Novel nanoparticle SARS-CoV-2 vaccine combines immune focusing and self- assembling nanoparticles to elicit more potent protection
Engineered to use DNA to instruct cells to make vaccine in vivo, and can
be stored at room temperature, easily transported to remote locations

Date:
February 1, 2022
Source:
The Wistar Institute
Summary:
First generation COVID-19 vaccines have been highly effective,
but also have limitations. Now, scientists have developed a more
targeted vaccine that, in animal studies, shows stronger, broader,
and more durable protection in a single, low dose.



FULL STORY ==========================================================================
The first generation of COVID-19 vaccines have been highly effective, but
also have limitations: their efficacy can wane without a booster shot,
and they may be less effective against some variants. Now scientists
at The Wistar Institute have developed a more targeted vaccine that,
in animal studies, shows stronger, broader, and more durable protection
in a single, low dose.


==========================================================================
The vaccine combines three technologies -- immune focusing,
self-assembling nanoparticles, and DNA delivery -- into a single platform
for the first time.

In addition to its other advantages, the vaccine could be stored at
room temperature, making it potentially easier to transport to remote
or developing locations than existing mRNA vaccines, which require
specialized cold storage.

"This is among the first next-generation vaccines that will have more
advanced features and broader protection," said Daniel Kulp, Ph.D.,
associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author of the study.

The paper, "Nucleic acid delivery of immune-focused SARS-CoV-2
nanoparticles drive rapid and potent immunogenicity capable of single-dose protection," was published in the journalCell Reports.

Existing vaccines include an unmodifided receptor binding domain
of SARS-CoV- 2 spike protein. The new vaccine includes a rationally
engineered receptor binding domain using computational and structure-based design methodologies.

The energinered receptor binding domain blocks 'immune distracting' sites
and can therefore elicit stronger levels of protective, neutralizing antibodies.

Researchers then used naturally self-assembling proteins to form
nanoparticles which display these highly engineered immunogens. By
arranging themselves into structures that resemble an actual virus,
the nanoparticles are more easily recognized by the immune system and transported to the germinal centers, where they activate B cells which
produce protective antibodies.



========================================================================== Using nucleic acid vaccine delivery technology similar to mRNA,
the nanoparticle vaccine is encoded in DNA and delivered into cells
thereby giving genetic instructions for the body to build the immunogen internally. This is an advance over traditional vaccines that must be manufactured in specialized factories through complex vaccine production processes. In contrast to other vaccines, Dr. Kulp noted that one
advantage of the DNA platform is that it doesn't require refrigeration
and it can also be quickly reformulated to target new variants.

In animal models, researchers found that the DNA delivered immune-focused nanoparticle vaccine produced much higher levels of neutralizing
antibodies than the vaccine that wasn't immune-focused.

"A difficulty with current vaccines is that neutralizing antibodies
decline over time," Kulp said. The nanoparticle vaccine produced durable responses after a single immunization out to six months in mice, unlike
what we are seeing with current SARS-CoV-2 vaccines in people.

The ultimate test for SARS-CoV-2 vaccine candidates is protection from
death in SARS-CoV-2 challenge experiments. The researchers found that in
a lethal challenge model 100% of mice who received the immune-focused nanoparticle vaccine were protected from death with a single low
dose. Most mice who received the standard, non-immune focused vaccine
died within 10 days of challenge.

The vaccine assessment was conducted in both wild-type mice and mice
that were genetically engineered to mimic human immune systems, he noted.



==========================================================================
Even without being updated, the immune-focused vaccine showed a
comparable level of antibody production to Delta, and other variants,
Kulp said. That's partly because of the immune focusing approach itself,
he noted; in blocking parts of the receptive binding domain for the
purpose of inhibiting non- neutralizing antibodies, it also blocks many
of the areas affected by spike protein mutations. Studies on the Omicron variant are underway.

Researchers are seeking funding to begin human trials of the vaccine.

Co-author David B. Weiner, Ph.D., executive vice president, director
of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable
Trust Professor in Cancer Research, at The Wistar Institute, said
the vaccine could provide a needed step forward to improve protection
against COVID-19.

"Current vaccine effects on reducing transmission of SARS-CoV-2 variants
of concern including Delta and Omicron could be improved for their breadth
of protection as well as their immune potency," Weiner said. "This study demonstrates that using a nucleic acid approach combined with in vivo structural assembly of a glycan immune-focused nanoparticle drives single protection and neutralization against diverse variants of concern in a
dose- sparing formulation. Additional studies of this vaccine approach for SARS-CoV- 2 appear timely and important." Co-authors: Kylie M. Konrath,
Kevin Liaw, Yuanhan Wu, Xizhou Zhu, Susanne N.

Walker, Ziyang Xu, Neethu Chokkalingam, Nicholas J. Tursi, Mansi Purwar,
Emma Reuschel, Drew Frase, Benjamin Fry, and Ami Patel from Wistar;
Katherine Schultheis, Igor Maricic, Viviane M. Andrade, Kate E. Broderick, Laurent M.P.F.

Humeau, and Trevor R.F. Smith from Inovio Pharmaceuticals; Himanshi
Chawla and Max Crispin from the University of Southhampton; Jianqiu Du
and Alan Moore from Indiana University; Jared Adolf-Bryfogle and Jesper Pallesen from the Institute for Protein Innovation; Matthew Sullivan
from the University of Pennsylvania; and Christel Iffland from Ligand Pharmaceuticals.

Work supported by: Wistar Coronavirus Discovery Fund and CURE/PA
Department of Health grant SAP# 4100083104, COVID/PA Department
of Human Services grant SAP# 4100089371, NIH/NIAID CIVICs grant
75N93019C00051, Wistar Coronavirus Discovery Fund, Wistar SRA 16-4 /
Inovio Pharmaceuticals, COVID/PA Department of Human Services grant SAP# 410089371; Indiana University.

========================================================================== Story Source: Materials provided by The_Wistar_Institute. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Kylie M. Konrath, Kevin Liaw, Yuanhan Wu, Xizhou Zhu, Susanne
N. Walker,
Ziyang Xu, Katherine Schultheis, Neethu Chokkalingam, Himanshi
Chawla, Jianqiu Du, Nicholas J. Tursi, Alan Moore, Jared
Adolf-Bryfogle, Mansi Purwar, Emma L. Reuschel, Drew Frase,
Matthew Sullivan, Benjamin Fry, Igor Maricic, Viviane M. Andrade,
Christel Iffland, Max Crispin, Kate E.

Broderick, Laurent M.P.F. Humeau, Ami Patel, Trevor R.F. Smith,
Jesper Pallesen, David B. Weiner, Daniel W. Kulp. Nucleic acid
delivery of immune-focused SARS-CoV-2 nanoparticles drives rapid
and potent immunogenicity capable of single-dose protection. Cell
Reports, 2022; 38 (5): 110318 DOI: 10.1016/j.celrep.2022.110318 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220201115253.htm

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