Targeted Induction of B-cells Using Next-Generation DNA Vaccines: A Breakthrough in HIV Vaccine Development
A primary challenge in contemporary vaccinology and immunotherapy is the induction of antibodies capable of neutralizing the human immunodeficiency virus (HIV). Of particular interest is the stimulation of broadly neutralizing antibodies (bnAbs), as they possess the capacity to neutralize a wide array of viral strains. Achieving this objective is significantly complicated by the fact that HIV undergoes rapid mutation to evade the immune system, thereby severely hindering the development of an effective vaccine.
Scientists from the Massachusetts Institute of Technology (MIT) and Scripps Research have developed a novel vaccine that generates a significant population of rare precursor B-cells capable of adaptation and bnAb production. The expansion of these specific cells represents a successful initial step toward the creation of an effective HIV vaccine.
To develop the vaccine, the researchers utilized synthetic DNA as a structural scaffold for a virus-like particle (VLP), rather than protein-based scaffolds. This particle displays numerous copies of the eOD-GT8 HIV immunogen—an antigen capable of eliciting an immune response—which was engineered at Scripps Research. A fundamental approach to stimulating rare B-cells involves immunization with particles that express multiple copies of the same antigen on their surface (multivalent antigen display).
In preclinical studies conducted in mice, the new vaccine generated a significantly higher number of precursor B-cells compared to protein-based VLPs, which had previously passed early-stage human clinical trials. Specifically, the DNA-VLP generated an eightfold increase in on-target B-cells compared to its predecessor, which was already considered highly effective.
“We were all surprised that the DNA-based particle significantly outperformed the already highly effective VLP from Scripps Research. These results point to a potential breakthrough—an entirely new, first-in-class virus-like particle that could fundamentally shift our approach to active immunotherapy and vaccine design across various indications,” stated Mark Bathe, a professor of biological engineering at MIT and an associate member of the Broad Institute of MIT and Harvard.
The study further demonstrated that the DNA structure, when used in combination with the engineered HIV antigen, does not elicit an independent immune response against the scaffold itself. This implies that DNA-VLPs can be successfully utilized to deliver a variety of antigens, particularly in scenarios requiring sequential (multistage) vaccination strategies.
A central target for HIV-neutralizing antibodies is the VRC01 monoclonal antibody, first described in 2010 by scientists at the U.S. National Institutes of Health (NIH) in individuals living with HIV who had not progressed to AIDS. This discovery initiated large-scale research into creating a vaccine capable of stimulating these target antibodies; however, this challenge remains largely unresolved to this day.
Immunologists posit that the generation of HIV-neutralizing antibodies requires a three-stage vaccination process. Each stage is initiated with a different antigen, guiding B-cell differentiation toward the ultimate target: the native envelope protein of HIV (gp120). Neutralization of this glycoprotein is critical, as it constitutes the primary structural element the virus uses to bind to and enter CD4+ T-lymphocyte (T-helper) cells.
In 2013, William Schief, a professor of immunology and microbiology at Scripps Research, described an engineered antigen in a scientific publication known as eOD-GT6, intended for use in the initial priming stage. His team subsequently updated this antigen to the eOD-GT8 version. Vaccination with eOD-GT8 displayed on protein VLPs generated precursors of VRC01-class antibodies in both mice and human clinical trials.
However, the use of protein VLPs possessed an inherent limitation: immunization via this method elicited a significant quantity of “off-target” antibodies that bound directly to the VLP scaffold, serving as a potent distracter for the immune system. This competition could have unpredictable consequences on the proliferation of target B-cells critical for HIV defense.
To address this issue, the Bathe and Irvine laboratories aimed to deliver the priming antigen using DNA-based particles rather than protein. These nanoscale structures are fabricated using “DNA origami,” a method that provides precise control over the synthetic DNA structure, allowing researchers to conjugate viral antigens at specific sites.
In 2024, scientists at Harvard Medical School demonstrated that DNA-VLPs could be used to generate neutralizing antibodies against SARS-CoV-2 in mice. It was also determined that, unlike proteins, the DNA structure does not generate antibodies against the VLP itself, rendering it virtually “invisible” to the immune system.
Building upon this research, scientists began incorporating DNA-VLPs into the Scripps initial HIV vaccine based on the eOD-GT8 antigen.
Initial studies in mice indicated that the primary dose did not produce the required quantity of precursor B-cells. However, following structural optimization of the DNA-VLP, researchers determined that a version with a smaller diameter, equipped with 60 copies of the antigen instead of 30, significantly outperformed the control protein model in efficacy. This was evidenced by an increase in both the total number of antigen-specific B-cells and the fraction of B-cells targeted specifically toward the HIV domain. This effect was achieved through improved retention of the particles in lymph nodes and optimal interaction with helper T-cells.
Because the DNA-VLP does not induce structure-specific antibodies, it can be utilized to deliver the second and potentially third antigens required in a series, which is currently under investigation. This suggests that DNA-VLPs may be successfully employed for delivering multiple diverse antigens, particularly when multistage vaccination strategies are required.
In the future, this methodology could be applied to induce protective antibodies against global pandemic threats (e.g., emerging influenza strains) and chemical warfare agents. Furthermore, the technology is being considered as an active immunotherapeutic tool for the treatment of neurodegenerative diseases, including Alzheimer’s disease (by generating antibodies against amyloid-beta and tau proteins), as well as for addressing opioid and nicotine addiction.
Sources: news.mit.edu
