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.
Highlights
The human immunodeficiency virus 1 (HIV-1) STEP trial showed how pre-existing antibodies to adenovirus 5 (Ad5) resulted in the increase in HIV-1 infection in men vaccinated with the MRKAd5 HIV-1 Gag/Pol/Nef vaccine [4]
Previous work carried out by our group has shown that the presentation of expressing HIV-1 CAP256.SU gp150 (Env) on the surface of Gag virus-like particles (VLPs) leads to better neutralizing immune responses, when compared to the HIV-1 envelope protein alone [36]
Only rabbits vaccinated with the DDLMLM regimen developed autologous CAP256.SU Tier 2 neutralizing antibodies. These results showed that the lumpy skin disease virus (LSDV)-vectored vaccine elicited very similar responses to
Summary
Despite the recent developments in vaccine technology [1], there remains a need for additional vaccine vectors, and live attenuated viral vectors are no exception [2]. The repeated use of the same live attenuated viral vector can result in anti-vector immunity, which could either be beneficial to the improvement of vaccine immunogenicity, or detrimental in the enhancement of viral infections [3]. The human immunodeficiency virus 1 (HIV-1) STEP trial showed how pre-existing antibodies to adenovirus 5 (Ad5) resulted in the increase in HIV-1 infection in men vaccinated with the MRKAd5 HIV-1 Gag/Pol/Nef vaccine [4]. Rare human adenovirus serotypes, as well as non-human primate adenoviruses, have been developed to overcome the problem of pre-existing antibodies; refinements to the adenovirus vector platform are ongoing [5]
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