Weiss Vaccine Discovery Consortium

OVERVIEW:

The human immune system fights HIV-1 in numerous ways, including via the production of T-cell responses and antibodies. Researchers are studying these natural immune defenses to find clues that could help them design an HIV-1 vaccine that can neutralize the virus.
 
Several naturally occurring antibodies against HIV-1 have been discovered. A handful of them are capable of neutralizing a broad range of strains. Researchers in the Weiss-led Vaccine Discovery Consortium (VDC) at University College London (UCL) have found new relatively broad neutralizing antibodies in human HIV-1-infected blood samples. Using these antibodies, the researchers can identify the epitopes that elicit these antibodies. Using the epitopes as models, the investigators then can attempt to design new immunogens capable of eliciting antibodies to HIV-1.

The UCL VDC is looking for additional naturally occurring neutralizing monoclonal antibodies (NMAbs), especially those that can neutralize Clades C and A/CRF02_AG which represent over 50% and ~27.5% respectively of the currently circulating viruses. A vaccine for these Clades will potentially protect individuals from 75% of new HIV-1 infections, the majority in sub-Saharan Africa.

RESEARCH OBJECTIVES:

1. Identify novel monoclonal antibodies that cross-neutralize HIV-1 between and within clades.

2. Direct the selection of novel immunogens recognized by these monoclonal antibodies. These novel immunogens will serve as the basis for the creation of HIV-1 vaccine candidates.

3. Demonstrate the ability of these novel immunogen vaccine candidates to elicit anti-HIV-1 antibodies in animal models. Successful candidates will progress to testing in human Phase I trials.

PROGRESS:

At the start of the CAVD in 2006, only five neutralizing monoclonal antibodies (NMAbs) that broadly cross-neutralized multiple HIV-1 strains were known. Using blood from HIV-1-infected humans, the Weiss VDC researchers have identified 3 novel reasonably broad neutralizing human monoclonal antibodies (NMAbs) which have been comprehensively characterized for epitope specificity and neutralization activity. All 3 NMAbs have been produced in large scale and one is undergoing in vivo macaque passive immunization studies.

In addition to the NMAbs isolated from infected people, the Weiss VDC researchers have successfully isolated NMAbs from llamas immunized with HIV-1 Env cloned from African HIV-1 isolates. Llamas produce heavy chain-based NMAbs which provide properties that will be useful in screening and characterizing candidate components of an HIV-1 vaccine. The researchers have discovered eight groups of broadly neutralizing monoclonal antibodies in llamas.

The researchers have also produced NMAbs from genetically engineered HuIg mice that have been immunized with HIV-1 Env from African strains. HuIg mice produce antibodies with features of human immunoglobulins that may be important in HIV-1 neutralization. The researchers have produced several mouse-derived monoclonal antibodies, one of which is broadly reactive with HIV Clade A and C.

Researchers at the UCL VDC are using the NMAbs to identify protein and peptide structures that are derived from, or mimic, epitopes on the HIV-1 envelope as candidate components of a vaccine. By re-iterative screening of slightly different molecules the aim is to identify ones that can be used to immunize individuals so as to generate protective Abs in the body. In parallel the researchers are exploring other strategies for designing Env-based antigens that are not reliant on antibody-based ‘reverse vaccinology’.

The selected immunogens are being tested for their ability to induce NAbs in animals to evaluate which immunogens might be useful to take forward into preliminary clinical trials in humans. Currently, the immunogens are tested in rabbits and subsequently the best candidates will be tested in macaques which can be challenged with a live virus bearing an HIV-1 Env to determine whether the Abs actually protect against infection.

Novel adjuvants, which are molecules that stimulate immune responses, are being evaluated for their efficacy with HIV-1 immunogens.