pfizer vaccine produced
only the normal, blood-borne response. The nasal booster also better
protected the animals against severe disease.

The biotech company Vaxart is testing another mucosal vaccine — this
one given in pill form, another way of inducing mucosal immunity —
against the Covid virus. In early clinical trials, the vaccine
generated antibodies against SARS-CoV-2, especially when given as a
booster after a standard mRNA vaccine. Best of all, the
immunity seems to cover a wide range of Covid variants, including
Omicron
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that standard vaccines are less effective against.

In theory, the antibodies from this mucosal immune response should
block viruses from entering the body, and it could also capture
viruses as they are being shed by infected cells. Both should reduce
the rate of viral transmission.

However, no studies have directly verified this so far for any
respiratory virus. And people previously infected by Covid-19 can
still get reinfected later, so natural mucosal immunity is clearly not
enough to block transmission completely, says Maria Elena Bottazzi
[[link removed]], a vaccine
researcher at Baylor College of Medicine and codirector of Texas
Children’s Center for Vaccine Development. Moreover, one attempt at
nasal vaccination, using AstraZeneca’s version of the Covid vaccine,
failed to provide immunity in a clinical trial, researchers announced
in early October.

On the other hand, volunteers who received the Codagenix
live-attenuated nasal vaccine had no detectable virus in their airways
after their second dose, says Coleman. Since the vaccine itself
delivered live viruses to the nose, this suggests that airway cells
infected by the vaccine virus were not shedding much.

Nasal vaccine technology is still relatively new, and researchers may
find ways to enhance the effects. “There’s still a lot to do to
understand mucosal immunity,” Bottazzi says. “We haven’t seen
any mucosal vaccines that have been stellar — but that doesn’t
mean it’s not going to work for coronaviruses.”

Broad-spectrum vaccines

In the last two decades, three serious coronavirus diseases have
emerged in the human population: SARS in 2002-03 and MERS in 2012 —
both of which fizzled — and Covid-19, which caused a global
pandemic. Public health experts say that there are more coronaviruses
coming. And so vaccine researchers are working hard to come up with
broad-spectrum vaccines that could protect against a wide range of
known and unknown coronaviruses, including those that caused the SARS
and MERS outbreaks. Even if they’re not perfect, such vaccines could
also help tame new variants of SARS-CoV-2, which have proved better at
evading current vaccines.

“Coronaviruses are still going to be out there, so we need to look
for strategies that broaden protection,” says Bottazzi.

One way to build a broad-spectrum vaccine is to collect antigens from
several different coronaviruses and combine them into a single
vaccine. In its simplest form, that’s what the recently approved
bivalent Covid vaccine does, by combining spike proteins from the
original virus and the Omicron variant to make a shot that responds to
both.

Pushing this approach further, virologist Ralph Baric
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University of North Carolina is building synthetic spike proteins that
combine parts from as many as three different sarbecoviruses — the
subset of coronaviruses that includes SARS and Covid viruses, and some
potentially nasty viruses of bats and other animals. Baric hopes to
create a vaccine that protects against all three. A second dose —
built from three other coronaviruses — could extend coverage still
further against current and future threats such as MERS. He’s
testing the strategy in animals now, in partnership with research
teams working with a variety of vaccine systems.

Other researchers are trying an alternative approach to a
broad-spectrum vaccine: searching through genome sequences of a
variety of coronaviruses to identify parts of the genome that are the
same in most or all.

One good candidate is a stretch of DNA within the gene that codes for
the spike protein. This stretch carries instructions for making the
fusion peptide, the portion of the spike that helps the virus merge
with the membrane of the cell it’s invading. The fusion peptide is
crucial to the virus’s ability to infect someone — and,
importantly, “it doesn’t change,” says Steven Zeichner
[[link removed]], a vaccine
researcher at the University of Virginia. “There are six amino acids
in that fusion peptide that are completely invariant across every
single coronavirus that’s ever been sequenced.” The sequences that
flank the unchanging region are also very similar among all
coronaviruses.

Zeichner and his colleagues are genetically modifying _E.
coli_ bacteria so that they display the virus’s fusion peptide on
their cell surface. These bacteria — killed by formaldehyde — form
the basis of his vaccine. Such killed, whole-cell bacterial vaccines
are common and effective for bacterial diseases such as cholera and
pertussis, but Zeichner’s is unusual in using the bacteria to
vaccinate against a viral disease.

In tests on pigs, a vaccine using the fusion peptide from either
SARS-CoV-2 or a distantly related pig coronavirus protected the
animals against the pig virus
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hint that the fusion peptide vaccine could work against a wide range
of coronaviruses. Zeichner’s team is now working on several ways to
tweak the fusion peptide antigen to enhance the vaccine’s potency.
“I think we’re pretty close,” he says. Given enough money, he
adds, he could probably have a vaccine ready to test in humans within
a few months.

In another effort, Mohamad-Gabriel Alameh, a vaccine developer at the
University of Pennsylvania, and his colleagues are developing vaccines
that contain several different SARS-CoV-2 antigens, including several
variants of the spike as well as some other proteins that don’t
change much in a variety of coronaviruses. Having several antigens
displayed on a single virus-like particle seems to activate immune
cells more strongly and enhance both the potency of the immune
response and the range of viruses it protects against, he says. An
early test using just two antigens — the spike and another viral
protein called the nucleoprotein — outperformed spike-only vaccines
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hamsters, the team reported. Alameh hopes to begin testing in people
in January.

Vaccine developers can also add other ingredients, known as adjuvants
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to vaccines to tweak the immune system’s response, says Christopher
Fox, a vaccine adjuvant developer at the Access to Advanced Health
Institute in Seattle. “We’ve spent a lot of time working on
adjuvant formulations that can shape the immune response to make it
more potent, but also broader and more durable,” he says.

Promising as these broad-spectrum vaccines are, a lot of work remains
before they’re ready for use, and many vaccines that show promise in
animal tests never pan out in people. The step is such a big one that
vaccine researchers sometimes talk about the “Valley of Death”
between animal research and human trials, says Kim of the
International Vaccine Institute. Even in the best-case scenario, the
first broad-spectrum vaccine probably won’t be in clinics for
another year or two, he thinks.

Self-boosting vaccines 

Many vaccines, including most of those for Covid-19, require two or
more doses to amp up the immune system enough to give full protection.
That poses a public health problem, because in many parts of the
world, people can’t or won’t get timely boosters as recommended by
public health officials. This is one reason the virus has been able
to evolve new variants
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readily.

One solution could be to deliver the boosters at the same time as the
initial dose, but in a form that will delay the release of the
boosters to the appropriate time. Recently, researchers at the
Massachusetts Institute of Technology reported a way to do just
that. 

The team encapsulates the booster doses in tiny boxes, smaller than a
grain of sand, made from a material similar to that used for
dissolving surgical sutures, then injects them along with the primary
vaccine dose. “By changing the chemistry of these materials, you can
change the degradation,” says Ana Jaklenec
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leads the team. The boxes slowly break down until, at a certain point,
the lid suddenly falls off to  release the contents in a single burst
weeks or months after injection
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boxes may be needed for each dose, but all of these can be designed to
release their contents nearly simultaneously, in an unusually precise
form of time-release. 

Jaklenec is now testing a self-boosting Covid vaccine using her
approach in lab animals, and she hopes that human trials can begin
within a year or two. The approach could also be useful for other
vaccines that require multiple injections. 

With these and other novel vaccines on the horizon, public health
officials may have a variety of options available in the next few
years — nasal and broad-spectrum vaccines to reduce the spread of
existing and future variants, new applications of familiar
technologies like live-attenuated and bacteria-based vaccines, and
self-boosting jabs for hard-to-reach people. Having multiple arrows in
the vaccine quiver might give officials more flexibility in fighting
an ever-changing virus, experts say. “I think,” says Bottazzi,
“it’s going to have to be a combination strategy.”

10.1146/knowable-110322-1

BOB HOLMES is a fully vaccinated and boosted science writer in
Edmonton, Canada.

This article originally appeared in _Knowable Magazine_
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endeavor from Annual Reviews. Sign up for the newsletter
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