Engineers use 'DNA origami' to identify vaccine design rules
In lab tests, virus-like DNA structures coated with viral proteins
provoke a strong immune response in human B cells

Date:
June 29, 2020
Source:
Massachusetts Institute of Technology
Summary:
Using DNA origami as a virus-like scaffold, researchers designed
an HIV- like particle that provokes a strong response from human
immune cells grown in the lab. They are now testing this approach
as a potential vaccine candidate in live animals, and adapting it
to SARS-CoV-2, as well as other pathogens.



FULL STORY ==========================================================================
By folding DNA into a virus-like structure, MIT researchers have designed
HIV- like particles that provoke a strong immune response from human
immune cells grown in a lab dish. Such particles might eventually be
used as an HIV vaccine.


==========================================================================
The DNA particles, which closely mimic the size and shape of viruses,
are coated with HIV proteins, or antigens, arranged in precise patterns designed to provoke a strong immune response. The researchers are now
working on adapting this approach to develop a potential vaccine for SARS-CoV-2, and they anticipate it could work for a wide variety of
viral diseases.

"The rough design rules that are starting to come out of this work
should be generically applicable across disease antigens and diseases,"
says Darrell Irvine, who is the Underwood-Prescott Professor with
appointments in the departments of Biological Engineering and Materials
Science and Engineering; an associate director of MIT's Koch Institute
for Integrative Cancer Research; and a member of the Ragon Institute of
MGH, MIT, and Harvard.

Irvine and Mark Bathe, an MIT professor of biological engineering
and an associate member of the Broad Institute of MIT and Harvard,
are the senior authors of the study, which appears today in Nature Nanotechnology. The paper's lead authors are former MIT postdocs Re'mi Veneziano and Tyson Moyer.

DNA design Because DNA molecules are highly programmable, scientists
have been working since the 1980s on methods to design DNA molecules
that could be used for drug delivery and many other applications, most
recently using a technique called DNA origami that was invented in 2006
by Paul Rothemund of Caltech.



==========================================================================
In 2016, Bathe's lab developed an algorithm that can automatically
design and build arbitrary three-dimensional virus-like shapes using
DNA origami. This method offers precise control over the structure of
synthetic DNA, allowing researchers to attach a variety of molecules,
such as viral antigens, at specific locations.

"The DNA structure is like a pegboard where the antigens can be attached
at any position," Bathe says. "These virus-like particles have now enabled
us to reveal fundamental molecular principles of immune cell recognition
for the first time." Natural viruses are nanoparticles with antigens
arrayed on the particle surface, and it is thought that the immune
system (especially B cells) has evolved to efficiently recognize such particulate antigens. Vaccines are now being developed to mimic natural
viral structures, and such nanoparticle vaccines are believed to be very effective at producing a B cell immune response because they are the right
size to be carried to the lymphatic vessels, which send them directly to
B cells waiting in the lymph nodes. The particles are also the right size
to interact with B cells and can present a dense array of viral particles.

However, determining the right particle size, spacing between antigens,
and number of antigens per particle to optimally stimulate B cells
(which bind to target antigens through their B cell receptors) has been a challenge. Bathe and Irvine set out to use these DNA scaffolds to mimic
such viral and vaccine particle structures, in hopes of discovering the
best particle designs for B cell activation.

"There is a lot of interest in the use of virus-like particle structures,
where you take a vaccine antigen and array it on the surface of a
particle, to drive optimal B-cell responses," Irvine says. "However,
the rules for how to design that display are really not well-understood."
Other researchers have tried to create subunit vaccines using other kinds
of synthetic particles, such as polymers, liposomes, or self-assembling proteins, but with those materials, it is not possible to control the
placement of viral proteins as precisely as with DNA origami.



==========================================================================
For this study, the researchers designed icosahedral particles with a
similar size and shape as a typical virus. They attached an engineered
HIV antigen related to the gp120 protein to the scaffold at a variety
of distances and densities. To their surprise, they found that the
vaccines that produced the strongest response B cell responses were not necessarily those that packed the antigens as closely as possible on
the scaffold surface.

"It is often assumed that the higher the antigen density, the better, with
the idea that bringing B cell receptors as close together as possible is
what drives signaling. However, the experimental result, which was very
clear, was that actually the closest possible spacing we could make was
not the best. And, and as you widen the distance between two antigens, signaling increased," Irvine says.

The findings from this study have the potential to guide HIV vaccine development, as the HIV antigen used in these studies is currently
being tested in a clinical trial in humans, using a protein nanoparticle scaffold.

Based on their data, the MIT researchers worked with Jayajit Das,
a professor of immunology and microbiology at Ohio State University,
to develop a model to explain why greater distances between antigens
produce better results. When antigens bind to receptors on the surface
of B cells, the activated receptors crosslink with each other inside the
cell, enhancing their response. However, the model suggests that if the antigens are too close together, this response is diminished.

Beyond HIV In recent months, Bathe's lab has created a variant of this
vaccine with the Aaron Schmidt and Daniel Lingwood labs at the Ragon
Institute, in which they swapped out the HIV antigens for a protein found
on the surface of the SARS- CoV-2 virus. They are now testing whether
this vaccine will produce an effective response against the coronavirus SARS-CoV-2 in isolated B cells, and in mice.

"Our platform technology allows you to easily swap out different subunit antigens and peptides from different types of viruses to test whether
they may potentially be functional as vaccines," Bathe says.

Because this approach allows for antigens from different viruses to
be carried on the same DNA scaffold, it could be possible to design
variants that target multiple types of coronaviruses, including past
and potentially future variants that may emerge, the researchers say.


========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Re'mi Veneziano, Tyson J. Moyer, Matthew B. Stone, Eike-Christian
Wamhoff, Benjamin J. Read, Sayak Mukherjee, Tyson R. Shepherd,
Jayajit Das, William R. Schief, Darrell J. Irvine, Mark Bathe. Role
of nanoscale antigen organization on B-cell activation probed
using DNA origami.

Nature Nanotechnology, 2020; DOI: 10.1038/s41565-020-0719-0 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200629120159.htm

--- up 22 weeks, 6 days, 2 hours, 38 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)