Human antibody discovery demonstrates steps to developing HIV vaccine

Kymab the Cambridge-based antibodies-to-medicines company, improves discovery and testing of promising HIV vaccine strategies through collaboration.

Kymab has announced a publication of a new approach to developing a human vaccine against HIV. The paper is entitled “Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice”.

The publication 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).

The research, which tested the first step in an approach to develop effective vaccines against the range of HIV variants existing worldwide, was published in Science and was supported by funding from the International AIDS Vaccine Initiative and the US National Institutes of Health.

The results show that Kymouse, which is 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.

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 it 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 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.

  HIV has proved an extremely difficult challenge in vaccine development. The new research shows that Kymouse can produce antibodies of the type that could evolve to confer protection, suggests ways in which the immunisation regime can be improved.

“About 35 million people have died of HIV/AIDS and 36 million are currently infected. Although a vaccine is the most likely way to stem this loss, no successful vaccine has been found in more than thirty years of HIV research,” says Professor Paul Kellam, vice president of infectious diseases and vaccines at Kymab. “This is a pressing need and these results show that our Kymouse technologies can serve a vital part in the search for effective vaccines that help to protect against this most challenging disease.”

“This dramatic proof of concept gives us hope we can find better broadly effective vaccines for HIV and, indeed, for other infections, using the human immune system to help guide us along the best path.”