Human antibody discovery platform successfully demonstrates steps to developing HIV vaccine

A new approach to developing a human vaccine against HIV has been published in the internationally renowned scientific journal Science by Kymab, the Cambridge-based antibodies-to-medicines company.

The paper, entitled 'Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice', presents new findings from a collaboration between researchers at Kymab, The Scripps Research Institute (TSRI) of San Diego, California, and the International AIDS Vaccine Initiative (IAVI). HIV is one of the most intransigent targets for vaccine development, and no effective vaccine has been developed in thirty years of global research.

The research, which tested the first step in an approach to develop effective vaccines against the range of HIV variants existing worldwide, was supported by funding from the International AIDS Vaccine Initiative and the US National Institutes of Health. The results show that Kymouse, a mouse that has been modified to mimic human antibody responses, is an effective platform for discovering and testing possible vaccines and suggest ways in which testing of vaccine candidates can be improved.

'We increasingly recognise that traditional vaccine strategies will not be successful against all viruses, especially not HIV,' says Dennis Burton, chair of the TSRI Department of Immunology and Microbial Science and scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center (NAC) at TSRI and the National Institutes of Health (NIH) Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). 'Together with the Kymab team, we have taken a novel approach in which we have induced human antibodies in Kymouse that are at the beginning of the pathway to protective antibodies and which is a huge boost to our mission to develop a HIV vaccine.'

The work is based on the observation that a fraction of people who become infected by HIV develop broadly neutralising antibodies against diverse HIV strains. Such antibodies would be ideal to protect against or possibly treat HIV infection, if a vaccine could be made to elicit them.

However, these antibodies originate from a limited number of precursor antibody-producing cells in the body and acquire their unusual and protective properties only during a long course of infection. Moreover, although these cells have been activated when immunising certain biased animal models, this is the first time this has been achieved through immunisation of an immune system, as in the Kymouse, that resembles the human. The researchers injected Kymouse strains with a nanoparticle formed of 60 copies of a small protein that mimics HIV and was designed to bind and stimulate the specific precursor cells for one class of broadly neutralising antibody. They expected to find just one such precursor cell (among tens of millions of such cells) in each immunised mouse.

The research team then looked to see whether or not the mice had mounted an antibody response to this injection. Given the combined challenges of a complex immunogen structure and the rarity of the right antibodies, an effective response against the HIV immunogen was elicited remarkably efficiently.

'Our phenomenal results with the teams at TSRI and IAVI came from work at the boundaries of protein engineering, immunology and vaccine technology,' explains Professor Allan Bradley, Chief Technical Officer at Kymab and Director Emeritus of the Wellcome Trust Sanger Institute, who developed the Kymouse platform. 'Using Kymouse, we show how an advanced vaccine candidate can search out the one cell among tens of million antibody-producing cells and make it proliferate. Kymouse can deliver antibody responses that we need to build effective HIV vaccines.'

The team validated their antibody response by sequencing genes from more than 10,000 cell samples, and showed that genes from responding mice had the expected sequence for precursors to broadly neutralising antibodies against the HIV target.

'It is a big step forward in this branch of HIV vaccine development,' says William Schief, TSRI Professor and Director of Vaccine Design for the IAVI Neutralizing Antibody Center at TSRI, in whose lab the vaccine nanoparticle was developed. 'We have the first proof of principle that this HIV vaccine strategy and our vaccine candidate can work in a human immune system and trigger the first step in the pathway to developing broadly neutralising and protective antibodies against the virus.

'It is the very sort of response we’d want to see as we test components of a future vaccine.'