August 7, 2020


Aim for Excellence

Engineers use “DNA origami” to identify vaccine design rules

By folding DNA into a virus-like composition, MIT researchers have intended HIV-like particles that provoke...

By folding DNA into a virus-like composition, MIT researchers have intended HIV-like particles that provoke a sturdy immune reaction from human immune cells grown in a lab dish. This sort of particles could eventually be used as an HIV vaccine.

The DNA particles, which carefully mimic the dimension and form of viruses, are coated with HIV proteins, or antigens, arranged in precise designs intended to provoke a sturdy immune reaction. The researchers are now doing the job on adapting this tactic to acquire a potential vaccine for SARS-CoV-2, and they foresee it could function for a vast range of viral illnesses.

“The rough layout procedures that are starting up to come out of this function should really be generically relevant throughout illness antigens and illnesses,” states Darrell Irvine, who is the Underwood-Prescott Professor with appointments in the departments of Organic Engineering and Components Science and Engineering an affiliate director of MIT’s Koch Institute for Integrative Cancer Exploration and a member of the Ragon Institute of MGH, MIT, and Harvard.

Irvine and Mark Bathe, an MIT professor of organic engineering and an affiliate member of the Wide Institute of MIT and Harvard, are the senior authors of the examine, which appears now in Character Nanotechnology. The paper’s guide authors are former MIT postdocs Rémi Veneziano and Tyson Moyer.

DNA layout

Simply because DNA molecules are very programmable, experts have been doing the job given that the eighties on solutions to layout DNA molecules that could be used for drug shipping and delivery and quite a few other applications, most lately making use of a technique known as DNA origami that was invented in 2006 by Paul Rothemund of Caltech.

In 2016, Bathe’s lab produced an algorithm that can routinely layout and develop arbitrary three-dimensional virus-like styles making use of DNA origami. This process offers precise control in excess of the composition of artificial DNA, allowing researchers to attach a range of molecules, this sort of as viral antigens, at specific spots.

“The DNA composition is like a pegboard exactly where the antigens can be attached at any position,” Bathe states. “These virus-like particles have now enabled us to expose elementary molecular concepts of immune mobile recognition for the 1st time.”

Normal viruses are nanoparticles with antigens arrayed on the particle surface area, and it is assumed that the immune program (particularly B cells) has developed to competently figure out this sort of particulate antigens. Vaccines are now being produced to mimic organic viral buildings, and this sort of nanoparticle vaccines are believed to be extremely helpful at generating a B mobile immune reaction because they are the ideal dimension to be carried to the lymphatic vessels, which ship them specifically to B cells ready in the lymph nodes. The particles are also the ideal dimension to interact with B cells and can existing a dense array of viral particles.

On the other hand, deciding the ideal particle dimension, spacing concerning antigens, and range of antigens for each particle to optimally stimulate B cells (which bind to target antigens as a result of their B mobile receptors) has been a obstacle. Bathe and Irvine set out to use these DNA scaffolds to mimic this sort of viral and vaccine particle buildings, in hopes of identifying the most effective particle patterns for B mobile activation.

“There is a good deal of interest in the use of virus-like particle buildings, exactly where you choose a vaccine antigen and array it on the surface area of a particle, to push ideal B-mobile responses,” Irvine states. “However, the procedures for how to layout that exhibit are truly not perfectly-recognized.”

Other researchers have attempted to build subunit vaccines making use of other kinds of artificial particles, this sort of as polymers, liposomes, or self-assembling proteins, but with all those supplies, it is not achievable to control the placement of viral proteins as exactly as with DNA origami.

For this examine, the researchers intended icosahedral particles with a identical dimension and form as a common virus. They attached an engineered HIV antigen similar to the gp120 protein to the scaffold at a range of distances and densities. To their surprise, they identified that the vaccines that produced the strongest reaction B mobile responses ended up not necessarily all those that packed the antigens as carefully as achievable on the scaffold surface area.

“It is usually assumed that the increased the antigen density, the much better, with the concept that bringing B mobile receptors as close jointly as achievable is what drives signaling. On the other hand, the experimental outcome, which was extremely crystal clear, was that truly the closest achievable spacing we could make was not the most effective. And, and as you widen the distance concerning two antigens, signaling greater,” Irvine states.

The findings from this examine have the potential to information HIV vaccine growth, as the HIV antigen used in these scientific studies is at the moment being analyzed in a clinical demo in individuals, making use of a protein nanoparticle scaffold.

Based mostly on their knowledge, the MIT researchers worked with Jayajit Das, a professor of immunology and microbiology at Ohio State College, to acquire a design to clarify why higher distances concerning antigens make much better outcomes. When antigens bind to receptors on the surface area of B cells, the activated receptors crosslink with every single other within the mobile, maximizing their reaction. On the other hand, the design suggests that if the antigens are too close jointly, this reaction is diminished.

Over and above HIV

In current months, Bathe’s lab has developed 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 identified on the surface area of the SARS-CoV-2 virus. They are now screening irrespective of whether this vaccine will make an helpful reaction in opposition to the coronavirus SARS-CoV-2 in isolated B cells, and in mice.

“Our platform technological innovation permits you to very easily swap out diverse subunit antigens and peptides from diverse types of viruses to exam irrespective of whether they may possibly potentially be purposeful as vaccines,” Bathe states.

Simply because this tactic permits for antigens from diverse viruses to be carried on the very same DNA scaffold, it could be achievable to layout variants that target a number of types of coronaviruses, together with past and potentially long term variants that may possibly arise, the researchers say.

Bathe was lately awarded a grant from the Quickly Grants Covid-19 fund to acquire their SARS-CoV-2 vaccine. The HIV investigation offered in the Character Nanotechnology paper was funded by the Human Frontier Science Plan, the U.S. Place of work of Naval Exploration, the U.S. Army Exploration Place of work as a result of MIT’s Institute for Soldier Nanotechnologies, the Ragon Institute, and the U.S. Nationwide Institutes of Health.