How broadly neutralising antibodies are driving the quest for an HIV vaccine

Most vaccines work by triggering the immune system to make antibodies that can protect against (or neutralise) infection. Vaccination typically elicits antibodies that are the same as those created in infection, and they do a good job at protecting the vaccinated person from infection.

Neutralising antibodies are rare in HIV infection

In HIV infection, the immune system makes loads of antibodies. HIV diagnosis relies on the detection of these antibodies. Unfortunately, most of these antibodies do not block or neutralise the virus. HIV prevents neutralising antibodies from being made against it through two main strategies: shielding and changing. The virus particle itself is shielded by a layer of sugar molecules called glycans. Antibodies that bind to glycans are generally not able to neutralise infection. To neutralise, antibodies need to get to the underlying viral proteins that help get viral particles into the host cell. Here is where the second strategy comes into play. HIV is incredibly variable, quickly evolving so that few regions remain the same between virus strains and in the same strain over time. This variety means that antibodies that bind to one viral particle may not bind to another. On top of this, variable parts of the virus are often positioned right next to the small regions that do remain steady, making it challenging for antibodies to only bind to fixed sequences.

Despite all of these challenges, some people with HIV infection do develop broadly neutralising antibodies (bnAbs). These antibodies are able to block a wide variety of HIV isolates (hence the name ‘broadly neutralising’). The development of these antibodies usually takes a long time, so by the time they emerge, infection is well established and their neutralisation effect is limited. The existence, and isolation, of these antibodies is still an amazing opportunity for researchers and ultimately for people living with HIV. Clinical trials are underway using bnAbs as therapy, and for use in HIV prevention. BnAbs are also being studied to develop new and better methods for HIV prevention, including in the development of an HIV vaccine.

The potential of bNAbs

Understanding which parts of the virus bnAbs target, how they interact with the virus and how and when they are made are all critical questions. Isolating and studying bnAbs from people living with HIV can help to answer these questions.

All bnAbs bind to spikes on the HIV envelope. These spikes are made of two glycoproteins (proteins with glycan residues attached), gp120 and gp41, which form a triplet cluster (or trimer) on the viral particle. We know which parts of the envelope spike bnAbs bind to. Binding sites include the parts that interact with the CD4 receptor and chemokine co-receptors on host T cells. Isolation of bnAbs from a range of people with HIV from different parts of the world (harbouring different virus strains) has helped characterise a range of binding sites on the envelope spike. Neutralisation can therefore occur in a variety of ways – blocking binding to host cells, blocking the shape changes needed for infection, or by destabilising the envelope so that it falls apart. All these insights have come from the study of bnAbs.

The big question is whether it is possible to direct the formation of bnAbs in people (through vaccination), or in the lab. Developing a version of the HIV envelope that can drive the formation of bnAbs is hard. Soluble versions tend to fall apart or they don’t look enough like the envelope on a virus particle.

Studies of prevention and treatment with human bnAbs in animal models and humans with HIV have shown the potential to reduce viral loads (often only temporarily), or to delay virus rebound in people stopping their antiretroviral therapy.

While bnAbs could be used as treatment, the biggest potential for bnAbs is in vaccine development. If a vaccine could trigger bnAb development, well, let’s just say it would revolutionise HIV prevention. The discovery of bnAbs and work to understand their structure and interaction with HIV is the lifeblood of current progress towards an HIV vaccine. The use of existing bnAbs to inform vaccine development is dubbed ‘reverse vaccinology’, a reference to the process of reverse engineering that sees an end product pulled apart to establish its components and workings.

bnAb examples

Recent advances in bNAb research

Three recent studies highlight the enormous potential of bnAbs as well as some of the barriers that exist in trying to develop an HIV vaccine for use around the world.

Cows get things mooving

Looking to sway the generation of bnAbs towards those with an unusual shape to reach shielded binding sites, researchers associated with the International AIDS Vaccine Initiative tried vaccinating cows. The researchers knew that human bnAbs had a longer than average loop called the HCDR3. Cows are known to make antibodies with longer HCDR3 loops than humans, so these researchers thought they’d try vaccinating cows. The team used a version of soluble HIV envelope called BG505 SOSIP, which is stable and shown to mimic the HIV envelope. Incredibly, the cows not only made really potent bnAbs, but they did it fast.

This study has answered a few important questions. Firstly, it shows that the BG505 SOSIP construct can drive bnAb formation. Secondly, it shows that long HCDR3 loops are beneficial, and vaccine strategies should try to favour the development of long HCDR3 loops. Finally, the speed of bnAb development in this study means that cows may hold more clues to effective bnAb evolution. “HIV is a human virus,” said Devin Sok, first author and Antibody Discovery and Development Director at IAVI, “but researchers can certainly learn from immune responses across the animal kingdom.” See here for more details.

How a shield can also be an anchor

Glycan residues covering the HIV envelope protein are typically considered to shield the virus from antibody binding. A new study has looked more closely at the influence of glycan residues on bnAb development over time. Researchers from The Scripps Research Institute in California studied a family of bnAbs from a single donor that bind to the top (or apex) of the HIV envelope spike. These antibodies came from a single donor, CAP256, from about 1-4 years after HIV infection. The researchers discovered that specific glycan locations and types were critical for antibody binding and helped bnAb development. First author Raiees Andrabi explains “these glygans essentially provided an ‘anchor’ for antibodies in this lineage as the surrounding viral proteins changed.” This study highlights the complexity of bnAb development in people with HIV. The work suggests that specific glycan residues may be as important for bnAb development as the virus sequence itself. Curiously, and linked to the findings of the cow study above, the CAP256 antibodies have an unusually long HCDR3 loop. For more details see here.

The triple threat: bnAbs that bind three separate parts of the envelope

Diagram of the “three-in-one” HIV antibody. The blue, purple and green segments each bind to a different critical site on the virus. Sanofi.

Researchers from the NIH and Sanofi have engineered a broadly neutralising antibody that binds to three independent parts of the HIV envelope. The strategy takes binding sites from three separate antibodies – VRC01, PGDM1400 and 10E8v4 – and builds them into a single molecule. As listed in the table above, VRC01 targets the CD4 binding site; PGDM1400 the trimer apex (like CAP256) and 10E8v4 targets the base of the trimer stalk, just near the viral membrane. The recent study details the stability and potency of the new three-in-one antibody (hint: it’s pretty stable and highly potent). The three-pronged antibody was given to monkeys and compared to infusions of either VRC01 or PGDM1400 alone. Only animals given the three-pronged antibody were protected from infection. 100% of animals given the trispecific antibody remained uninfected, compared to 25% of animals given VRC01 alone and 38% of animals given PGDM1400 alone. More detail can be found here. Preparations are now underway for human clinical trials.

antibodies bNAbs broadly neutralising antibodies clinical trial HIV research vaccine