Nanoparticle vaccine protects against a spectrum of COVID-19-causing variants and related viruses
California Institute of Technology
Betacoronaviruses, including those that caused the SARS, MERS, and COVID-19 pandemics, are a subset of coronaviruses that infect humans and animals. The vaccine works by presenting the immune system with pieces of the spike proteins from SARS-CoV-2 and seven other SARS-like betacoronaviruses, attached to a protein nanoparticle structure, to induce the production of a broad spectrum of cross-reactive antibodies.
Notably, when vaccinated with this so-called mosaic nanoparticle,
animal models were protected from an additional coronavirus, SARS-CoV, that was
not one of the eight represented on the nanoparticle vaccine.
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| This infographic illustrates the new vaccine, composed of RBDs from eight different viruses. The table shows the broad spectrum of SARS-CoV-2 variants and related coronaviruses that the vaccine induces protection against.Credit: Courtesy of Wellcome Leap, Caltech, and Merkin Institute |
"Animals vaccinated with the mosaic-8 nanoparticles elicited antibodies that recognized virtually every SARS-like betacoronavirus strain we evaluated," says Caltech postdoctoral scholar Alexander Cohen (PhD '21), co-first author on the new study. "Some of these viruses could be related to the strain that causes the next SARS-like betacoronavirus outbreak, so what we really want would be something that targets this entre group of viruses. We believe we have that."
The
research appears in a paper in the journal Science on July 5.
"SARS-CoV-2
has proven itself capable of making new variants that could prolong the global
COVID-19 pandemic," says Bjorkman, who is also a Merkin Institute
Professor and executive officer for Biology and Biological Engineering.
"In addition, the fact that three betacoronaviruses -- SARS-CoV, MERS-CoV,
and SARS-CoV-2 -- have spilled over into humans from animal hosts in the last
20 years illustrates the need for making broadly protective vaccines."
Such
broad protection is needed, Bjorkman says, "because we can't predict which
virus or viruses among the vast numbers in animals will evolve in the future to
infect humans to cause another epidemic or pandemic. What we're trying to do is
make an all-in-one vaccine protective against SARS-like betacoronaviruses
regardless of which animal viruses might evolve to allow human infection and
spread. This sort of vaccine would also protect against current and future
SARS-CoV-2 variants without the need for updating."
How
it works: A vaccine composed of spike domains from eight different SARS-like
coronaviruses
The
vaccine technology to attach pieces of a virus to protein nanoparticles was
developed initially by collaborators at the University of Oxford. The basis of
the technology is a tiny cage-like structure (a "nanoparticle") made
up of proteins engineered to have "sticky" appendages on its surface,
upon which researchers can attach tagged viral proteins. These nanoparticles
can be prepared to display pieces of one virus only ("homotypic"
nanoparticles) or pieces of several different viruses ("mosaic"
nanoparticles). When injected into an animal, the nanoparticle vaccine presents
these viral fragments to the immune system. This induces the production of
antibodies, immune system proteins that recognize and fight off specific
pathogens, as well as cellular immune responses involving T lymphocytes and
innate immune cells.
In
this study, the researchers chose eight different SARS-like betacoronaviruses
-- including SARS-CoV-2, the virus that has caused the COVID-19 pandemic, along
with seven related animal viruses that could have potential to start a pandemic
in humans -- and attached fragments from those eight viruses onto the
nanoparticle scaffold. The team chose specific fragments of the viral
structures, called receptor-binding domains (RBDs), that are critical for
coronaviruses to enter human cells. In fact, human antibodies that neutralize
coronaviruses primarily target the virus's RBDs.
The
idea is that such a vaccine could induce the body to produce antibodies that
broadly recognize SARS-like betacoronaviruses to fight off variants in addition
to those presented on the nanoparticle by targeting common characteristics of
viral RBDs. This design comes from the idea that the diversity and physical
arrangement of RBDs on the nanoparticle will focus the immune response toward
parts of the RBD that are shared by the entire SARS family of coronaviruses,
thus achieving immunity to all. The data reported in Science today demonstrates
the potential efficacy of this approach.
Designing
experiments to measure the vaccine's protection in mice
The
resulting vaccine (here dubbed mosaic-8) is composed of RBDs from eight
coronaviruses. Previous experiments led by the Bjorkman lab showed that
mosaic-8 induces mice to produce antibodies that react to a variety of
coronaviruses in a lab dish (Cohen et al., 2021, Science). Led by Cohen, the
new study aimed to build from this research to see if vaccination with the
mosaic-8 vaccine could induce protective antibodies in a living animal upon
challenge (in other words, infection) with SARS-CoV-2 or SARS-CoV.
The
team aimed to compare how much protection against infection was provided by a
nanoparticle covered in different coronavirus fragments (mosaic-8) versus a
nanoparticle covered in only fragments of SARS-CoV-2 (a "homotypic"
nanoparticle).
The
team conducted three sets of experiments in mice. In one, the control, they
inoculated mice with just the bare nanoparticle cage structure without any
virus fragments attached. A second group of mice were injected with a homotypic
nanoparticle covered only in SARS-CoV-2 RBDs, and a third group was injected
with mosaic-8 nanoparticles. One experimental goal was to see if inoculation
with mosaic-8 would protect the animals against SARS-CoV-2 to the same degree
as the homotypic SARS-CoV-2-immunized animals; a second goal was to evaluate
protection from a so-called "mismatched virus" -- one that was not
represented by an RBD on the mosaic-8 nanoparticle.
Notably,
the eight strains of coronavirus covering the mosaic nanoparticle intentionally
did not include SARS-CoV, the virus that caused the original SARS pandemic in
the early 2000s. Thus, the team aimed to also investigate the degree of
protection against a challenge with the original SARS-CoV virus, using it to
represent an unknown SARS-like betacoronavirus that could spill over into
humans.
The
mice used in the experiments were genetically engineered to express the human
ACE2 receptor, which is the receptor on human cells that is used by SARS-CoV-2
and related viruses to gain entry into cells during infection. In this animal
challenge model, unvaccinated mice die if infected with a SARS-like
betacoronavirus, thus providing a stringent test to evaluate the potential for
protection from infection and disease in humans.
Mosaic
vaccine protects mice against a similar SARS-like betacoronavirus
As
expected, mice inoculated with the bare nanoparticle structure did die when
infected with SARS-CoV or SARS-CoV-2. Mice that were inoculated with a
homotypic nanoparticle only coated in SARS-CoV-2 RBDs were protected against
SARS-CoV-2 infection but died upon exposure to SARS-CoV. These results suggest
that current homotypic SARS-CoV-2 nanoparticle vaccine candidates being
developed elsewhere would be effective against SARS-CoV-2 but may not protect
broadly against other SARS-like betacoronaviruses crossing over from animal
reservoirs or against future SARS-CoV-2 variants.
However,
all of the mice inoculated with mosaic-8 nanoparticles survived both the
SARS-CoV-2 and SARS-CoV challenges with no weight loss or other significant
pathologies.
Nonhuman
primate research also confirms the mosaic vaccine's efficacy
The
team then performed similar challenge experiments in nonhuman primates, this
time using the most promising vaccine candidate, mosaic-8, and comparing the
effects of mosaic-8 vaccination versus no vaccination in animal challenge
studies. When inoculated with mosaic-8, the animals showed little to no
detectable infection when exposed to SARS-CoV-2 or SARS-CoV, again
demonstrating the potential for the mosaic-8 vaccine candidate to be protective
for current and future variants of the virus causing the COVID-19 pandemic as
well as against potential future viral spillovers of SARS-like
betacoronaviruses from animal hosts.
Importantly,
in collaboration with virologist Jesse Bloom (PhD '07) of the Fred Hutchinson
Cancer Research Center, the team found that antibodies elicited by mosaic-8
targeted the most common elements of the RBDs across a diverse set of other
SARS-like betacoronaviruses -- the so-called "conserved" part of the
RBD -- thus providing evidence for the hypothesized mechanism by which the
vaccine would be effective against new variants of SARS-CoV-2 or animal
SARS-like betacoronaviruses. By contrast, homotypic SARS-CoV-2 nanoparticle
injections elicited antibodies against mainly strain-specific RBD regions,
suggesting these types of vaccines would likely protect against SARS-CoV-2 but
not against newly arising variants or potential emerging animal viruses.
As
a next step, Bjorkman and colleagues will evaluate mosaic-8 nanoparticle
immunizations in humans in a Phase 1 clinical trial supported by the Coalition
for Epidemic Preparedness Initiative (CEPI). To prepare for the clinical trial,
which will largely enroll people who have been vaccinated and/or previously
infected with SARS-CoV-2, the Bjorkman lab is planning preclinical animal model
experiments to compare immune responses in animals previously vaccinated with a
current COVID-19 vaccine to responses in animals that are immunologically naïve
with respect to SARS-CoV-2 infection or vaccination.
"We
have talked about the need for diversity in vaccine development since the very
beginning of the pandemic," says Dr. Richard J. Hatchett, CEO of CEPI.
"The breakthrough exhibited in the Bjorkman lab study demonstrates huge
potential for a strategy that pursues a new vaccine platform altogether,
potentially overcoming hurdles created by new variants. I am delighted to
announce that CEPI will be supporting this novel approach to pandemic
prevention in Phase I clinical trials. The accelerated speed the study achieved
after receiving Wellcome Leap funding facilitated our relationship with them
today. The non-human primate data is extremely encouraging and we're excited to
support the next phase of trials."
Wellcome
Leap provided critical funding at a crucial time to accelerate the development
of the Caltech technology, shortening the timeline to reach Phase 1 clinical
trials by more than 18 months. Regina E. Dugan (PhD '93), CEO of Wellcome Leap,
says, "This early transition success demonstrates the value of global
partnerships working collaboratively and with the urgency needed to address
future pandemic risks."
The
paper is titled "Mosaic RBD nanoparticles protect against challenge by
diverse sarbecoviruses in animal models." Neeltje van Doremalen of the
National Institute of Allergy and Infectious Diseases (National Institutes of
Health) Rocky Mountain Laboratories is a co-first author along with Cohen.
Additional
Caltech co-authors are Jennifer Keeffe, research scientist; Chengcheng Fan,
postdoctoral scholar research associate in Biology and Biological Engineering;
Priyanthi Gnanapragasam, research technician; former research technician Leesa
Kakutani; Anthony P. West Jr., senior research specialist; former research
technician Yu Lee; Han Gao, research technician; and former graduate student
Claudia Jette (PhD '22).
Other
co-authors are Allison Greaney, Tyler Starr, and Jesse Bloom of the Fred
Hutchinson Cancer Research Center; Hanne Andersen, Ankur Sharma, and Mark Lewis
of BIOQUAL; Jonathan Schulz, Greg Saturday, and Vincent Munster of the Rocky
Mountain National Laboratories; and Tiong Tan and Alain Townsend of the
University of Oxford.
This
preclinical vaccine validation study was funded by Wellcome Leap, and built
directly on initial development and proof-of-principle studies funded early in
the pandemic by Caltech's Merkin Institute for Translational Medicine. Other
ongoing coronavirus work in the Bjorkman group is supported by the Bill and
Melinda Gates Foundation and George Mason Fast Grants.
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