Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen

Author:

Ou, Li

Kong, Wing-Pui

Chuang, Gwo-Yu

Ghosh, Mridul

Gulla, Krishana

O'Dell, Sijy

Varriale, Joseph

Barefoot, Nathan

Changela, Anita

Chao, Cara W

Cheng, Cheng

Druz, Aliaksandr

Kong, Rui

McKee, Krisha

Rawi, Reda

Sarfo, Edward K

Schön, Arne

Shaddeau, Andrew

Tsybovsky,Yaroslav

Verardi, Raffaello

Wang, Shuishu

Wanninger, Timothy G

Xu, Kai

Yang, Gengcheng J

Zhang, Baoshan

Zhang, Yaqiu

Zhou, Tongqing

Arnold, Frank J

Doria-Rose, Nicole A

Lei, Q Paula

Ryan, Edward T

Vann, Willie F

Mascola, John R

Kwong, Peter D
Author Address

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA., Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA., Massachusetts General Hospital, Boston, 02114, MA, USA., Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, 20993, MD, USA., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA. pdkwong@nih.gov.,

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.

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