Duke Uni: Holy grail of HIV vaccine in sight using ‘paradoxical’ bnAbs

For it to work globally against different HIV-1 strains, any future vaccine must target multiple antibody lineages, requiring several immunogens and novel adjuvant formulations, lead researcher Tony Moody told BioProcess International conference in Boston this week.  

HIV: ‘orders of magnitude’ more diverse than flu​

Moody told a keynote audience the enormous genetic diversity of HIV pathogens requires a completely novel approach to get to a vaccine. Creating a new vaccine every season or for different regions is unfeasible: “We make a new vaccine every year for flu because of the virus’s diversity. The differences in HIV strains are orders of magnitude greater.​”

To combat the diversity of strains, an effective vaccine will need to provide sterilising immunity – preventing infection rather than delaying progression or transmission – a first in the vaccine world.

Broadly neutralising antibodies ​

The Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) is pursuing a strategy that turns one of HIV’s most pernicious characteristics on its head – the way it acts on the immune system differently from other viruses.

In most people with HIV, infection occurs with a single strain of the virus, but soon mutates while the immune system attempts to chase it. Some infected individuals produce monoclonal antibodies (mAbs) which have already been shown to protect against HIV infection in rhesus macaques.​ Vaccine developers hope to find a way to induce these antibodies in others – but how?

B-cell lineages​

The HIV patients who produce these broadly neutralising antibodies (bnAbs) tend to also display higher viral loads, lower CD4 T-cell counts, higher frequency of plasma auto-antibodies, and higher T-follicular helper cells in the blood.

According to Moody, these properties provide a clue to the HIV vaccine problem as they suggest the virus causes disruptions to the immune system that could be mimicked with adjuvants to induce desirable bnAbs.

But it’s a complicated task. Paradoxially, bnAbs are driven to develop by evolving “envelope” mutations; but these envelope mutations are themselves escape mutations from bnAbs.

A paper published in Cell ​last year​ showed bnAb production is driven by cooperation between two B-cell lineages in an HIV-infected individual, due to these heterologous envelope motifs.

The implication is that an HIV-1 vaccine will need to target more than one bnAb lineage to extend its breadth. A successful regime will be complicated and have to involve multiple immunogens, most likely administered separately rather than as a cocktail, Moody concluded.

First in humans​

The macaque studies show scientists can start the correct lineages to drive bnAb pathways. Clinical studies are in the planning stages; “It’s incredibly important to understand human trials are probably where the whole problem will be solved,​” said Duke’s researcher. Immunogens for targeting HIV are being designed based on information from the human immune system, so Phase I is critical.

Partnerships between pharma and academia are “key​” to gathering the resources needed to transition to clinical stage, he said.   

The research is being funded by CHAVI-ID and the Gates Foundation.