Oral Presentation Lorne Infection and Immunity 2019

Antigenic engineering of a HIV-1 glycoprotein vaccine for the elicitation of broadly neutralizing antibodies (#39)

Hannah AD King 1 2 , Christine Langer 1 , David N Harrison 3 , Vani GS Narasimhulu 1 4 , Rob J Center 1 2 , Heidi E Drummer 1 2 4 , Andy Poumbourios 1 4
  1. Virus Entry and Vaccines Laboratory, Burnet Institute, Melbourne , Victoria , Australia
  2. Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC
  3. Burnet Institute, Melbourne, VIC, Australia
  4. Department of Microbiology, Monash University, Clayton, VIC

In 2017, ninety-five percent of the estimated 4,900 daily new HIV-1 infections occurred in low-to-middle income countries even though worldwide antiretroviral (ART) coverage reached 54% in people living with HIV. These statistics highlight a need for effective prevention strategies with prophylactic vaccines remaining the best hope. A protective vaccine would have a profound impact on the HIV pandemic by blocking the chain of viral transmission and is therefore a global priority. Broadly neutralizing monoclonal antibodies (bNAbs) isolated from infected humans can protect non-human primates from experimental HIV infection and can suppress viral rebound in HIV-infected humans undergoing ART interruption. However, the induction of bNAbs by experimental HIV glycoprotein vaccines has been problematic due to a number of factors including a high degree of sequence variability in gp120-gp41 and the subdominance of conserved neutralization epitopes due to shielding by glycans and flexibility in gp120-gp41 as it oscillates between “closed” and “open” conformations. We developed a novel approach for enhancing the presentation of bNAb epitopes in a soluble disulfide-linked gp120-gp41 trimer vaccine modality (SOSIP) via a glycan deletion (ΔN) in variable loop 1 (V1) of gp120. The bNAb epitope-enhancing effects of ΔN were coupled with mutations that stabilize the gp120-gp41 SOSIP trimer in a non-neutralizing antibody epitope-occluded ‘closed’ conformation for preferential presentation of conserved neutralization epitopes. By screening a panel of SOSIP vaccines with different levels of bNAb epitope exposure and nNAb occlusion, we identified 2 highly thermostable epitope-enhanced immunogens that could be purified in multi-milligram quantities. In small animals, the 2 trimeric Env immunogens elicited bNAbs that were effective against a global panel of difficult to neutralize ‘Tier 2’ HIV-1 reference isolates that are representative of global pandemic strains.  Our discovery represents a major advance for the HIV vaccine research field and we now aim to move our discovery forward into macaque protection studies and ultimately clinical trials.