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 develop a GMP manufacturing process for production of MPER peptide-liposomes (a.k.a MPER-656 Liposomes) at the appropriate quality and scale for use in a first-in-human phase I clinical trial to evaluate safety and immunogenicity. Specifically, we will determine if the MPER peptide-liposomes can expand gp41 proximal MPER broadly neutralizing precursors after vaccination.
- Formulation of research grade MPER peptide-liposomes and immunological evaluation in murine and NHP animal models.
- GMP vaccine production of MPER peptide-liposomes by IDRI in Seattle, WA in collaboration with the IAVI VxPDC team.
- Carry out a Phase I safety and immunogenicity trial with the HVTN.
- 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.
- A preclinical study in 2F5 mature knock-in mice conﬁrmed the immunogenicity of MPER-656 Liposomes after several months of frozen storage. Additionally, continuous stability testing of early R&D lots has demonstrated that MPER-656 Liposomes are stable for at least 24 months when stored at -20°C.
- Process development for the GMP manufacturing process was completed at IDRI in 2017 with the support of the IAVI VxPDC team, and material was produced for use in the toxicology study.
- An ID50/ potency study was performed in mice using the toxicology study batch (engineering run) of MPER-656 Liposomes. These data will provide a baseline by which to compare potency of subsequent MPER-656 Liposomes lots.
- A preclinical GLP toxicology study in rabbits was conducted by Charles River Laboratories (CRL) in 2018 to verify safety of vaccination with MPER-peptide liposomes plus Alum adjuvant. There were no unscheduled deaths, no evidence of systemic toxicity, and no local irritation at the administration sites that were related to treatment with MPER-656 Liposomes. The in-life phase of the study ran from April to July 2018, and the full final report was received in November 2018.
- Manufacture of the GMP grade clinical trial material (CTM) was completed by IDRI at the end of 2018.
- The HVTN 133 IND was submitted in June 2019 and received the “safe-to-proceed” from the FDA in July 2019.
- The Phase I clinical trial, HVTN 133, opened for enrollment in September 2019. The trial is currently active, and immunizations for all participants will be completed by the end of November 2020.