Overcoming the obstacles of eliciting broadly neutralizing antibodies (NAb) to HIV-1 will be a major step? forward to developing a successful AIDS vaccine. The long-term objectives of project 2 are to design,? evaluate and select novel HIV-1 enveloped based immunogens which are capable of inducing broad? neutralizing antibodies which will have a protective effect in vaccinated individuals. The challenge and? reason for this B-cell epitope focused approach is that HIV-1 has developed multiple mechanisms to shield? itself and evade the antiviral effects of many antibodies. By far most host antibodies directed to the envelope? (Env) of HIV-1 are ineffective in eliciting broad Nab responses. There are however several conserved B-cell? epitopes which are rarely exposed, but when recognized by the host are able to elicit a broad Nab response.? Here we aim to develop vaccine immunogens which together will focus the antibody response to highly? conserved Env epitopes. Specifically our aims are to:? 1. To improve the presentation of conformational Nab B-cell epitopes (mimotopes) for optimal presentation in? vivo by; a) Combinatorial Synthesis and """"""""Click"""""""" chemistry through direct collaboration and interaction with? Core D, and, b) Engineered virus-like particles (VLPs) expressing Nab epitopes. Experience in VLPs? expressing HIV peptides will include p55 Gag as well as Hepatitis B particles (Univ Regensburg, this? project).? 2. To identify the optimal vaccine platforms (protein, peptide, and/or viral vector) and regimen for either? priming or boosting conformationaly dependent epitope specificities. This will be facilitated by close? interaction with the vaccine technologies core (B) as well as complementary Env structures developed in? projects 1 and 3.? 3. To determine how many Nab peptide epitopes can optimally be combined in a prime boost immunization? protocol to ultimately generate robust neutralizing antibody responses in an outbred population, evaluated? first in rabbits and subsequently more stringently in non-human-primates models (Core C).? 4. To determine """"""""proof of principle"""""""" protective efficacy of these optimized mimotope-based vaccine regimens? in the SHIV rhesus macaque vaccine challenge model. The best combination of NAb B-cell epitope? presenting structures and delivery systems will be revealed in heterologous and mucosal challenge studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Novartis Vaccines and Diagnostics, Inc.
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Shen, Xiaoying; Bogers, Willy M; Yates, Nicole L et al. (2017) Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques. J Virol 91:
Bogers, Willy M J M; Barnett, Susan W; Oostermeijer, Herman et al. (2017) Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site. J Virol 91:
Bruun, Tim-Henrik; Grassmann, Veronika; Zimmer, Benjamin et al. (2017) Mammalian cell surface display for monoclonal antibody-based FACS selection of viral envelope proteins. MAbs 9:1052-1064
Liang, Frank; Lindgren, Gustaf; Sandgren, Kerrie J et al. (2017) Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake. Sci Transl Med 9:
Vassell, Russell; He, Yong; Vennakalanti, Prasad et al. (2015) Immunogens Modeling a Fusion-Intermediate Conformation of gp41 Elicit Antibodies to the Membrane Proximal External Region of the HIV Envelope Glycoprotein. PLoS One 10:e0128562
Bogers, Willy M; Oostermeijer, Herman; Mooij, Petra et al. (2015) Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion. J Infect Dis 211:947-55
Tuero, Iskra; Mohanram, Venkatramanan; Musich, Thomas et al. (2015) Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge. PLoS Pathog 11:e1005101
Brito, Luis A; Chan, Michelle; Shaw, Christine A et al. (2014) A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol Ther 22:2118-29
Kassa, Aemro; Dey, Antu K; Sarkar, Pampi et al. (2013) Stabilizing exposure of conserved epitopes by structure guided insertion of disulfide bond in HIV-1 envelope glycoprotein. PLoS One 8:e76139
Dey, Antu K; Burke, Brian; Sun, Yide et al. (2012) Elicitation of neutralizing antibodies directed against CD4-induced epitope(s) using a CD4 mimetic cross-linked to a HIV-1 envelope glycoprotein. PLoS One 7:e30233

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