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

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 neu...

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Published in:Scientific reports 2020-02, Vol.10 (1), p.3032, Article 3032
Main Authors: 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
Format: Article
Language:English
Subjects:
Adjuvants, Immunologic
AIDS Vaccines - immunology
Amino Acid Sequence
Animal models
Animals
Cross Reactions - immunology
Diphtheria
Diphtheria toxin
Female
HIV
HIV-1 - immunology
Human immunodeficiency virus
Immunization
Mice, Inbred BALB C
Mice, Inbred C57BL
Neutralization Tests
Peptides
Peptides - chemistry
Peptides - immunology
Protein D
Recombinant Fusion Proteins - immunology
Tetanus
Toxins
Vaccines
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-59711-y