Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis c virus infections uncover molecular determinants for E2 targeting and vaccine design

Zhen Yong Keck; Brian G. Pierce; Patrick Lau; Janine Lu; Yong Wang; Alexander Underwood; Rowena A. Bull; Jannick Prentoe; Rodrigo Velázquez-Moctezuma; Melanie R. Walker; Fabio Luciani; Johnathan D. Guest; Catherine Fauvelle; Thomas F. Baumert; Jens Bukh; Andrew R. Lloyd; Steven K.H. Foung

doi:10.1371/journal.ppat.1007772

Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis c virus infections uncover molecular determinants for E2 targeting and vaccine design

Zhen Yong Keck, Brian G. Pierce, Patrick Lau, Janine Lu, Yong Wang, Alexander Underwood, Rowena A. Bull, Jannick Prentoe, Rodrigo Velázquez-Moctezuma, Melanie R. Walker, Fabio Luciani, Johnathan D. Guest, Catherine Fauvelle, Thomas F. Baumert, Jens Bukh, Andrew R. Lloyd, Steven K.H. Foung^*

^*Corresponding author for this work

19 Citations (Scopus)

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Abstract

Cumulative evidence supports a role for neutralizing antibodies contributing to spontaneous viral clearance during acute hepatitis C virus (HCV) infection. Information on the timing and specificity of the B cell response associated with clearance is crucial to inform vaccine design. From an individual who cleared three sequential HCV infections with genotypes 1b, 1a and 3a strains, respectively, we employed peripheral B cells to isolate and characterize neutralizing human monoclonal antibodies (HMAbs) to HCV after the genotype 1 infections. The majority of isolated antibodies, designated as HMAbs 212, target conformational epitopes on the envelope glycoprotein E2 and bound broadly to genotype 1–6 E1E2 proteins. Further, some of these antibodies showed neutralization potential against cultured genotype 1–6 viruses. Competition studies with defined broadly neutralizing HCV HMAbs to epitopes in distinct clusters, designated antigenic domains B, C, D and E, revealed that the selected HMAbs compete with B, C and D HMAbs, previously isolated from subjects with chronic HCV infections. Epitope mapping studies revealed domain B and C specificity of these HMAbs 212. Sequential serum samples from the studied subject inhibited the binding of HMAbs 212 to autologous E2 and blocked a representative domain D HMAb. The specificity of this antibody response appears similar to that observed during chronic infection, suggesting that the timing and affinity maturation of the antibody response are the critical determinants in successful and repeated viral clearance. While additional studies should be performed for individuals with clearance or persistence of HCV, our results define epitope determinants for antibody E2 targeting with important implications for the development of a B cell vaccine.

Original language	English
Article number	e1007772
Journal	P L o S Pathogens
Volume	15
Issue number	5
Number of pages	28
ISSN	1553-7366
DOIs	https://doi.org/10.1371/journal.ppat.1007772
Publication status	Published - 2019

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Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis C virus infections uncover molecular determinants for E2 targeting and vaccine designFinal published version, 2.63 MBLicence: CC BY

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Keck, Z. Y., Pierce, B. G., Lau, P., Lu, J., Wang, Y., Underwood, A., Bull, R. A., Prentoe, J., Velázquez-Moctezuma, R., Walker, M. R., Luciani, F., Guest, J. D., Fauvelle, C., Baumert, T. F., Bukh, J., Lloyd, A. R., & Foung, S. K. H. (2019). Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis c virus infections uncover molecular determinants for E2 targeting and vaccine design. P L o S Pathogens, 15(5), Article e1007772. https://doi.org/10.1371/journal.ppat.1007772

Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis c virus infections uncover molecular determinants for E2 targeting and vaccine design. / Keck, Zhen Yong; Pierce, Brian G.; Lau, Patrick et al.
In: P L o S Pathogens, Vol. 15, No. 5, e1007772, 2019.

Research output: Contribution to journal › Journal article › Research › peer-review

Keck, ZY, Pierce, BG, Lau, P, Lu, J, Wang, Y, Underwood, A, Bull, RA, Prentoe, J, Velázquez-Moctezuma, R, Walker, MR, Luciani, F, Guest, JD, Fauvelle, C, Baumert, TF, Bukh, J, Lloyd, AR & Foung, SKH 2019, 'Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis c virus infections uncover molecular determinants for E2 targeting and vaccine design', P L o S Pathogens, vol. 15, no. 5, e1007772. https://doi.org/10.1371/journal.ppat.1007772

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title = "Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis c virus infections uncover molecular determinants for E2 targeting and vaccine design",

abstract = "Cumulative evidence supports a role for neutralizing antibodies contributing to spontaneous viral clearance during acute hepatitis C virus (HCV) infection. Information on the timing and specificity of the B cell response associated with clearance is crucial to inform vaccine design. From an individual who cleared three sequential HCV infections with genotypes 1b, 1a and 3a strains, respectively, we employed peripheral B cells to isolate and characterize neutralizing human monoclonal antibodies (HMAbs) to HCV after the genotype 1 infections. The majority of isolated antibodies, designated as HMAbs 212, target conformational epitopes on the envelope glycoprotein E2 and bound broadly to genotype 1–6 E1E2 proteins. Further, some of these antibodies showed neutralization potential against cultured genotype 1–6 viruses. Competition studies with defined broadly neutralizing HCV HMAbs to epitopes in distinct clusters, designated antigenic domains B, C, D and E, revealed that the selected HMAbs compete with B, C and D HMAbs, previously isolated from subjects with chronic HCV infections. Epitope mapping studies revealed domain B and C specificity of these HMAbs 212. Sequential serum samples from the studied subject inhibited the binding of HMAbs 212 to autologous E2 and blocked a representative domain D HMAb. The specificity of this antibody response appears similar to that observed during chronic infection, suggesting that the timing and affinity maturation of the antibody response are the critical determinants in successful and repeated viral clearance. While additional studies should be performed for individuals with clearance or persistence of HCV, our results define epitope determinants for antibody E2 targeting with important implications for the development of a B cell vaccine.",

author = "Keck, {Zhen Yong} and Pierce, {Brian G.} and Patrick Lau and Janine Lu and Yong Wang and Alexander Underwood and Bull, {Rowena A.} and Jannick Prentoe and Rodrigo Vel{\'a}zquez-Moctezuma and Walker, {Melanie R.} and Fabio Luciani and Guest, {Johnathan D.} and Catherine Fauvelle and Baumert, {Thomas F.} and Jens Bukh and Lloyd, {Andrew R.} and Foung, {Steven K.H.}",

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AU - Keck, Zhen Yong

AU - Pierce, Brian G.

AU - Lau, Patrick

AU - Lu, Janine

AU - Wang, Yong

AU - Underwood, Alexander

AU - Bull, Rowena A.

AU - Prentoe, Jannick

AU - Velázquez-Moctezuma, Rodrigo

AU - Walker, Melanie R.

AU - Luciani, Fabio

AU - Guest, Johnathan D.

AU - Fauvelle, Catherine

AU - Baumert, Thomas F.

AU - Bukh, Jens

AU - Lloyd, Andrew R.

AU - Foung, Steven K.H.

PY - 2019

Y1 - 2019

N2 - Cumulative evidence supports a role for neutralizing antibodies contributing to spontaneous viral clearance during acute hepatitis C virus (HCV) infection. Information on the timing and specificity of the B cell response associated with clearance is crucial to inform vaccine design. From an individual who cleared three sequential HCV infections with genotypes 1b, 1a and 3a strains, respectively, we employed peripheral B cells to isolate and characterize neutralizing human monoclonal antibodies (HMAbs) to HCV after the genotype 1 infections. The majority of isolated antibodies, designated as HMAbs 212, target conformational epitopes on the envelope glycoprotein E2 and bound broadly to genotype 1–6 E1E2 proteins. Further, some of these antibodies showed neutralization potential against cultured genotype 1–6 viruses. Competition studies with defined broadly neutralizing HCV HMAbs to epitopes in distinct clusters, designated antigenic domains B, C, D and E, revealed that the selected HMAbs compete with B, C and D HMAbs, previously isolated from subjects with chronic HCV infections. Epitope mapping studies revealed domain B and C specificity of these HMAbs 212. Sequential serum samples from the studied subject inhibited the binding of HMAbs 212 to autologous E2 and blocked a representative domain D HMAb. The specificity of this antibody response appears similar to that observed during chronic infection, suggesting that the timing and affinity maturation of the antibody response are the critical determinants in successful and repeated viral clearance. While additional studies should be performed for individuals with clearance or persistence of HCV, our results define epitope determinants for antibody E2 targeting with important implications for the development of a B cell vaccine.

AB - Cumulative evidence supports a role for neutralizing antibodies contributing to spontaneous viral clearance during acute hepatitis C virus (HCV) infection. Information on the timing and specificity of the B cell response associated with clearance is crucial to inform vaccine design. From an individual who cleared three sequential HCV infections with genotypes 1b, 1a and 3a strains, respectively, we employed peripheral B cells to isolate and characterize neutralizing human monoclonal antibodies (HMAbs) to HCV after the genotype 1 infections. The majority of isolated antibodies, designated as HMAbs 212, target conformational epitopes on the envelope glycoprotein E2 and bound broadly to genotype 1–6 E1E2 proteins. Further, some of these antibodies showed neutralization potential against cultured genotype 1–6 viruses. Competition studies with defined broadly neutralizing HCV HMAbs to epitopes in distinct clusters, designated antigenic domains B, C, D and E, revealed that the selected HMAbs compete with B, C and D HMAbs, previously isolated from subjects with chronic HCV infections. Epitope mapping studies revealed domain B and C specificity of these HMAbs 212. Sequential serum samples from the studied subject inhibited the binding of HMAbs 212 to autologous E2 and blocked a representative domain D HMAb. The specificity of this antibody response appears similar to that observed during chronic infection, suggesting that the timing and affinity maturation of the antibody response are the critical determinants in successful and repeated viral clearance. While additional studies should be performed for individuals with clearance or persistence of HCV, our results define epitope determinants for antibody E2 targeting with important implications for the development of a B cell vaccine.

U2 - 10.1371/journal.ppat.1007772

DO - 10.1371/journal.ppat.1007772

M3 - Journal article

C2 - 31100098

AN - SCOPUS:85067269593

SN - 1553-7366

VL - 15

JO - P L o S Pathogens

JF - P L o S Pathogens

IS - 5

M1 - e1007772

ER -

Broadly neutralizing antibodies from an individual that naturally cleared multiple hepatitis c virus infections uncover molecular determinants for E2 targeting and vaccine design

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