A mammalian cell-derived quadrivalent hepatitis C virus (HCV) vaccine has produced broad HCV-specific immune responses in mice, which were apparent after just two doses, according to Australian researchers. Their discovery is hoped to pave the way in the development of a preventative vaccine for HCV that could lower the incidence of HCV, and possibly eradicate it worldwide.
“In countries where modern antiviral therapies are now widely available, there are estimated to be a large number of individuals who are unaware that they are infected, leaving a large residual pool of chronically infected individuals acting as a persistent source for ongoing HCV transmission,” wrote these researchers, led by Dr. Dale Christiansen, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia, in Nature Scientific Reports. “An effective preventative vaccine would therefore have a significant impact on HCV prevalence.
In their study, mice were inoculated with a quadrivalent genotype 1a/1b/2a/3a HCV viral-like particle (VLP) vaccine with or without adjuvant. The vaccine was given as two doses 2 weeks apart.
A vaccine derived from a single genotype can elicit neutralizing antibodies (NAbs), “however, as shown with human papilloma virus vaccine, the inclusion of antigens of a number of different genotypes could be expected to produce broader cross NAb responses,” wrote Dr. Christiansen and colleagues to explain their choice of a quadrivalent vaccine.
Strong antibody responses were demonstrated, with the highest titers in the group receiving the vaccine with alum as adjuvant. The antibody response to the vaccine in phosphate-buffered saline (PBS) as a negative control was comparable to vaccine supplemented with either montanide or Complete Freund’s Adjuvant (CFA).
The geometric mean titer for anti-HCV VLP antibody was highest in mice receiving the quadrivalent HCV VLPs in alum (3.58 log10) compared with HCV VLPs in CFA (3.20 log10; P=0.06), HCV VLPs in montanide (3.10 log10; P=0.006), and HCV VLPs in PBS (3.21 log10; P < 0.023). Mice in all vaccination groups also developed genotype specific antibody responses, with the strongest consistently found against HCV genotype 1b VLPs. In all groups, responses to genotype 1a VLPs were lowest in all groups.
Sera from the mice immunized with HCV VLPs in alum inhibited entry of HCV infectious cell culture system by 72.9% compared with 69.4% with VLPs in PBS and 32.9% with non-immune sera (P < 0.0001). The authors noted that this level of neutralizing antibody response is comparable to that with the monoclonal antibody Mab24.
B-cell responses were assessed following vaccination. The number of antibody secreting cells (ASC) from splenocytes was a mean of 232 with vaccination without adjuvant, and was modestly increased to 266 with VLP with alum. Lower numbers of ASCs were seen after vaccination with CFA or montanide. VLPs with alum adjuvant showed an increase in the number of ASCs for each specific HCV genotype, but the increase was not significant.
Vaccination with VLPs alone resulted in maximal induction of VLP specific T-cell responses, with the mean number of T cells secreting IFNγ following vaccination with VLP alone being 3,396 cells/million splenocytes, which was similar to the number observed following vaccination with VLP and alum (mean: 2,706 /million splenocytes) and significantly higher than the T-cell responses following vaccination of VLPs with either CFA or montanide as adjuvants. The quadrivalent vaccine produced strong CD4+ T-cell and granzyme B-cell responses.
Selective neutralizing human monoclonal antibodies targeting conserved antigenic domain B and D epitopes of the E2 protein bound strongly to the HCV VLPs, “suggesting that these critical epitopes are expressed on the surface of the particles,” the authors wrote. “The overriding message from our data is that crucial epitopes important for neutralization of HCV are expressed on our VLPs.”
“Our data demonstrate that a quadrivalent HCV VLP based vaccine, in the absence of adjuvant, is able to produce broad humoral and cellular immune responses that are necessary for protection against HCV infection,” they concluded.
This work was supported by the National Health and Medical Research Council (NHMRC) of Australia, the National Institute of Allergy and Infectious Diseases/NIH.