DNA particles that mimic viruses show promise as vaccines

Using a virus particle made from DNA, researchers at MIT and the Ragon Institute at MGH, MIT and Harvard have created a vaccine capable of inducing a strong antibody response against SARS-CoV-2.

The vaccine, which was tested on mice, consists of DNA that contains many copies of a viral antigen. This type of vaccine, called a particulate vaccine, mimics the structure of a virus. Most previous work on particle vaccines has relied on protein scaffolds, but the proteins used in these vaccines tend to generate an unnecessary immune response that can distract the immune system from the target.

In the mouse study, researchers found that the DNA scaffold does not induce an immune response, allowing the immune system to focus its antibody response on the target antigen.

“DNA, as we discovered in this work, does not produce antibodies that can distract from the protein of interest,” says Mark Bathe, professor of biological engineering at MIT. “What you can imagine is that your B cells and your immune system are completely driven by this target antigen, and that’s what you want: for your immune system to be laser-focused on the antigen of interest .”

This approach, which strongly stimulates B cells (the cells that produce antibodies), could facilitate the development of vaccines against hard-to-target viruses, including HIV and influenza, as well as SARS-CoV-2, researchers say . Unlike T cells, which are stimulated by other types of vaccines, these B cells can persist for decades, providing long-term protection.

“We want to determine whether we can teach the immune system to deliver higher levels of immunity against pathogens that are resistant to conventional vaccine approaches, such as influenza, HIV and SARS-CoV-2,” explains Daniel Lingwood, associate professor at Harvard. Medical School and Principal Investigator at the Ragon Institute.

“This idea of ​​decoupling the response against the target antigen from the platform itself is a potentially powerful immunological trick that can now be leveraged to help these immunological targeting decisions move in a more targeted direction.”

Bathe, Lingwood and Aaron Schmidt, associate professor at Harvard Medical School and principal investigator at the Ragon Institute, are senior authors of the paper, which appears in Natural communications.

The paper’s lead authors are Eike-Christian Wamhoff, a former postdoctoral fellow at MIT; Larance Ronsard, postdoctoral fellow at the Ragon Institute; Jared Feldman, former Harvard University graduate student; Grant Knappe, MIT graduate student; and Blake Hauser, a former Harvard graduate student.

Mimicking viruses

Particulate vaccines generally consist of a protein nanoparticle, similar in structure to a virus, which can carry many copies of a viral antigen. This high density of antigens can lead to a stronger immune response than traditional vaccines because the body sees it as similar to an actual virus.

Particulate vaccines have been developed against a handful of pathogens, including hepatitis B and human papillomavirus, and a particulate vaccine against SARS-CoV-2 has been approved for use in South Korea.

These vaccines are particularly effective at activating B cells, which produce antibodies specific to the vaccine antigen.

“Particulate vaccines are of great interest to many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is different from the T cell-based immunity that mRNA vaccines seem to have. arouse more strongly,” Bathe explains. .

However, a potential drawback of this type of vaccine is that the proteins used for the structure often stimulate the body to produce antibodies targeting the structure. This can distract the immune system and prevent it from mounting as robust a response as one would like, Bathe says.

“To neutralize the SARS-CoV-2 virus, you want to have a vaccine that generates antibodies against the receptor-binding domain part of the spike protein of the virus,” he says. “When you display that on a protein-based particle, your immune system recognizes not only that receptor-binding domain protein, but any other proteins that are irrelevant to the immune response you’re trying to elicit.”

Another potential disadvantage is that if the same person receives more than one vaccine carried by the same protein scaffold, for example that of SARS-CoV-2 and then influenza, their immune system would likely react immediately to the protein scaffold, having already been initiated. to react to it. This could weaken the immune response to the antigen carried by the second vaccine.

“If you want to apply this protein-based particle to immunize against a different virus like influenza, then your immune system may be dependent on the underlying protein scaffold that it has already seen and developed a response against immune,” says Bathe. “This can hypothetically decrease the quality of your antibody response for the actual antigen of interest.”

As an alternative, Bathe’s lab has developed scaffolds made using DNA origami, a method that provides precise control over the structure of synthetic DNA and allows researchers to attach various molecules, such as viral antigens, at specific locations.

In a 2020 study, Bathe and Darrell Irvine, professor of biological engineering and materials science and engineering at MIT, showed that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong response in antibodies in B cells grown in the laboratory. This type of structure is optimal for activating B cells because it closely mimics the structure of nanometer-sized viruses, which have many copies of viral proteins on their surface.

“This approach builds on a fundamental principle of B cell antigen recognition, which is that if you have an organized display of antigen, it promotes B cell responses and gives a better quantity and quality of antibody production,” Lingwood explains.

“Immunologically silent”

In the new study, researchers exchanged an antigen made of the spike protein receptor-binding protein from the original SARS-CoV-2 strain. When they gave the vaccine to mice, they found that the mice generated high levels of antibodies against the spike protein, but generated none against the DNA scaffold.

In contrast, a vaccine based on a scaffolding protein called ferritin, coated with SARS-CoV-2 antigens, generated many antibodies against ferritin as well as SARS-CoV-2.

“The DNA nanoparticle itself is silent immunogenic,” explains Lingwood. “If you use a protein-based platform, you get equally high-titer antibody responses against the platform and against the antigen of interest, which can make it difficult to use that platform repeatedly because you will develop a high affinity immune memory against it.”

Reducing these off-target effects could also help scientists achieve their goal of developing a vaccine that would induce broadly neutralizing antibodies against any variant of SARS-CoV-2, or even against all sarbecoviruses, the subgenus of the virus that includes the SARS-CoV-2. as well as the viruses responsible for SARS and MERS.

To this end, researchers are currently investigating whether a DNA scaffold with many different viral antigens attached could induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses.

This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and education.