Inactivated genotype 1a, 2a and 3a HCV vaccine candidates induced broadly neutralising antibodies in mice
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Inactivated genotype 1a, 2a and 3a HCV vaccine candidates induced broadly neutralising antibodies in mice. / Alzua, Garazi Pena; Pihl, Anne Finne; Offersgaard, Anna; Duarte Hernandez, Carlos Rene; Duan, Zhe; Feng, Shan; Fahnøe, Ulrik; Sølund, Christina; Weis, Nina; Law, Mansun; Prentoe, Jannick C.; Christensen, Jan Pravsgaard; Bukh, Jens; Gottwein, Judith Margarete.
In: Gut, Vol. 72, No. 3, 2023, p. 560-572.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Inactivated genotype 1a, 2a and 3a HCV vaccine candidates induced broadly neutralising antibodies in mice
AU - Alzua, Garazi Pena
AU - Pihl, Anne Finne
AU - Offersgaard, Anna
AU - Duarte Hernandez, Carlos Rene
AU - Duan, Zhe
AU - Feng, Shan
AU - Fahnøe, Ulrik
AU - Sølund, Christina
AU - Weis, Nina
AU - Law, Mansun
AU - Prentoe, Jannick C.
AU - Christensen, Jan Pravsgaard
AU - Bukh, Jens
AU - Gottwein, Judith Margarete
N1 - Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2023
Y1 - 2023
N2 - Objective: A prophylactic vaccine is needed to control the HCV epidemic, with genotypes 1-3 causing >80% of worldwide infections. Vaccine development is hampered by HCV heterogeneity, viral escape including protection of conserved neutralising epitopes and suboptimal efficacy of HCV cell culture systems. We developed cell culture-based inactivated genotype 1-3 HCV vaccine candidates to present natively folded envelope proteins to elicit neutralising antibodies. Design: High-yield genotype 1a, 2a and 3a HCV were developed by serial passage of TNcc, J6cc and DBN3acc in Huh7.5 cells and engineering of acquired mutations detected by next-generation sequencing. Neutralising epitope exposure was determined in cell-based neutralisation assays using human monoclonal antibodies AR3A and AR4A, and polyclonal antibody C211. BALB/c mice were immunised with processed and inactivated genotype 1a, 2a or 3a viruses using AddaVax, a homologue of the licenced adjuvant MF-59. Purified mouse and patient serum IgG were assayed for neutralisation capacity; mouse IgG and immune-sera were assayed for E1/E2 binding. Results: Compared with the original viruses, high-yield viruses had up to ∼1000 fold increased infectivity titres (peak titres: 6-7 log10 focus-forming units (FFU)/mL) and up to ∼2470 fold increased exposure of conserved neutralising epitopes. Vaccine-induced IgG broadly neutralised genotype 1-6 HCV (EC50: 30-193 μg/mL; mean 71 μg/mL), compared favourably with IgG from chronically infected patients, and bound genotype 1-3 E1/E2; immune-sera endpoint titres reached up to 32 000. Conclusion: High-yield genotype 1-3 HCV could be developed as basis for inactivated vaccine candidates inducing broadly neutralising antibodies in mice supporting further preclinical development.
AB - Objective: A prophylactic vaccine is needed to control the HCV epidemic, with genotypes 1-3 causing >80% of worldwide infections. Vaccine development is hampered by HCV heterogeneity, viral escape including protection of conserved neutralising epitopes and suboptimal efficacy of HCV cell culture systems. We developed cell culture-based inactivated genotype 1-3 HCV vaccine candidates to present natively folded envelope proteins to elicit neutralising antibodies. Design: High-yield genotype 1a, 2a and 3a HCV were developed by serial passage of TNcc, J6cc and DBN3acc in Huh7.5 cells and engineering of acquired mutations detected by next-generation sequencing. Neutralising epitope exposure was determined in cell-based neutralisation assays using human monoclonal antibodies AR3A and AR4A, and polyclonal antibody C211. BALB/c mice were immunised with processed and inactivated genotype 1a, 2a or 3a viruses using AddaVax, a homologue of the licenced adjuvant MF-59. Purified mouse and patient serum IgG were assayed for neutralisation capacity; mouse IgG and immune-sera were assayed for E1/E2 binding. Results: Compared with the original viruses, high-yield viruses had up to ∼1000 fold increased infectivity titres (peak titres: 6-7 log10 focus-forming units (FFU)/mL) and up to ∼2470 fold increased exposure of conserved neutralising epitopes. Vaccine-induced IgG broadly neutralised genotype 1-6 HCV (EC50: 30-193 μg/mL; mean 71 μg/mL), compared favourably with IgG from chronically infected patients, and bound genotype 1-3 E1/E2; immune-sera endpoint titres reached up to 32 000. Conclusion: High-yield genotype 1-3 HCV could be developed as basis for inactivated vaccine candidates inducing broadly neutralising antibodies in mice supporting further preclinical development.
KW - chronic viral hepatitis
KW - HCV
KW - hepatitis C
KW - immune response
KW - molecular biology
U2 - 10.1136/gutjnl-2021-326323
DO - 10.1136/gutjnl-2021-326323
M3 - Journal article
C2 - 35918103
AN - SCOPUS:85135905423
VL - 72
SP - 560
EP - 572
JO - Gut
JF - Gut
SN - 0017-5749
IS - 3
ER -
ID: 319162664