Researchers at MIT, MGH's Ragon Institute, MIT and Harvard have developed a vaccine that induces a strong antibody response against SARS-CoV-2 using a virus-like delivery particle made from DNA.
The vaccine, which has been tested on mice, consists of a DNA scaffold with many copies of viral antigens. The vaccine, called a particulate vaccine, mimics the structure of the virus. Most previous work on particulate vaccines has relied on protein scaffolds, but the proteins used in these vaccines often generate unnecessary immune responses that distract the immune system from its target.
In studies in mice, the researchers found that the DNA scaffolds did not induce an immune response, allowing the immune system to focus the antibody response on the target antigen.
"What we found in this work is that the DNA does not induce antibodies that distract attention from the protein in question," said Mark Bathe, a professor of bioengineering at MIT. "It's conceivable that the B cells and the immune system are being fully trained on the target antigen, and that's exactly what you want - to have the immune system laser-focused on the antigen of interest."
Researchers say this approach, which strongly stimulates B cells, the cells that produce antibodies, could make it easier to develop vaccines against hard-to-target viruses such as HIV, influenza and SARS-CoV-2. Unlike T cells stimulated by other types of vaccines, these B cells can last for decades, providing long-term protection.
"We are interested in exploring whether we can enable the immune system to generate higher levels of immunity against pathogens that traditional vaccine approaches protect against, such as influenza, HIV, and SARS-CoV-2," said Daniel Lingwood, associate professor at Harvard Medical School and principal investigator at the Ragon Institute. "This idea of decoupling the response to a target antigen from the platform itself is a potentially powerful immunology trick that we can now exploit to help move these immunology targeting decisions 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 was published today (January 30) in the journal Nature Communications. The main authors of the paper include former MIT postdoc Eike Christian Wamhoff, Ragon Institute postdoc Larance Lonza, former Harvard graduate student Jared Feldman, MIT graduate student Grant Knapp and former Harvard graduate student Blake Hauser.
Particulate vaccines typically consist of a protein nanoparticle that is structurally similar to a virus and can carry many copies of a viral antigen. This high density of antigens produces a stronger immune response than traditional vaccines because the body perceives it as similar to the real virus. Particulate vaccines have been developed against a few 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 good at activating B cells, causing them to produce antibodies specific to the vaccine antigens. "Many people in the field of immunology are very interested in particulate vaccines because they can produce strong humoral immunity, which is antibody-based immunity, which is different from T-cell-based immunity, and mRNA vaccines seem to stimulate T-cell immunity more strongly," Bathe said.
One potential drawback of this vaccine, however, is that the proteins used in the scaffolds often stimulate the body to produce antibodies against the scaffolds. This distracts the immune system from mounting a robust response as it should, Bhatt said.
"Neutralizing the SARS-CoV-2 virus requires a vaccine that generates antibodies against the receptor-binding domain portion of the viral spike protein," he said. "When such antibodies are displayed on protein-based particles, the immune system recognizes not only the receptor-binding domain protein, but also all other proteins that are not relevant to the immune response it is trying to elicit."
Another potential drawback is that if the same person receives more than one vaccine carried by the same protein scaffold, such as a SARS-CoV-2 vaccine and then a flu vaccine, their immune system is likely to react immediately to the protein scaffold because they are already primed to react to it. This may weaken the immune response to the antigen contained in the second vaccine.
"If you were to use protein-based particles to immunize against a different virus, such as influenza, then the immune system would become obsessed with the underlying protein scaffold that it has already seen and generated an immune response to," Bathe said. "This could reduce the quality of the body's antibody response to the actual antigen."
As an alternative, Bathe's lab has been developing scaffolds made using DNA origami, a method that allows precise control of the structure of synthetic DNA and allows researchers to attach various molecules, such as viral antigens, at specific locations.
In a 2020 study, Bart and Darrell Irvine, a professor of bioengineering and materials science and engineering at MIT, found that a DNA scaffold carrying 30 copies of an HIV antigen could generate a strong antibody response in lab-grown B cells. This structure is the best choice for activating B cells because it is very similar to the structure of nanoscale viruses, which display many copies of viral proteins on their surfaces.
"This method is based on the basic principle of B cell antigen recognition, which is that if the antigen is displayed on an array, it can promote the B cell response and increase the quantity and quality of the antibody output," Lingwood said.
In the new study, the researchers switched to an antigen composed of the receptor-binding protein for the spike protein from the original strain of SARS-CoV-2. When they injected the mice with the vaccine, they found that they developed high levels of antibodies to the spike protein but not any antibodies to the DNA scaffold.
In contrast, vaccines based on a scaffold protein called ferritin and coated with SARS-CoV-2 antigens produced many antibodies against both ferritin and SARS-CoV-2.
"DNA nanoparticles themselves are not immunogenic," Lingwood said. "Using a protein-based platform will generate equally high-titer antibody responses to the platform and the antigen of interest, which complicates reuse of the platform as the body develops a high-affinity immune memory of it."
Reducing these off-target effects could also help scientists achieve their goal of developing a vaccine that induces broadly neutralizing antibodies against any variant of SARS-CoV-2 or even all coronaviruses, the subgenus of viruses that includes SARS-CoV-2 and the viruses that cause SARS and MERS.
To this end, researchers are exploring whether a DNA scaffold with multiple different viral antigens attached can induce broadly neutralizing antibodies against SARS-CoV-2 and related viruses.
Compiled source: ScitechDaily