Engineers use “DNA origami” to identify vaccine design rules

By folding DNA into a virus-like framework, MIT researchers have built HIV-like particles that provoke a robust immune reaction from human immune cells developed in a lab dish. These particles could ultimately be employed as an HIV vaccine.

The DNA particles, which closely mimic the dimensions and condition of viruses, are coated with HIV proteins, or antigens, arranged in exact patterns built to provoke a robust immune reaction. The researchers are now operating on adapting this tactic to build a possible vaccine for SARS-CoV-two, and they anticipate it could do the job for a extensive assortment of viral health conditions.

“The rough structure policies that are setting up to come out of this do the job need to be generically relevant throughout ailment antigens and health conditions,” suggests Darrell Irvine, who is the Underwood-Prescott Professor with appointments in the departments of Organic Engineering and Elements Science and Engineering an associate director of MIT’s Koch Institute for Integrative Most cancers Research and a member of the Ragon Institute of MGH, MIT, and Harvard.

Irvine and Mark Bathe, an MIT professor of organic engineering and an associate member of the Broad Institute of MIT and Harvard, are the senior authors of the research, which appears today in Character Nanotechnology. The paper’s direct authors are former MIT postdocs Rémi Veneziano and Tyson Moyer.

DNA structure

Since DNA molecules are highly programmable, scientists have been operating considering the fact that the eighties on methods to structure DNA molecules that could be employed for drug shipping and several other purposes, most lately working with a procedure termed DNA origami that was invented in 2006 by Paul Rothemund of Caltech.

In 2016, Bathe’s lab developed an algorithm that can instantly structure and construct arbitrary 3-dimensional virus-like designs working with DNA origami. This approach provides exact control in excess of the framework of synthetic DNA, allowing researchers to attach a assortment of molecules, such as viral antigens, at unique locations.

“The DNA framework is like a pegboard exactly where the antigens can be connected at any posture,” Bathe suggests. “These virus-like particles have now enabled us to reveal elementary molecular principles of immune cell recognition for the initially time.”

All-natural viruses are nanoparticles with antigens arrayed on the particle area, and it is assumed that the immune procedure (in particular B cells) has progressed to effectively understand such particulate antigens. Vaccines are now getting developed to mimic natural viral structures, and such nanoparticle vaccines are believed to be quite powerful at generating a B cell immune reaction due to the fact they are the correct dimensions to be carried to the lymphatic vessels, which ship them directly to B cells waiting around in the lymph nodes. The particles are also the correct dimensions to interact with B cells and can existing a dense array of viral particles.

Having said that, figuring out the correct particle dimensions, spacing between antigens, and variety of antigens for each particle to optimally promote B cells (which bind to goal antigens via their B cell receptors) has been a obstacle. Bathe and Irvine set out to use these DNA scaffolds to mimic such viral and vaccine particle structures, in hopes of identifying the best particle designs for B cell activation.

“There is a good deal of interest in the use of virus-like particle structures, exactly where you take a vaccine antigen and array it on the area of a particle, to generate best B-cell responses,” Irvine suggests. “However, the policies for how to structure that exhibit are actually not properly-comprehended.”

Other researchers have tried out to create subunit vaccines working with other types of synthetic particles, such as polymers, liposomes, or self-assembling proteins, but with individuals materials, it is not feasible to control the placement of viral proteins as specifically as with DNA origami.

For this research, the researchers built icosahedral particles with a very similar dimensions and condition as a regular virus. They connected an engineered HIV antigen relevant to the gp120 protein to the scaffold at a assortment of distances and densities. To their shock, they discovered that the vaccines that developed the strongest reaction B cell responses were not essentially individuals that packed the antigens as closely as feasible on the scaffold area.

“It is typically assumed that the greater the antigen density, the better, with the idea that bringing B cell receptors as close together as feasible is what drives signaling. Having said that, the experimental consequence, which was quite distinct, was that really the closest feasible spacing we could make was not the best. And, and as you widen the distance between two antigens, signaling improved,” Irvine suggests.

The conclusions from this research have the possible to manual HIV vaccine improvement, as the HIV antigen employed in these studies is presently getting examined in a medical trial in people, working with a protein nanoparticle scaffold.

Dependent on their data, the MIT researchers labored with Jayajit Das, a professor of immunology and microbiology at Ohio Condition University, to build a design to demonstrate why better distances between antigens create better benefits. When antigens bind to receptors on the area of B cells, the activated receptors crosslink with just about every other inside of the cell, enhancing their reaction. Having said that, the design implies that if the antigens are far too close together, this reaction is diminished.

Beyond HIV

In the latest months, Bathe’s lab has produced 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 discovered on the area of the SARS-CoV-two virus. They are now screening whether or not this vaccine will create an powerful reaction versus the coronavirus SARS-CoV-two in isolated B cells, and in mice.

“Our system technologies permits you to conveniently swap out distinct subunit antigens and peptides from distinct kinds of viruses to take a look at whether or not they may potentially be functional as vaccines,” Bathe suggests.

Since this tactic permits for antigens from distinct viruses to be carried on the exact same DNA scaffold, it could be feasible to structure variants that goal numerous kinds of coronaviruses, which include past and potentially long run variants that may emerge, the researchers say.

Bathe was lately awarded a grant from the Rapid Grants Covid-19 fund to build their SARS-CoV-two vaccine. The HIV analysis offered in the Character Nanotechnology paper was funded by the Human Frontier Science System, the U.S. Office environment of Naval Research, the U.S. Army Research Office environment via MIT’s Institute for Soldier Nanotechnologies, the Ragon Institute, and the U.S. National Institutes of Health.