Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen
Li Ou, Wing‐Pui Kong, Gwo‐Yu Chuang, Mridul Ghosh, Krishana Gulla, Sijy O’Dell, Joseph Varriale, Nathan Barefoot, Anita Changela, Cara W. Chao, Cheng Cheng, Aliaksandr Druz, Rui Kong, Krisha McKee, Reda Rawi, Edward K. Sarfo, Arne Schön, Andrew Shaddeau, Yaroslav Tsybovsky, Raffaello Verardi, Shuishu Wang, Timothy G. Wanninger, Kai Xu, Gengcheng Yang, Baoshan Zhang, Yaqiu Zhang, Tongqing Zhou, The VRC Production Program, Nadia Amharref, Christopher R. Barry, Boonchai B. Boonyaratanakornkit, Elizabeth J. Carey, Ria T. Caringal, Kevin Carlton, Naga Chalamalsetty, Adam Charlton, Rajoshi Chaudhuri, Mingzhong Chen, Peifeng Chen, Nicole Cibelli, Jonathan W. Cooper, Hussain Dahodwala, Marianna L. Fleischman, Julia C. Frederick, Haley Fuller, Jason G. Gall, Isaac Godfroy, Deepika Gollapudi, Daniel B. Gowetski, Joe Horwitz, Althaf I. Hussain, Vera B. Ivleva, Lisa A. Kueltzo, Yile Li, Venkata Mangalampalli, Gabriel Moxey, Sarah O’Connell, Aakash Patel, Erwin Rosales‐Zavala, Elizabeth Scheideman, Nicole A. Schneck, Zachary J. Schneiderman, William R. Shadrick, Alison Vinitsky, Xiangchun E. Wang, Sara Witter, Yanhong Yang, Frank Arnold, Nicole A. Doria‐Rose, Q. Paula Lei, Edward T. Ryan, Willie F. Vann, John R. Mascola, Peter D. Kwong
Abstract
The vaccine elicitation of broadly neutralizing antibodies against HIV-1 is a long-sought goal. We previously reported the amino-terminal eight residues of the HIV-1-fusion peptide (FP8) - when conjugated to the carrier protein, keyhole limpet hemocyanin (KLH) - to be capable of inducing broadly neutralizing responses against HIV-1 in animal models. However, KLH is a multi-subunit particle derived from a natural source, and its manufacture as a clinical product remains a challenge. Here we report the preclinical development of recombinant tetanus toxoid heavy chain fragment (rTTHC) linked to FP8 (FP8-rTTHC) as a suitable FP-conjugate vaccine immunogen. We assessed 16 conjugates, made by coupling the 4 most prevalent FP8 sequences with 4 carrier proteins: the aforementioned KLH and rTTHC; the H. influenzae protein D (HiD); and the cross-reactive material from diphtheria toxin (CRM197). While each of the 16 FP8-carrier conjugates could elicit HIV-1-neutralizing responses, rTTHC conjugates induced higher FP-directed responses overall. A Sulfo-SIAB linker yielded superior results over an SM(PEG)2 linker but combinations of carriers, conjugation ratio of peptide to carrier, or choice of adjuvant (Adjuplex or Alum) did not significantly impact elicited FP-directed neutralizing responses in mice. Overall, SIAB-linked FP8-rTTHC appears to be a promising vaccine candidate for advancing to clinical assessment.