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Volume 6 Supplement 3

AIDS Vaccine 2009

OAO5-04. Gp96-Ig-SIV vaccines induce predominant immune responses at mucosal sites

Background

We have developed a vaccine design that utilizes the unique property of the endoplasmic reticulum chaperon, heat shock protein (HSP) gp96, to bind antigenic peptides and deliver them to APCs. Cell-based gp96-Ig vaccines, by prolonged in vivo secretion of gp96-Ig peptide, imitate viral replication and provide immune stimuli comparable to attenuated viruses. In model systems in mice we have shown that gp96-Ig transfected, antigen expressing cells secrete gp96-Ig in vivo and stimulate both systemic and strong mucosal immunity. The aim of our study was to evaluate safety and systemic and mucosal SIV-immunity with secreted gp96-Ig-SIV vaccines in non-human primates.

Methods

Gp96-Ig was generated by replacing the ER retention sequence KDEL with the IgG1-Fc tag. HEK-293 cells were transfected with gp96-Ig and with the cDNAs encoding the SIV antigens gag, pol, env and retanef. Irradiated, transfected 293 cells that secrete 1, 5 or 50 micrograms gp96-Ig-SIV-peptide complexes in 24 h, were injected intraperitoneally in Mamu-A*01+ macaques at 0, 4 and 25 weeks.

Results

After the third immunization the SIV-specific CD8 response was boosted to very high levels in the rectum and jejunum (30 – 50% tetramer positive cells in the CD8 gate in LPL and IEL). In vaginal IEL gag-specific CD8 responses reached 4%. Tetramer+ cells expressed appropriate functional (granzymeB) and migration markers (CD103). Control macaques immunized with 293 cells not secreting gp96, showed only background tetramer binding. The mucosal CD8+ and CD4+ T cells from lamina propria and intraepithelial compartment secrete IL-2 or IFN-gamma or both simultaneously in response to peptide stimulation.

Conclusion

We conclude that the cell secreted gp96-Ig-SIV vaccine is safe and can induce strong poly-specific, multifunctional and predominant CD8 responses in mucosal compartments that are thought to be critical for protection from SIV/HIV infection.

Public Health Service Grants R21 AI068515, R21/R33 AI073234, PO1 CA109094.

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Correspondence to N Strbo.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Strbo, N., Vaccari, M., Pahwa, S. et al. OAO5-04. Gp96-Ig-SIV vaccines induce predominant immune responses at mucosal sites. Retrovirology 6, O34 (2009). https://doi.org/10.1186/1742-4690-6-S3-O34

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Keywords

  • Endoplasmic Reticulum Chaperon
  • Public Health Service Grant
  • Tetramer Binding
  • Tetramer Positive Cell
  • Sequence KDEL