Molecular Biology Conference
A novel
COVID-19 vaccine using modified bacterial DNA
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Experimental vaccine based on altered plasmid DNA produced
antibody response in mice that effectively blocked cell infection across all
variants of concern tested.
Researchers describe
a different way to build a COVID-19 vaccine, one that would, in theory, remain
effective against new and emerging variants and could be taken as a pill, by
inhalation or other delivery methods.
Researchers
at University of California San Diego School of Medicine, with colleagues
elsewhere, describe a different way to build a COVID-19 vaccine, one that
would, in theory, remain effective against new and emerging variants and could
be taken as a pill, by inhalation or other delivery methods.
Their
findings publish in the July 21, 2022 online issue of PLOS Pathogens.
The research
involved building plasmids genetically altered to contain bits of genetic
material specifically intended to target a vulnerability in the SARS-CoV-2
virus's spike protein, a portion of the virus critical to binding and infecting
cells. Plasmids are small, circular DNA molecules from bacteria that are
physically separate from chromosomal DNA and can replicate independently. They
can be used by scientists to transfer genetic material from one cell to
another, after which the introduced genetic material can replicate in the
receiving cell.
The approach, said senior author
Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine
and head of the Laboratory of Immunology at UC San Diego Moores Cancer Center,
points to the possibility of a more durable, and more broadly effective,
COVID-19 vaccine.
"The details are complicated, but
the fundamentals are simple," said Zanetti. "They are based on
well-known and proven principles and methods."
COVID-19 mRNA vaccines, such as those by
Pfizer and Moderna, are the result of decades of previous research and
development. The pandemic added new urgency, focus and resources. These
vaccines promised a faster way to people, though not without significant
challenges, such as the need of an ultralow temperature cold chain.
The resulting mRNA vaccines have
fundamentally altered the course of the pandemic, dramatically mitigating the
severity of disease, hospitalizations and deaths. But notably, said Zanetti,
they do little at blocking transmission of the virus. Case rates still rise and
fall with the emergence of viral variants.
"The goal at the beginning wasn't
to stop the disease," said Zanetti. "It was to mitigate the consequences,
to reduce COVID's severity and outcomes. The vaccines have done that.
Vaccinated persons tend not to get as sick. They don't require hospitalization
as often. Death rates are down. All of this has greatly reduced pressures on
health systems and society, which is a good thing."
But the ever-evolving nature of the
SARS-CoV-2 virus has revealed that the vaccines' efficacy varies, depending
upon variant, often diminishing. The Alpha variant, for example, proved more
contagious than the "wild-type" strain that originated in Wuhan,
China. The Delta variant was more transmissible than Alpha and Omicron more
than Delta. Though the vaccines continue to provide substantial protection
against severe disease, the antibodies they induce are consistently less
powerful at neutralizing the virus, thus the increased transmission. SARS-CoV-2
continues to be an unrelenting global public health threat.
Zanetti said the newest work emphasizes
"quality over quantity," seeking the induction of antibodies
preferentially blocking virus binding to its cell receptor and transmission.
This results in a more focused antibody response with the vaccine.
"In the early days of COVID vaccine
development, it was about generating a broad, robust immune response,"
Zanetti said. "But it was a scattered approach. The vaccines response
targeted many epitopes (parts of the virus that the host's immune system
recognizes) and it resulted in an immune response that was largely noise. Most
of the resulting antibodies produced didn't affect the virus's ability to
infect."
"The new research narrows the focus
to a part of the viral spike specifically involved in the virus's ability to
infect that appears to be evolutionarily conserved," said co-senior author
Aaron F. Carlin, MD, PhD, assistant professor in the Division of Infectious
Diseases and Global Public Health at UC San Diego Health. In other words, the
site doesn't change with new variants, and represents a persisting site of
vulnerability and a reliable vaccine target.
How it works
Zanetti and colleagues built plasmids
containing immunogens -- molecules that cause B lymphocytes to create
antibodies -- that were specifically designed to display a knob of the spike
protein that is part of the receptor binding motif or RBM. Specifically, these
were amino acid residues that act like keys to unlock the cell door. The keys
and lock don't change.
B lymphocytes are part of the immune
system. They are prodigious producers of antibodies created to respond and
protect against specific antigens or unwanted substances in the body, such as
viruses. The average B lymphocyte can spit out 1,000 antibody molecules per
second, an incredibly robust production if it is the right antibody for the
job.
Zanetti and colleagues cloned the
selected spike protein amino acids into a plasmid DNA so that, when injected
into the spleen of mice, the introduced immunogen molecules would provoke the
production of neutralizing antibodies specifically tuned to the targeted nob on
the RBM of the virus protein spike. The researchers then tested their approach
on mice with variants of the original SARS-CoV-2 strain (Beta, Delta and
Omicron) and found that the immune response was similar across all variants.
"We were a bit lucky in picking our
target on the spike," said Zanetti, "though it was also the result of
experience and intuition. I've been doing this for 30 years. Earlier
experiments by others had suggested this might be a 'supersite.' I followed my
instincts."
Zanetti said translating these findings
into a vaccine suitable for clinical trials will be "an uphill
battle." There is much invested in current approaches, and it's a
considerable leap from mouse studies to human clinical trials.
But the promise of a consistently
effective and easy to administer vaccine is irresistible.
"DNA is very stable. The new ideas for delivery include a pill that survives the digestive system and releases the plasmid DNA to be picked up by B lymphocytes that seem to possess an ancestral property for taking up plasmid DNA. Alternatively, the DNA can be formulated for delivery to the upper airways by suitable formulation for inhalation. Many other researchers and I have investigated and pursued this basic idea before in other ways. It's time to try it with COVID."
Source: https://www.sciencedaily.com/releases/2022/07/220721141456.htm
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