TY - JOUR

T1 - Virus-like vaccines against HIV/SIV synergize with a subdominant antigen T cell vaccine

AU - Schwerdtfeger, Melanie

AU - Andersson, Anne Marie Carola

AU - Neukirch, Lasse

AU - Holst, Peter Johannes

PY - 2019

Y1 - 2019

N2 - Background: In non-human primates (NHPs) and humans, partial protection from HIV/SIV infection or suppression of replication is achievable by Env-binding antibodies and Gag-specific CD8+ T-cells targeting protective epitopes. Unfortunately, such T-cell responses are frequently dominated by responses to non-protective, variable epitopes. In this study we attempt to combine three independent approaches, each developed to prevent immunodominance of non-protective epitopes. These approaches were (1) vaccines consisting exclusively of putatively protective p24 Gag highly conserved elements (CEs), (2) vaccines using solely subdominant antigens which were acutely protective in a recent NHP trial, and (3) virus-encoded virus-like particle vaccines (virus-like vaccines/VLVs) using heterologous Env and Gag sequences to enable selection of broadly cross-reactive responses and to avoid immunodominance of non-conserved sequences in prime-boost regimens as previously observed. Methods: We vaccinated outbred CD1 mice with HIV-1 clade B Gag/Env encoded in an adenoviral prime and SIVmac239 Gag/Env in an MVA boost. We combined this completely heterologous immunization regimen and the homologous SIVmac239 Gag/Env immunization regimen with an additional prime encoding SIV CEs and accessory antigens Rev, Vif and Vpr (Ad-Ii-SIVCErvv). T-cell responses were analyzed by intracellular cytokine staining of splenocytes and antibody responses by trimer-specific ELISA, avidity and isotype-specific ELISA. Results: Env dominance could be avoided successfully in the completely heterologous prime-boost regimen, but Env immunodominance reappeared when Ad-Ii-SIVCErvv was added to the prime. This regimen did however still induce more cross-reactive Gag-specific CD8+ T-cells and Env-specific antibodies. Including Ad-Ii-SIVCErvv in the homologous prime-boost not only elicited accessory antigen-specific CD8+ memory T-cells, but also significantly increased the ratio of Gag- to Env-specific CD8+ T-cells. The CD4+ T-cell response shifted away from structural antigens previously associated with infection-enhancement. Conclusion: The homologous Gag/Env prime-boost with Ad-Ii-SIVCErvv prime combined acutely protective CD8+ T-cell responses to subdominant antigens and Env-binding antibodies with chronically protective Gag-specific CD8+ T-cells in outbred mice. This vaccine regimen should be tested in an NHP efficacy trial.

AB - Background: In non-human primates (NHPs) and humans, partial protection from HIV/SIV infection or suppression of replication is achievable by Env-binding antibodies and Gag-specific CD8+ T-cells targeting protective epitopes. Unfortunately, such T-cell responses are frequently dominated by responses to non-protective, variable epitopes. In this study we attempt to combine three independent approaches, each developed to prevent immunodominance of non-protective epitopes. These approaches were (1) vaccines consisting exclusively of putatively protective p24 Gag highly conserved elements (CEs), (2) vaccines using solely subdominant antigens which were acutely protective in a recent NHP trial, and (3) virus-encoded virus-like particle vaccines (virus-like vaccines/VLVs) using heterologous Env and Gag sequences to enable selection of broadly cross-reactive responses and to avoid immunodominance of non-conserved sequences in prime-boost regimens as previously observed. Methods: We vaccinated outbred CD1 mice with HIV-1 clade B Gag/Env encoded in an adenoviral prime and SIVmac239 Gag/Env in an MVA boost. We combined this completely heterologous immunization regimen and the homologous SIVmac239 Gag/Env immunization regimen with an additional prime encoding SIV CEs and accessory antigens Rev, Vif and Vpr (Ad-Ii-SIVCErvv). T-cell responses were analyzed by intracellular cytokine staining of splenocytes and antibody responses by trimer-specific ELISA, avidity and isotype-specific ELISA. Results: Env dominance could be avoided successfully in the completely heterologous prime-boost regimen, but Env immunodominance reappeared when Ad-Ii-SIVCErvv was added to the prime. This regimen did however still induce more cross-reactive Gag-specific CD8+ T-cells and Env-specific antibodies. Including Ad-Ii-SIVCErvv in the homologous prime-boost not only elicited accessory antigen-specific CD8+ memory T-cells, but also significantly increased the ratio of Gag- to Env-specific CD8+ T-cells. The CD4+ T-cell response shifted away from structural antigens previously associated with infection-enhancement. Conclusion: The homologous Gag/Env prime-boost with Ad-Ii-SIVCErvv prime combined acutely protective CD8+ T-cell responses to subdominant antigens and Env-binding antibodies with chronically protective Gag-specific CD8+ T-cells in outbred mice. This vaccine regimen should be tested in an NHP efficacy trial.

KW - Adenoviral vectors

KW - Antibodies

KW - Heterologous viral vectored prime-boost immunization

KW - Human immunodeficiency virus

KW - Subdominant antigen vaccine

KW - T-cells

KW - Virus-like particles

KW - Virus-like vaccines

U2 - 10.1186/s12967-019-1924-1

DO - 10.1186/s12967-019-1924-1

M3 - Journal article

C2 - 31126293

AN - SCOPUS:85066438898

VL - 17

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

IS - 1

M1 - 175

ER -