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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033230/ https://www.ncbi.nlm.nih.gov/pubmed/32080235 http://dx.doi.org/10.1038/s41598-020-59711-y |
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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_facet | 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_sort | Ou, Li |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7033230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70332302020-02-28 Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen 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. Sci Rep Article 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. Nature Publishing Group UK 2020-02-20 /pmc/articles/PMC7033230/ /pubmed/32080235 http://dx.doi.org/10.1038/s41598-020-59711-y Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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. Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen |
title | Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen |
title_full | Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen |
title_fullStr | Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen |
title_full_unstemmed | Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen |
title_short | Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen |
title_sort | preclinical development of a fusion peptide conjugate as an hiv vaccine immunogen |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033230/ https://www.ncbi.nlm.nih.gov/pubmed/32080235 http://dx.doi.org/10.1038/s41598-020-59711-y |
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