Design, Test, Repeat: Paths to Elicit Neutralizing Antibodies
A Virtual Mini-Symposium
“Design, Test, Repeat: Paths to Elicit Neutralizing Antibodies” is a 2-hr virtual mini-symposium highlighting some of the latest research in the development of antibody-based HIV vaccines, held on 22 May 2015.
This mini-symposium focuses on selected efforts to design immunogens, develop novel immunization regimens, and track the resulting antibody response with the goal of eliciting broadly protective neutralizing antibodies against HIV. This mini-symposium is inspired by presentations at the “Keystone Symposia March 2015 meeting on “HIV Vaccines” in Banff, Alberta, Canada” and features the following four short, 20 minute talks followed by a panel discussion.
Richard T. Wyatt, IAVI Neutralizing Antibody Center, The Scripps Research Institute
Design of soluble native-like Env proteins
Design of more stabilized native-like Env trimers using native flexibly linked (NFL) and SOSIP approaches opens up new avenues to study Env structure and neutralization mechanisms. These next-generation trimers representing multiple clades also hold promise of presenting to the immune system native Env-like structures, potentially leading to development of more broadly reactive neutralizing antibody responses.
John Mascola, Vaccine Research Center, NIAID, NIH
HIV-1 antibody lineages: Implications for vaccine strategies
The isolation of new neutralizing monoclonal antibodies against the HIV-1 envelope glycoprotein continues to provide insights into regions of Env that can be targeted by active and passive immunization. In addition, there is a growing appreciation that the approach to elicitation of neutralizing antibodies will require both antigenically appropriate antigens, including soluble native trimers, and new strategies of immunization, informed by knowledge of the ontogeny of antibody responses.
Larry Liao, Duke Human Vaccine Institute, Duke University School of Medicine
Pathways and mechanisms of broadly reactive neutralizing antibody induction
Studies of infected individuals described sequential changes in bNAbs during their evolution from germline ancestors to mature forms and matched them to the corresponding changes in Env sequence occurring during immune escape. These findings have led to the design of immunization strategies in which multiple sequential forms of Env are used to guide antibody maturation along pathways predicted to lead to formation of bNAbs. Studies in humans that make bNAbs have demonstrated mechanism of bNAb generation, and identified potential challenges that need to be overcome in future work.
Gunilla Karlsson Hedestam, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
Tracking induced antibody responses
The evolution of HIV-1 Env trimer-specific antibody responses has been tracked in immunized rhesus macaques following single cell sorting and characterization of isolated monoclonal antibodies (MAbs). The MAbs were genetically diverse, even within groups of Abs targeting the same sub-determinant of Env, consistent with a highly polyclonal response. MAbs directed against the CD4 binding site (CD4bs) and the V3 region accounted for the neutralizing activity observed in the plasma of the animal from which they were cloned. We further show that removal of a single N-linked glycosylation site at the base of the V3 region rendered several tier 2 viruses sensitive to the vaccine-induced V3- and CD4bs-directed MAbs, highlighting the effective immune shielding by this glycan. These detailed studies establish baseline results and an approach that will next be applied to evaluate B cell responses elicited by the new generation well-folded trimers now available.