An MVA Vector Expressing HIV-1 Envelope under the Control of a Potent Vaccinia Virus Promoter as a Promising Strategy in HIV/AIDS Vaccine Design

Abstract

Highly attenuated poxviral vectors, such as modified vaccinia virus ankara (MVA), are promising vaccine candidates against several infectious diseases. One of the approaches developed to enhance the immunogenicity of poxvirus vectors is increasing the promoter strength and accelerating during infection production levels of heterologous antigens. Here, we have generated and characterized the biology and immunogenicity of an optimized MVA-based vaccine candidate against HIV/AIDS expressing HIV-1 clade B gp120 protein under the control of a novel synthetic late/early optimized (LEO) promoter (LEO160 promoter; with a spacer length of 160 nucleotides), termed MVA-LEO160-gp120. In infected cells, MVA-LEO160-gp120 significantly increased the expression levels of HIV-1 gp120 mRNA and protein, compared to the clinical vaccine MVA-B vector expressing HIV-1 gp120 under the control of the commonly used synthetic early/late promoter. When mice were immunized with a heterologous DNA-prime/MVA-boost protocol, the immunization group DNA-gp120/MVA-LEO160-gp120 induced an enhancement in the magnitude of gp120-specific CD4 + and CD8 + T-cell responses, compared to DNA-gp120/MVA-B; with most of the responses being mediated by the CD8 + T-cell compartment, with a T effector memory phenotype. DNA-gp120/MVA-LEO160-gp120 also elicited a trend to a higher magnitude of gp120-specific CD4 + T follicular helper cells, and modest enhanced levels of antibodies against HIV-1 gp120. These findings revealed that this new optimized vaccinia virus promoter could be considered a promising strategy in HIV/AIDS vaccine design, confirming the importance of early expression of heterologous antigen and its impact on the antigen-specific immunogenicity elicited by poxvirus-based vectors.

A Single Dose of an MVA Vaccine Expressing a Prefusion-Stabilized SARS-CoV-2 Spike Protein Neutralizes Variants of Concern and Protects Mice From a Lethal SARS-CoV-2 Infection

“…It has been reported that enhancing the expression levels of an antigen by recombinant MVA-based vaccine candidates results in a further increase of the antigen-specific immunogenicity (43)(44)(45). Thus, the increased levels of S(3P) protein expression are likely responsible for the observed induction of higher titers of IgG antibodies against S and RBD proteins in both wild-type C57BL/6 and transgenic K18-hACE2 mice immunized with one dose of MVA-S(3P), as well as of the higher levels of neutralizing antibodies against live parental SARS-CoV-2 virus that also cross-neutralized different VoC.…”

Highly Attenuated Poxvirus-Based Vaccines Against Emerging Viral Diseases

“… 243 The LEO promoter enhanced green fluorescent protein (GFP) and HIV-1 gp120 expression in vitro and the magnitude of HIV-1 gp120-specific B and T cells responses in mice. 243 , 250 Moreover, this novel promoter has been recently used in the generation of an MVA-based vaccine candidate against ZIKV that achieved full protection in challenged mice. 172 …”

Rendezvous with Vaccinia Virus in the Post-smallpox Era: R&D Advances

“…Most focus on viral diseases of clinical relevance. A wide array of vaccine research centers around HIV-1 [ 109 , 116 , 121 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 ]. Plentiful studies target arboviruses that are on the rise: dengue virus [ 161 ], Zika virus [ 50 , 162 , 163 , 164 , 165 ], West Nile virus [ 166 ], yellow fever virus [ 167 ], tick-borne encephalitis virus [ 168 , 169 ], chikungunya virus [ 163 , 170 ], and Crimean-Congo hemorrhagic fever virus [ 171 ].…”