Assessment of an LSDV-Vectored Vaccine for Heterologous Prime-Boost Immunizations against HIV

Abstract

The modest protective effects of the RV144 HIV-1 vaccine trial have prompted the further exploration of improved poxvirus vector systems that can yield better immune responses and protection. In this study, a recombinant lumpy skin disease virus (LSDV) expressing HIV-1 CAP256.SU gp150 (Env) and a subtype C mosaic Gag was constructed (LSDVGC5) and compared to the equivalent recombinant modified vaccinia Ankara (MVAGC5). In vitro characterization confirmed that cells infected with recombinant LSDV produced Gag virus-like particles containing Env, and that Env expressed on the surface of the cells infected with LSDV was in a native-like conformation. This candidate HIV-1 vaccine (L) was tested in a rabbit model using different heterologous vaccination regimens, in combination with DNA (D) and MVA (M) vectors expressing the equivalent HIV-1 antigens. The four different vaccination regimens (DDMMLL, DDMLML, DDLMLM, and DDLLMM) all elicited high titers of binding and Tier 1A neutralizing antibodies (NAbs), and some regimens induced Tier 1B NAbs. Furthermore, two rabbits in the DDLMLM group developed low levels of autologous Tier 2 NAbs. The humoral immune responses elicited against HIV-1 Env by the recombinant LSDVGC5 were comparable to those induced by MVAGC5.

Improved DNA Vaccine Delivery with Needle-Free Injection Systems

“…The effect of adjuvanting the DNA vaccines with CpG oligodeoxynucleotide (ODN) 1826 combined with Stratis delivery was found to further improve the immune response, with 10 out 15 rabbits developing binding antibody responses to HIV Env after a single DNA vaccination and all of them after two DNA vaccinations. Similar results were seen in other studies by this group when DNA vaccines were administered IM using Stratis both with and without CpG [ 88 , 89 ]. Overall, these studies showed that the immunogenicity of DNA vaccines delivering HIV antigens was significantly improved when delivered using NFIS as compared to NS.…”

“…Dr. Williamson’s group at the University of Cape Town has developed DNA vaccines expressing HIV Gag virus-like particles and envelope (Env), which have been tested in rabbits using heterologous prime–boost regimens ( Table 2 ) [ 89 ]. Rabbits were inoculated with two DNA primes followed by two to four poxvirus-vectored boosts and, in some studies, two HIV envelope protein boosts.…”

“…In a study comparing poxviral-vector boosts, rabbits received a DNA prime followed by boosts with either MVA or lumpy skin disease virus (LSDV) in different sequences, given with Stratis only [ 89 ]. Serum binding and Tier 1A neutralizing antibodies were produced at similar levels in all of the vector combinations tried throughout the study period.…”

“…Overall, this study showed the immunogenicity of the LSDV vector boost and feasibility in using this type of vector for HIV vaccine development using NFIS. The authors noted that altering envelope sequences or increasing the time period between homologous boosting could increase immune responses [ 89 ].…”

Lumpy Skin Disease—An Emerging Cattle Disease in Europe and Asia

“…A putative non-essential gene encoding a G-protein-coupled chemokine receptor subfamily homologue has been tested as a site for homologous recombination [ 103 ]. The region between the convergent LSDV open reading frames (ORFs) 49 and 50 have also been used without gene disruption [ 20 , 104 , 105 ].…”