Virus-like particle vaccine has expanded rare HIV-targeting B cells in lab studies

Researchers at MIT and Scripps have reported that a DNA-based virus-like particle vaccine has generated markedly higher numbers of rare precursor B cells needed to produce broadly neutralising antibodies against HIV

A long-standing goal of both immunotherapy and vaccine research has been to induce antibodies capable of neutralising highly mutable and lethal viruses, including human immunodeficiency virus (HIV) and influenza. Particular focus has centred on broadly neutralising antibodies which can recognise and inactivate multiple viral strains despite rapid antigenic variation that enables immune evasion.

Researchers at the Massachusetts Institute of Technology (MIT), Cambridge, USA and the Scripps Research Institute (SRI), San Diego, California, USA, have now reported the development of a vaccine platform that expands a population of exceptionally rare precursor B cells capable of evolving into producers of broadly neutralising antibodies.

Expansion of these cells represents a critical first step towards an effective HIV vaccine, as all humans possess the genetic capacity to generate such antibodies but do so at extremely low frequencies.

The vaccine design relied on DNA rather than protein as a structural scaffold to assemble a virus-like particle displaying multiple copies of an engineered HIV immunogen known as eOD-GT8, originally developed at the SRI. In a humanised mouse model, the DNA-based particle generated substantially more of the desired precursor B cells than a protein-based virus-like particle that has already demonstrated strong performance in human clinical trials.

Preclinical analyses showed that the DNA scaffold induced approximately eight times more on-target B cells than the existing clinical product. These cells recognised the specific HIV epitope required to initiate the pathway towards broadly neutralising antibody production.

“We were all surprised that this already outstanding virus-like particle from Scripps was significantly outperformed by the DNA-based virus-like particle,” said Dr. Mark Bathe, professor of biological engineering at the MIT.

“These early preclinical results suggested a potential breakthrough as an entirely novel, first-in-class virus-like particle that could transform the way researchers think about active immunotherapies and vaccine design across a variety of indications,” he added.

The study also showed that the DNA scaffold itself did not provoke an immune response when paired with the engineered HIV antigen. This feature is particularly important, as immune recognition of the scaffold can divert antibody responses away from the intended viral target. The apparent immunological silence of the DNA platform suggests it could support complex boosting strategies that require sequential delivery of multiple antigens, which is widely regarded as essential for challenging targets such as HIV.

“The DNA virus-like particle allowed us for the first time to assess whether B cells targeting the particle itself limited the development of on-target B cell responses which has been a longstanding question in vaccine immunology,” said Dr. Darrell Irvine, professor of immunology and microbiology at the SRI.

The lead author was Dr. Anna Romanov, a researcher at MIT into biological engineering.

The work forms part of an international effort to design vaccines that selectively expand defined lineages of B cells. In the case of HIV, broadly neutralising antibodies require an unusually long maturation process involving many successive mutations. Although the genetic templates for such antibodies exist in all individuals, the relevant precursor B cells are exceptionally rare and require precise immunological guidance to evolve towards effective viral neutralisation.

One of the most intensively studied HIV-neutralising antibodies, VRC01, was identified in 2010 through studies of individuals living with HIV who did not progress to acquired immune deficiency syndrome. This discovery triggered a global effort to develop vaccines capable of inducing similar antibodies.

Current models suggest that induction of HIV-neutralising antibodies requires a staged vaccination strategy, in which each immunisation presents a distinct antigen designed to steer B cell evolution towards recognition of the native HIV envelope protein gp120. Earlier work showed that eOD-GT8, when displayed on a protein-based virus-like particle, could induce early VRC01 precursor responses in animal models and later in human volunteers.

Despite this progress, protein-based virus-like particles also generated substantial off-target antibody responses directed against the scaffold itself. Such responses may distract the immune system and potentially hinder propagation of the rare B cells required for effective HIV immunity.

To address this limitation, the researchers explored whether a particle constructed from DNA rather than protein could deliver the priming antigen more selectively. These nanoscale assemblies were fabricated using DNA ‘origami’ – a technique that allows precise control of particle geometry and antigen positioning.

Romanov applied this platform to the eOD-GT8 HIV priming antigen. Initial experiments showed that early designs did not generate a sufficient B cell response. However, redesign of the particle geometry proved decisive. A smaller-diameter DNA virus-like particle displaying 60 copies of eOD-GT8 substantially outperformed the clinical protein-based comparator.

The redesigned construct generated higher numbers of antigen-specific B cells and a markedly greater proportion of cells that were on-target for the relevant HIV epitope. Mechanistic studies linked this improvement to enhanced retention of the particles within B cell follicles in lymph nodes and more effective cooperation with helper T cells, which are essential for B cell survival and maturation.

Additional analyses showed that the DNA-based particles guided VRC01 precursor B cells more efficiently towards the desired antibody lineage than protein-based particles.

“This study showed convincingly that reducing off-target responses through use of a DNA virus-like particle can improve desired on-target responses,” said Dr. William Schief of the SRI’s department of immunology and microbiology.

The absence of scaffold-specific antibody induction suggests that the DNA platform could support later stages of HIV vaccination and may offer broader applications. The researchers suggested that it could improve vaccine responses against future pandemic threats such as influenza and support development of immunotherapies for neurodegenerative disorders or even addiction by inducing highly focused antibody responses.

For further reading please visit: 10.1126/science.adx6291