Generation and characterization of a bivalent protein boost for future clinical trials: HIV-1 subtypes CR01_AE and B gp120 antigens with a potent adjuvant.

Details

Serval ID
serval:BIB_5258142D29D7
Type
Article: article from journal or magazin.
Collection
Publications
Title
Generation and characterization of a bivalent protein boost for future clinical trials: HIV-1 subtypes CR01_AE and B gp120 antigens with a potent adjuvant.
Journal
PloS one
Author(s)
Wen Y., Trinh H.V., Linton C.E., Tani C., Norais N., Martinez-Guzman D., Ramesh P., Sun Y., Situ F., Karaca-Griffin S., Hamlin C., Onkar S., Tian S., Hilt S., Malyala P., Lodaya R., Li N., Otten G., Palladino G., Friedrich K., Aggarwal Y., LaBranche C., Duffy R., Shen X., Tomaras G.D., Montefiori D.C., Fulp W., Gottardo R., Burke B., Ulmer J.B., Zolla-Pazner S., Liao H.X., Haynes B.F., Michael N.L., Kim J.H., Rao M., O'Connell R.J., Carfi A., Barnett S.W.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2018
Peer-reviewed
Oui
Volume
13
Number
4
Pages
e0194266
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
The RV144 Phase III clinical trial with ALVAC-HIV prime and AIDSVAX B/E subtypes CRF01_AE (A244) and B (MN) gp120 boost vaccine regime in Thailand provided a foundation for the future development of improved vaccine strategies that may afford protection against the human immunodeficiency virus type 1 (HIV-1). Results from this trial showed that immune responses directed against specific regions V1V2 of the viral envelope (Env) glycoprotein gp120 of HIV-1, were inversely correlated to the risk of HIV-1 infection. Due to the low production of gp120 proteins in CHO cells (2-20 mg/L), cleavage sites in V1V2 loops (A244) and V3 loop (MN) causing heterogeneous antigen products, it was an urgent need to generate CHO cells harboring A244 gp120 with high production yields and an additional, homogenous and uncleaved subtype B gp120 protein to replace MN used in RV144 for the future clinical trials. Here we describe the generation of Chinese Hamster Ovary (CHO) cell lines stably expressing vaccine HIV-1 Env antigens for these purposes: one expressing an HIV-1 subtype CRF01_AE A244 Env gp120 protein (A244.AE) and one expressing an HIV-1 subtype B 6240 Env gp120 protein (6240.B) suitable for possible future manufacturing of Phase I clinical trial materials with cell culture expression levels of over 100 mg/L. The antigenic profiles of the molecules were elucidated by comprehensive approaches including analysis with a panel of well-characterized monoclonal antibodies recognizing critical epitopes using Biacore and ELISA, and glycosylation analysis by mass spectrometry, which confirmed previously identified glycosylation sites and revealed unknown sites of O-linked and N-linked glycosylations at non-consensus motifs. Overall, the vaccines given with MF59 adjuvant induced higher and more rapid antibody (Ab) responses as well as higher Ab avidity than groups given with aluminum hydroxide. Also, bivalent proteins (A244.AE and 6240.B) formulated with MF59 elicited distinct V2-specific Abs to the epitope previously shown to correlate with decreased risk of HIV-1 infection in the RV144 trial. All together, these results provide critical information allowing the consideration of these candidate gp120 proteins for future clinical evaluations in combination with a potent adjuvant.
Keywords
AIDS Vaccines/immunology, Adjuvants, Immunologic, Animals, Antibodies, Neutralizing/immunology, Antigen-Antibody Reactions, CHO Cells, Cricetinae, Cricetulus, Epitopes/immunology, Female, Glycosylation, Guinea Pigs, HIV Antibodies/blood, HIV Antibodies/immunology, HIV Antibodies/metabolism, HIV Antigens/genetics, HIV Antigens/immunology, HIV Antigens/metabolism, HIV Envelope Protein gp120/genetics, HIV Envelope Protein gp120/immunology, HIV Envelope Protein gp120/metabolism, HIV Infections/prevention & control, HIV-1/immunology, HIV-1/metabolism, Humans, Polysorbates, Recombinant Proteins/biosynthesis, Recombinant Proteins/immunology, Recombinant Proteins/isolation & purification, Squalene/immunology
Pubmed
Web of science
Open Access
Yes
Create date
28/02/2022 12:45
Last modification date
23/03/2024 8:24
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