Year: 2006
Type: article
Abstract: Another Cautionary Note for HCV VaccinesUsing the chimpanzee model, Puig and coworkers analyzed the protective effect of a vaccine-induced T cell response in the absence of neutralizing antibody.Two animals, previously recovered from HCV infection, were immunized with an NS3, NS5A, or NS5B DNA primer followed by a recombinant vaccinia virus-HCV protein boost containing only nonstructural proteins.One HCV-naı ¨ve chimpanzee received the same construct as a primary immunization.Each animal was challenged with the HCV1a infectious clone.Vaccination did not prevent infection in any of the animals, but the infection/disease in the 2 animals that had spontaneously recovered prior to reimmunization was markedly delayed and attenuated compared to that in the HCVnaı ¨ve animal.The attenuated infection coincided with enhanced postchallenge T cell responses that remained strong even after viral clearance.Of primary interest in this study is that the naı ¨ve-immunized animal initially contained infection with an approximate 4 log decline in HCV RNA levels, only to have rebound viremia at week 10 that then became persistent.Importantly, in this animal, compared to those who cleared infection, CD4ϩ T cell responses did not increase with the onset of viremia and showed decreased proliferative capacity in both the acute and chronic phases.Sequence analysis demonstrated 2 nonsynonymous mutations in the samples at 8 and 13 weeks after challenge.T cells recognized wild-type peptides, but did not recognize the mutant epitopes and thus the virus had developed critical escape mutations in both the NS3 and NS5 regions.Further, over an interval up to 53 weeks, T cell responses to the wild-type virus declined and no T cell response to the mutant virus emerged.Interestingly, the escape mutations occurred in CD4 epitopes whereas most previously described escape mutants have been in CD8ϩ epitopes.What can we take away from this? First, it would appear that subjects who recover from prior HCV infection are better positioned to control and clear a second infection by virtue of T cell memory and early T cell effector responses.Second, viral clearance can be achieved in the absence of neutralizing antibodies to envelope proteins.Third, persistent infection can be the result of viral escape mutants and that these critical mutations can occur in CD4ϩ epitopes as well as CD8ϩ epitopes.Fourth, a DNA prime-protein boost vaccination strategy did not achieve sterilizing immunity in any animal, but did appear to attenuate infection in those previously exposed.Fifth, an apparent successful early attenuation of infection following primary infection/immunization can be overcome by the emergence of T cell escape mutants and hence that vaccine-induced T cell responses before challenge do not necessarily prevent persistent HCV infection.Most HCV vaccine programs have retreated from the prospect of inducing sterilizing immu-nity and are basing success on the prevention of chronic infection.It appears that even this more limited goal will not always be achieved.This is one tough virus.(See
Source: Hepatology
DOI: 10.1002/hep.21371
Author: Harvey J. Alter
Language: English
Topic: Hepatitis C virus research
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4246110163