DNA Origami Boosts Anti-HIV Antibodies: Vaccine Breakthrough!

HIV is still an emergency, with hundreds of thousands of people dying each year.

And a solution is still far. Can DNA origami play its part and help us shed light on how the immune system reacts to HIV to create better vaccines?

Read up to find out!

HIV vs DNA Origami

HIV: The Silent Pandemic

With over 1.3 million people infected in 2024, the HIV pandemic is still going strong.

It started in the 80s, and, unlike COVID, it never stopped. Luckily, new antiretroviral therapy manages the condition, but over 600,000 people still died in 2024. And in 2025, the twice-yearly injectable Lenacapavir began rolling out in high-burden areas.

A giant scientific breakthrough, it offers an incredible near-total protection from new infections! Unfortunately, it’s still not enough. Twice-yearly injections require reliable healthcare access. In many parts of the world, that’s not an option.

The long-term solution? A vaccine.

Why Don’t We Have an HIV Vaccine Yet?

HIV is the sneakiest virus humanity has ever faced.

Evolution engineered it to win. And developing a vaccine is hard for many reasons:

• Extreme mutation rates: HIV evolves so fast that antibodies against one strain often fail on another.

• Immune evasion: The virus is cloaked in glycans to hide from immune detection.

• It attacks the immune system: HIV targets the very T cells that defend our body.

• No natural immunity: No one has ever cleared an established HIV infection on their own, so scientists don’t have a blueprint for vaccines.

• Genomic integration: The virus inserts itself into the host’s DNA to hide from immune surveillance.

So challenging! But scientists never step down from a challenge.

Broadly Neutralizing Antibodies: the Secret Weapon

Fast mutation is the problem here. A vaccine for one strain fails against another.

Scientists’ secret weapon? Broadly neutralizing antibodies (bnAbs).

These rare antibodies target conserved, essential regions of HIV, parts that the virus cannot easily change without breaking. Instead of recognizing one strain, bnAbs neutralize many. Some bnAbs are already in clinical trials as treatments.

But inducing bnAbs with a vaccine? Incredibly hard.

To generate lasting protection, vaccines need to activate B cells. After antigen presentation, B cells experience genetic recombination for antibody diversity, selection to eliminate self-targeting cells, and final maturation.

You get B cells that produce specific antibodies, and the immune system remembers.

But B cell precursors capable of producing bnAbs are:

• Extremely rare.

• Low affinity for HIV antigens.

• Outcompeted by other B cells.

To make matters worse, bnAbs require extensive maturation inside germinal centers (GCs). And getting the right B cells there in the first place is a real challenge!

A challenge that rational vaccine design wants to solve.

Solving Low Affinity

Well, if one antigen is not enough, what about using more?

Researchers have attached dozens of copies of eOD-GT8 (an HIV antigen engineered to promote bnAbs production) onto protein scaffolds. And it works! This multivalent display increased immune system response and B cell priming.

But do you remember how HIV antigens are weak, and B cells for bnAbs are rare?

It turns out, the protein scaffold itself is immunogenic.

So instead of just getting B cells against HIV, you also generate B cells against the nanoparticle scaffold. And those scaffold-specific B cells can dominate the germinal centers.

If the B cells against the protein scaffold overpower the ones for bnAbs, what’s the point?

Plus, you can’t reuse the same scaffold for boosting or for other drugs, because the immune system now recognizes it!

Are we stuck?

DNA Origami to The Rescue!

When I hear “scaffold”, I think DNA origami. 

And apparently, so did the authors of today’s paper.

DNA origami uses a long, single strand of DNA as a scaffold, together with a bunch of smaller “staple” strands, to create custom nanostructures. You can control shape, size, and molecular placement with nanometer precision!

But even more important here? DNA origami nanostructures are biocompatible and not immunogenic, so you don’t get an anti-scaffold response from B cells. Awesome!

The authors built icosahedral DNA-origami virus-like particles (DNA-VLPs) that present eOD-GT8 (engineered HIV immunogen). Their aim? To test whether removing scaffold immunogenicity focuses B cell responses on the HIV antigen!

What They Designed

The authors engineered several DNA-VLP designs.

The ingredients were:

• Antigen: The particles presented 30 or 60 copies of eOD-GT8 on their surface. A version also used the PADRE peptide to activate T cells (in addition to B cells).

• DNA-VLPs: Icosahedral DNA origami structures of two diameters (~30 and ~40 nm) and two valencies (30 or 60 antigen copies), called d30-30mer, d30-60mer, d40-30mer, d40-60mer. Structures were characterized via gels, DLS, and cryo-EM.

• Adjuvant: To boost the immune response, they used saponin-MPLA nanoparticles.

• Key variables tested: Antigen density, particle size, valency, stability, and more!

The team compared everything to p60mer. This is a protein-based nanoparticle with 60 copies of eOD-GT8, currently in clinical trials as an HIV vaccine.

Geometry and Complement Matter

Initially, things looked promising. DNA-VLPs induced antibody responses at high rates! But most designs failed to activate strong germinal centers. p60mer can do it. What’s the difference?

After injection, p60mer accumulates on follicular dendritic cells, where germinal centers are born. This happens through activation of the complement system, a part of the innate immune system. It covers p60mer in protein, activating GCs.

Can we replicate this with DNA-VLPs?

The key design levers are antigen density and valency. d30-60mer had the closest geometry to p60mer and performed the best. Both in vitro and in mice, d30-60mer had the closest results to p60mer!

T cells are another piece of the puzzle.

They are also involved, but small antigens like eOD-GT8 fail to recruit them. p60mer compensates with the protein scaffold, but DNA can’t do that. So, the researchers added PADRE, a peptide that recruits T cells, increasing GC magnitude!

Did all this vaccine design work?

p60mer still created more B cells. But the DNA origami-induced B cells had a 25x higher ratio of HIV-specific antibodies! Probably, with the DNA scaffold, most B cells are focused on HIV antigens, and none on the scaffold.

Even better: sequencing showed that DNA-VLP vaccination expanded the amino acid signature of bnAb precursors after just 2 weeks. p60mer failed in that short time frame! Removing the immunogenic scaffold shifted competition in favor of rare lineages.

In short: it works!

Focusing Response with DNA Origami

Awesome work!

This paper is a great example of iterative engineering. They tried something, it kinda worked, they figured out why, and then found another piece they didn’t account for. Super tough! But awesome to see in a paper.

Their hypothesis that an immunologically “inert” scaffold (DNA origami) would generate less competition for B cell populations was amazing. The lack of distractor B cells allows rare antigen-specific precursors to receive a larger share of GC resources.

I love DNA origami, it’s no secret. And their system has many strengths:

• Modular engineering allows for customizability and modifications: different valency, size, or even viruses!

• Direct comparison with p60mer, a clinical benchmark.

• Humanised mice for more relevant tests.

It has the usual DNA origami problems:

• Stability in vivo: It’s susceptible to nucleases degradation; PEG helped, but also reduced B cell recognition. We need better solutions.

• Translation questions: Manufacturing scale, DNA origami cost, regulatory path, and potential anti-DNA immune consequences. All unanswered questions.

But the team showed the power of rational vaccine design!

For all the details, read the paper here!

If you made it this far, thank you! What do you think of DNA origami? Do you think it has a place in vaccine development? Reply and let me know!

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