MPER-Peptide Liposome Immunogen Testing

OVERVIEW

One key strategy HIV vaccine development immunogen design is to identify immunogens that are selective for the binding of neutralizing versus non-neutralizing antibodies. This approach circumvents the induction of dominant non-neutralizing responses frequently observed during natural infection and with current vaccine protein immunogens. We previously demonstrated that the virion lipid is an important component of the binding immunogen for the gp41 membrane proximal external region (MPER) neutralizing epitope. Moreover, we have shown that antibodies that target this MPER neutralizing site are frequently polyreactive and negatively controlled by immune tolerance mechanisms. To overcome the disfavored status of MPER neutralizing antibodies, the Haynes team has designed an immunogen to recreate this neutralizing epitope that includes the gp41 MPER associated with lipid. It retains the same binding properties for the MPER neutralizing antibodies as seen with virions. Specifically, MPER-peptide liposomes selectively bind the 2F5 and 4E10 mAbs and their unmutated ancestor antibodies (the putative naïve B cell receptors), but do not bind non-neutralizing gp41 MPER antibodies. Additionally, in a 2F5 MPER bnAb variable Heavy and variable light chain (VHVL) mature knock-in mouse model, the team has demonstrated that the MPER-peptide liposome immunogen induces 2F5 bnAbs when formulated with the TLR4 agonist monophosphoryl lipid A. The overall goal of this project is to determine whether MPER peptide-liposomes can be manufactured in GMP for use in a phase I safety and immunogenicity trials. MPER peptide-liposome materials will also be tested to determine the optimal adjuvant formulation for use in clinical trials.

RESEARCH OBJECTIVES

1. Formulation of research grade MPER peptide-liposomes and immunological evaluation in murine and NHP animal models.

2. GMP vaccine production of MPER peptide-liposomes by IDRI in Seattle, WA in collaboration with the IAVI VxPDC team.

3. Carry out a Phase I safety and immunogenicity trial with the HVTN.

PROGRESS

​1. We have found formulations of lipids for use in stable liposomes and are in the final stages of developing GMP manufacturing processes with the support of the IAVI VxPDC team.

2. An adjuvant selection trial was performed in non-human primates (NHPs), and Alum was selected as the adjuvant for the GMP MPER-peptide liposome formulation.

3. A study in 2F5 mature knock-in mice confirmed the immunogenicity of MPER-peptide liposome after several months of storage.

4. The pre-IND was submitted and received favorable reviews. The investigator’s brochure, clinical trial protocol development, and IND submission will proceed once the GMP manufacturing process is finalized.