In lab exams, virus-like DNA buildings coated with viral proteins provoke a robust immune response in human B cells.
By folding DNA right into a virus-like construction, MIT researchers have designed HIV-like particles that provoke a robust immune response from human immune cells grown in a lab dish. Such particles would possibly ultimately be used as an HIV vaccine.
The DNA particles, which carefully mimic the dimensions and form of viruses, are coated with HIV proteins, or antigens, organized in exact patterns designed to impress a robust immune response. The researchers at the moment are engaged on adapting this strategy to develop a possible vaccine for SARS-CoV-2, they usually anticipate it might work for all kinds of viral illnesses.
“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’s the Underwood-Prescott Professor with appointments within the departments of Organic Engineering and Supplies Science and Engineering; an affiliate director of MIT’s Koch Institute for Integrative Most cancers Analysis; 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 Broad Institute of MIT and Harvard, are the senior authors of the research, which seems as we speak in Nature Nanotechnology. The paper’s lead authors are former MIT postdocs Rémi Veneziano and Tyson Moyer.
As a result of DNA molecules are extremely programmable, scientists have been working for the reason that 1980s on strategies to design DNA molecules that might be used for drug supply and lots of different functions, most just lately utilizing a method referred to as DNA origami that was invented in 2006 by Paul Rothemund of Caltech.
In 2016, Bathe’s lab developed an algorithm that may routinely design and construct arbitrary three-dimensional virus-like shapes utilizing DNA origami. This methodology presents exact management over the construction of artificial DNA, permitting researchers to connect a wide range of molecules, similar to viral antigens, at particular places.
“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.”
Pure viruses are nanoparticles with antigens arrayed on the particle floor, and it’s thought that the immune system (particularly B cells) has advanced to effectively acknowledge such particulate antigens. Vaccines at the moment are being developed to imitate pure viral buildings, and such nanoparticle vaccines are believed to be very efficient at producing a B cell immune response as a result of they’re the fitting measurement to be carried to the lymphatic vessels, which ship them on to B cells ready within the lymph nodes. The particles are additionally the fitting measurement to work together with B cells and may current a dense array of viral particles.
Nevertheless, figuring out the fitting particle measurement, spacing between antigens, and variety of antigens per particle to optimally stimulate B cells (which bind to focus on antigens by way of their B cell receptors) has been a problem. Bathe and Irvine got down to use these DNA scaffolds to imitate such viral and vaccine particle buildings, in hopes of discovering the most effective 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.”
Different researchers have tried to create subunit vaccines utilizing different kinds of artificial particles, similar to polymers, liposomes, or self-assembling proteins, however with these supplies, it’s not potential to regulate the location of viral proteins as exactly as with DNA origami.
For this research, the researchers designed icosahedral particles with an analogous measurement and form as a typical virus. They hooked up an engineered HIV antigen associated to the gp120 protein to the scaffold at a wide range of distances and densities. To their shock, they discovered that the vaccines that produced the strongest response B cell responses weren’t essentially those who packed the antigens as carefully as potential on the scaffold floor.
“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 research have the potential to information HIV vaccine improvement, because the HIV antigen utilized in these research is at the moment being examined in a medical trial in people, utilizing a protein nanoparticle scaffold.
Based mostly on their information, the MIT researchers labored with Jayajit Das, a professor of immunology and microbiology at Ohio State College, to develop a mannequin to elucidate why higher distances between antigens produce higher outcomes. When antigens bind to receptors on the floor of B cells, the activated receptors crosslink with one another contained in the cell, enhancing their response. Nevertheless, the mannequin means that if the antigens are too shut collectively, this response is diminished.
In current months, Bathe’s lab has created a variant of this vaccine with the Aaron Schmidt and Daniel Lingwood labs on the Ragon Institute, during which they swapped out the HIV antigens for a protein discovered on the floor of the SARS-CoV-2 virus. They’re now testing whether or not this vaccine will produce an efficient response towards the coronavirus SARS-CoV-2 in remoted 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.
As a result of this strategy permits for antigens from completely different viruses to be carried on the identical DNA scaffold, it might be potential to design variants that focus on a number of varieties of coronaviruses, together with previous and doubtlessly future variants that will emerge, the researchers say.
Reference: “Role of nanoscale antigen organization on B-cell activation probed using DNA origami” by Rémi Veneziano, Tyson J. Moyer, Matthew B. Stone, Eike-Christian Wamhoff, Benjamin J. Learn, Sayak Mukherjee, Tyson R. Shepherd, Jayajit Das, William R. Schief, Darrell J. Irvine and Mark Bathe, 29 June 2020, Nature Nanotechnology.
Bathe was just lately awarded a grant from the Quick Grants Covid-19 fund to develop their SARS-CoV-2 vaccine. The HIV analysis offered within the Nature Nanotechnology paper was funded by the Human Frontier Science Program, the U.S. Workplace of Naval Analysis, the U.S. Military Analysis Workplace by way of MIT’s Institute for Soldier Nanotechnologies, the Ragon Institute, and the U.S. Nationwide Institutes of Well being.