Pre-clinical evaluation of a quadrivalent HCV VLP vaccine in pigs following microneedle delivery

Abstract

The introduction of directly acting antiviral agents (DAAs) has produced significant improvements in the ability to cure chronic hepatitis C infection. However, with over 2% of the world’s population infected with HCV, complications arising from the development of cirrhosis of the liver, chronic hepatitis C infection remains the leading indication for liver transplantation. Several modelling studies have indicated that DAAs alone will not be sufficient to eliminate HCV, but if combined with an effective vaccine this regimen would provide a significant advance towards achieving this critical World Health Organisation goal. We have previously generated a genotype 1a, 1b, 2a, 3a HCV virus like particle (VLP) quadrivalent vaccine. The HCV VLPs contain the core and envelope proteins (E1 and E2) of HCV and the vaccine has been shown to produce broad humoral and T cell immune responses following vaccination of mice. In this report we further advanced this work by investigating vaccine responses in a large animal model. We demonstrate that intradermal microneedle vaccination of pigs with our quadrivalent HCV VLP based vaccine produces long-lived multi-genotype specific and neutralizing antibody (NAb) responses together with strong T cell and granzyme B responses and normal Th1 and Th2 cytokine responses. These responses were achieved without the addition of adjuvant. Our study demonstrates that our vaccine is able to produce broad immune responses in a large animal that, next to primates, is the closest animal model to humans. Our results are important as they show that the vaccine can produce robust immune responses in a large animal model before progressing the vaccine to human trials.

Systemic and intestinal porcine epidemic diarrhea virus-specific antibody response and distribution of antibody-secreting cells in experimentally infected conventional pigs

“…We thus further analyzed the distribution of memory B cells in PEDV-inoculated pigs by examining the level of antibodies produced by MNCs isolated from blood and each tissue following in vitro stimulation. We stimulated isolated MNCs with the TLR7/8 agonist R848, which induces polyclonal memory B-cell expansion and antibody production without a specific antigen [ 37 , 48 – 50 ]. Because B-cell responses can vary depending on the dose and virus proteins used for stimulation [ 32 , 51 ], we hypothesized that in vitro stimulation with R848 may provide a clearer picture of memory B-cell responses to PEDV than stimulation with recombinant proteins or partially purified viruses.…”

Vaccination into the Dermal Compartment: Techniques, Challenges, and Prospects

“…Specifically, after application of hepatitis B surface antigen-dissolving MN patches containing a 24 or a 48 µg dose for 20 min, 5 out of 7 animals had antibody titres above 10 mIU/mL, compared to 3 out of 4 after intramuscular injection of 10 µg of hepatitis B surface antigen. Microneedle vaccination also resulted in a higher induction of TNF-α levels, which has previously been shown to play a role in the migration of Langerhans cells to the lymph nodes [ 33 , 113 ]. In a separate study, dissolvable microneedles with hepatitis B surface antigen formulated with the adjuvant QS-21 also showed equivalent immunogenicity to intramuscularly injected hepatitis B with alum in pig models [ 107 ].…”

Promotion of Cellular and Humoral Immunity against Foot-and-Mouth Disease Virus by Immunization with Virus-Like Particles Encapsulated in Monophosphoryl Lipid A and Liposomes

“…Although a chemically inactivated whole FMD vaccine has been widely used and is known to provide a reduction in FMD prevalence in endemic areas, there is a clear need for a new generation of FMD vaccines to improve overall immunogenicity and safety [ 33 ]. Among the several types of vaccines employed for veterinary and human needs, VLP FMDV vaccines have been proven to show reliable immunogenicity and safety in pre-clinical and clinical studies [ 34 , 35 , 36 ]. Since VLPs can be manufactured in biosafety level 1 (BSL1) facilities, they are also certainly more safe and economical than the current inactivated FMD vaccine [ 37 ].…”