‘DNA origami’ may be the key to making an effective HIV vaccine, early research suggests. Here’s how it works:

Vaccines designed using “DNA origami” activated more of the key immune cells needed to fight HIV than traditional vaccines built on protein scaffolds, a new mouse study found.

“DNA origami” refers to precisely engineered three-dimensional scaffolds made of folded DNA that can hold and present viral antigens (fragments of the virus that the immune system can recognize and attack).

The results of the new mouse study, published Feb. 5 in the journal Science, suggest a “groundbreaking advance” that could “change the way we think about active immunotherapy and vaccine design,” study co-author Mark Beiss, a professor of bioengineering at MIT, said in a statement.

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Why can this origami approach be transformative? The answer may lie in how DNA-based vaccines are seen by the immune system compared to traditional vaccines.

How DNA origami vaccine works

Traditionally, vaccines have relied on weakened or killed viruses to wake up immune cells and produce antibodies against proteins on the virus’s surface. By binding to proteins, antibodies block the virus from entering human cells and alert the bacteria for destruction by other immune cells.

This process provides immunity by prompting the body to produce “memory B cells.” Memory B cells are activated more quickly and remain if the same pathogen is encountered again.

However, many vaccines currently use only surface antigens attached to synthetic virus-like particles, rather than the whole virus. These nanostructures mimic the size and shape of viruses, but are unable to cause infection.

Most virus-like particles currently in use are constructed using protein scaffolds that are considered “foreign” by the immune system, thus triggering “off-target” antibody responses against the scaffold itself. Previous research has suggested that in some situations, this may weaken the response to the antigen.

In the new study, scientists replaced the protein scaffold with a DNA-based scaffold and in doing so significantly reduced off-target reactions. This new vaccine design generated up to three times more critical memory B cells than state-of-the-art protein nanoparticle vaccines.

John Moore, an HIV researcher at Weill Cornell Medicine who was not involved in the study, called the study “elegant.” This clearly shows how eliminating the immune response associated with the scaffold pushes the immune response “in the right direction,” he told Live Science.

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But he cautioned that it remains to be seen whether similar levels of immune concentration would occur in humans.

What is your competitive advantage?

HIV evades the immune system by constantly rearranging its surface proteins so that antibodies that work against one strain often do not work against others. Adam Wheatley, an immunologist at the University of Melbourne who was not involved in the study, said this was why designing an HIV vaccine was “incredibly difficult”.

He said what a vaccine needs to produce is “broadly neutralizing antibodies” against the virus. These antibodies lock onto parts of the virus that change little between strains.

One example of such an antibody is called VRC01, and it has been identified in a small number of people with HIV infection who produce a broad antibody response in their bodies. VRC01 targets a vulnerable region on the outer envelope of HIV called the CD4 binding site. This is the “key” the virus uses to enter human immune cells, and there is no significant difference between strains.

The challenge is that B cells that can produce VRC01-like antibodies are extremely rare in the human body, said University of Pennsylvania immunologist Rais Andrabi, who was not involved in the study. Activating these elusive cells “becomes an engineering problem,” he told Live Science.

To target these rare B cells, researchers carefully designed a vaccine using HIV antigens on a DNA scaffold. Developed about a decade ago, the antigen mimics the CD4 binding site and binds selectively to a rare B cell receptor, triggering the production of broadly neutralizing antibodies.

Researchers came up with the idea of ​​combining antigens and DNA origami after testing the origami approach with an experimental COVID-19 vaccine. They found that the immune system had virtually no reaction to the DNA scaffold.

“This property seems particularly useful in cases like HIV, where the B cells of interest are extremely rare,” study lead author Anna Romanoff, an immunology researcher at MIT, said in a statement.

They hypothesized that delivering the antigen on a silent scaffold could reduce competition with other unrelated B cells, thereby increasing a “targeted” response against HIV. And the study found that the silent scaffold approach actually expanded B cells that produced broadly neutralizing antibodies. (However, how broadly neutralizing antibodies are actually generated remains to be evaluated; this needs to be considered in future studies.)

“We were all surprised” that the DNA origami outperformed the standard virus-like particles used to elicit the desired B cell response, Beiss said.

In general, Wheatley said, it’s unclear how harmful an immune response to scaffolds is to the body. However, in the case of HIV, desirable B cells are so rare that even small off-target responses appear to impair the response to the target antigen.

The road ahead

Designing a DNA origami vaccine wasn’t easy. Early versions produced a weak immune response. Part of the reason is that after injection, these vaccines were unable to reach specialized immune cells in the lymph nodes where B cells are trained.

To fix this, the team redesigned the DNA particles to more precisely and tightly pack the HIV antigens. This allowed them to be delivered to the appropriate area within the lymph nodes. The researchers also added molecules that help activate T cells, immune cells that help develop important immune responses. This T cell mobilization occurs naturally when using protein scaffold vaccines.

“I think it’s quite surprising how efficiently they modified the DNA scaffolds in different ways to make them work,” Wheatley said. “I think the main usefulness of it is: [that] It’s really adjustable. ”

In addition to HIV, the study authors suggest that DNA origami could be applied to create vaccines against other rapidly mutating viruses, such as influenza, and that focusing on the immune responses that vaccines trigger could improve their effectiveness.

However, it remains to be seen how well this technology will translate to humans. HIV vaccination is “very difficult” and can involve multiple factors that help develop an immune response over time, Andrabi explained, adding, “It’s not just one or two doses.”

But “they found the first step,” he said.