A nanomaterial path forward for COVID-19 vaccine development

Date:
July 15, 2020
Source:
University of California - San Diego
Summary:
From mRNA vaccines entering clinical trials, to peptide-based
vaccines and using molecular farming to scale vaccine production,
the COVID-19 pandemic is pushing new and emerging nanotechnologies
into the frontlines and the headlines. Nanoengineers detail the
current approaches to COVID- 19 vaccine development, and highlight
how nanotechnology has enabled these advances, in a review article.



FULL STORY ==========================================================================
From mRNA vaccines entering clinical trials, to peptide-based vaccines
and using molecular farming to scale vaccine production, the COVID-19
pandemic is pushing new and emerging nanotechnologies into the frontlines
and the headlines.


========================================================================== Nanoengineers at UC San Diego detail the current approaches to COVID-19
vaccine development, and highlight how nanotechnology has enabled these advances, in a review article in Nature Nanotechnology published July 15.

"Nanotechnology plays a major role in vaccine design," the researchers,
led by UC San Diego Nanoengineering Professor Nicole Steinmetz,
wrote. Steinmetz is also the founding director of UC San Diego's Center
for Nano ImmunoEngineering.

"Nanomaterials are ideal for delivery of antigens, serving as adjuvant platforms, and mimicking viral structures. The first candidates
launched into clinical trials are based on novel nanotechnologies
and are poised to make an impact." Steinmetz is leading a National
Science Foundation-funded effort to develop - - using a plant virus --
a stable, easy to manufacture COVID-19 vaccine patch that can be shipped
around the world and painlessly self-administered by patients. Both
the vaccine itself and the microneedle patch delivery platform rely
on nanotechnology. This vaccine falls into the peptide-based approach
described below.

"From a vaccine technology development point of view, this is an exciting
time and novel technologies and approaches are poised to make a clinical
impact for the first time. For example, to date, no mRNA vaccine has been clinically approved, yet Moderna's mRNA vaccine technology for COVID-19
is making headways and was the first vaccine to enter clinical testing
in the US." As of June 1, there are 157 COVID-19 vaccine candidates in development, with 12 in clinical trials.



========================================================================== "There are many nanotechnology platform technologies put toward
applications against SARS-CoV-2; while highly promising, many
of these however may be several years away from deployment and
therefore may not make an impact on the SARS-CoV-2 pandemic," Steinmetz
wrote. "Nevertheless, as devastating as COVID- 19 is, it may serve as an impetus for the scientific community, funding bodies, and stakeholders
to put more focused efforts toward development of platform technologies
to prepare nations for readiness for future pandemics," Steinmetz wrote.

To mitigate some of the downsides of contemporary vaccines -- namely
live- attenuated or inactivated strains of the virus itself -- advances
in nanotechnology have enabled several types of next-generation vaccines, including: Peptide-based vaccines: Using a combination of informatics and immunological investigation of antibodies and patient sera, various B-
and T-cell epitopes of the SARS-CoV-2 S protein have been identified. As
time passes and serum from convalescent COVID-19 patients are screened
for neutralizing antibodies, experimentally-derived peptide epitopes
will confirm useful epitope regions and lead to more optimal antigens
in second-generation SARS-CoV-2 peptide-vaccines.

The National Institutes of Health recently funded La Jolla Institute
for Immunology in this endeavor.

Peptide-based approaches represent the simplest form of vaccines that are easily designed, readily validated and rapidly manufactured. Peptide-based vaccines can be formulated as peptides plus adjuvant mixtures or peptides
can be delivered by an appropriate nanocarrier or be encoded by nucleic
acid vaccine formulations. Several peptide-based vaccines as well as
peptide- nanoparticle conjugates are in clinical testing and development targeting chronic diseases and cancer, and OncoGen and University of Cambridge/DIOSynVax are using immunoinformatics-derived peptide sequences
of S protein in their COVID-19 vaccine formulations.

An intriguing class of nanotechnology for peptide vaccines is virus
like particles (VLPs) from bacteriophages and plant viruses. While non-infectious toward mammals, these VLPs mimic the molecular patterns associated with pathogens, making them highly visible to the immune
system. This allows the VLPs to serve not only as the delivery
platform but also as adjuvant. VLPs enhance the uptake of viral
antigens by antigen-presenting cells, and they provide the additional immune-stimulus leading to activation and amplification of the ensuing
immune response. Steinmetz and Professor Jon Pokorski received an NSF
Rapid Research Response grant to develop a peptide-based COVID-19
vaccine from a plant virus. Their approach uses the Cowpea mosaic
virus that infects legumes, engineering it to look like SARS-CoV-2,
and weaving antigen peptides onto its surface, which will stimulate an
immune response.



========================================================================== Their approach, as well as other plant-based expression systems, can be
easily scaled up using molecular farming. In molecular farming, each
plant is a bioreactor. The more plants are grown, the more vaccine is
made. The speed and scalability of the platform was recently demonstrated
by Medicago manufacturing 10 million doses of influenza vaccine within
one month. In the 2014 Ebola epidemic, patients were treated with ZMapp,
an antibody cocktail manufactured through molecular farming. Molecular
farming has low manufacturing costs, and is safer since human pathogens
cannot replicate in plant cells.

Nucleic-acid based vaccines: For fast emerging viral infections
and pandemics such as COVID-19, rapid development and large scale
deployment of vaccines is a critical need that may not be fulfilled by
subunit vaccines. Delivering the genetic code for in situ production
of viral proteins is a promising alternative to conventional vaccine approaches. Both DNA vaccines and mRNA vaccines fall under this category
and are being pursued in the context of the COVID-19 pandemic.

* DNA vaccines are made up of small, circular pieces of bacterial
plasmids
which are engineered to target nuclear machinery and produce S
protein of SARS-CoV-2 downstream.

* mRNA vaccines on the other hand, are based on designer-mRNA
delivered
into the cytoplasm where the host cell machinery then translates
the gene into a protein -- in this case the full-length S protein
of SARS-CoV-2.

mRNA vaccines can be produced through in vitro transcription, which
precludes the need for cells and their associated regulatory hurdles While DNA vaccines offer higher stability over mRNA vaccines, the mRNA is
non- integrating and therefore poses no risk of insertional mutagenesis.

Additionally, the half-life, stability and immunogenicity of mRNA can
be tuned through established modifications.

Several COVID-19 vaccines using DNA or RNA are undergoing development:
Inovio Pharmaceuticals has a Phase I clinical trial underway, and
Entos Pharmeuticals is on track for a Phase I clinical trial using
DNA. Moderna's mRNA-based technology was the fastest to Phase I clinical
trial in the US, which began on March 16th, and BioNTech-Pfizer recently announced regulatory approval in Germany for Phase 1/2 clinical trials
to test four lead mRNA candidates.

Subunit vaccines: Subunit vaccines use only minimal structural elements
of the pathogenic virus that prime protective immunity -- either
proteins of the virus itself or assembled VLPs. Subunit vaccines can
also use non-infectious VLPs derived from the pathogen itself as the
antigen. These VLPs are devoid of genetic material and retain some or all
of the structural proteins of the pathogen, thus mimicking the immunogenic topological features of the infectious virus, and can be produced via recombinant expression and scalable through fermentation or molecular
farming. The frontrunners among developers are Novavax who initiated
a Phase I/II trial on May 25, 2020. Also Sanofi Pasteur/ GSK, Vaxine,
Johnson & Johnson and the University of Pittsburgh have announced that
they expect to begin Phase I clinical trials within the next few months.

Others including Clover Biopharmaceuticals and the University of
Queensland, Australia are independently developing subunit vaccines
engineered to present the prefusion trimer confirmation of S protein
using the molecular clamp technology and the Trimer-tag technology, respectively.

Delivery device development Lastly, the researchers note that
nanotechnology's impact on COVID-19 vaccine development does not end
with the vaccine itself, but extends through development of devices
and platforms to administer the vaccine. This has historically been
complicated by live attenuated and inactivated vaccines requiring constant refrigeration, as well as insufficient health care professionals where the vaccines are needed. "Recently, modern alternatives to such distribution
and access challenges have come to light, such as single-dose slow
release implants and microneedle-based patches which could reduce
reliance on the cold chain and ensure vaccination even in situations
where qualified health care professionals are rare or in high demand,"
the researchers write.

"Microneedle-based patches could even be self-administered which would dramatically hasten roll-out and dissemination of such vaccines as well
as reducing the burden on the healthcare system." Pokorski and Steinmetz
are co-developing a microneedle delivery platform with their plant virus COVID-19 vaccine for both of these reasons.

This work is supported by a grant from the National Science Foundation
(NSF CMMI-2027668) "Advances in bio/nanotechnology and advanced nanomanufacturing coupled with open reporting and data sharing
lay the foundation for rapid development of innovative vaccine
technologies to make an impact during the COVID-19 pandemic," the
researchers wrote. "Several of these platform technologies may serve
as plug-and-play technologies that can be tailored to seasonal or new
strains of coronaviruses. COVID-19 harbors the potential to become a
seasonal disease, underscoring the need for continued investment in
coronavirus vaccines."

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Katherine
Connor. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Matthew D. Shin, Sourabh Shukla, Young Hun Chung, Veronique
Beiss, Soo
Khim Chan, Oscar A. Ortega-Rivera, David M. Wirth, Angela Chen,
Markus Sack, Jonathan K. Pokorski, Nicole F. Steinmetz. COVID-19
vaccine development and a potential nanomaterial path
forward. Nature Nanotechnology, 2020; DOI: 10.1038/s41565-020-0737-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200715095500.htm

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