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Hepatology 2015 Dec;62(6):1670-82

Antibodies to an interfering epitope in hepatitis C Virus E2 can mask vaccine-induced neutralizing activity.

Kachko A, Frey SE, Sirota L, Ray R, Wells F, Zubkova I, Zhang P, Major ME

Abstract

Hepatitis C virus (HCV) neutralization occurring at the E2 region 412-426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434-446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred and twelve blinded serum samples from a Phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in ELISA for binding reactivity to peptides representing the E2 regions 412-426 (EP-I) and 434-446 (EP-II). All samples were subsequently tested for neutralizing activity using HCVcc 1a(H77)/2a chimera, HCVpp H77 and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only and 70 double negative. Depleting EP-II antibodies from double positive serum samples increased ID50 neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (p=0.0005) contrasting with ID50 neutralization titer increases in 2 of 70 double negative samples (2.9%) (p>0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (p<0.0003). CONCLUSION: These data show that antibodies to the region 434-446 are induced during immunization of individuals with recombinant E1E2 proteins and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP-II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins.


Category: Journal Article
PubMed ID: #26251214 DOI: 10.1002/hep.28108
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2016-02-29
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