Dendritic cell-targeted protein vaccines: a novel approach to induce T-cell immunity

Abstract

Current vaccines primarily work by inducing protective antibodies. However, in many infections like HIV, malaria and tuberculosis as well as cancers, there remains a need for durable and protective T-cell immunity. Here, we summarize our efforts to develop a safe T-cell-based protein vaccine that exploits the pivotal role of dendritic cells (DC) in initiating adaptive immunity. Focusing on HIV, gag-p24 protein antigen is introduced into a monoclonal antibody (mAb) that efficiently and specifically targets the DEC-205 antigen uptake receptor on DC. When administered together with synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly IC) or its analogue poly IC stabilized with carboxymethylcellulose and poly-L-lysine (poly ICLC), as adjuvant, HIV gag-p24 within anti-DEC-205 mAb is highly immunogenic in mice, rhesus macaques, and in ongoing research, healthy human volunteers. Human subjects form both T- and B-cell responses to DC-targeted protein. Thus, DC-targeted protein vaccines are a potential new vaccine platform, either alone or in combination with highly attenuated viral vectors, to induce integrated immune responses against microbial or cancer antigens, with improved ease of manufacturing and clinical use.

Conflict of interest statement

Conflict of Interest Statement

Tibor Keler is an employee of Celldex Therapeutics, which is developing human DEC-205-based vaccines. Ralph Steinman was on the scientific advisory board and held stock options in Celldex Therapeutics. The remaining authors declare no competing financial interests.

© 2011 The Association for the Publication of the Journal of Internal Medicine.

Figures

Fig. 1

HIV gag protein is highly immunogenic when targeted with anti-DEC mAb together with poly IC. C57BL/6 mice were injected with poly IC and graded doses of anti-DEC gag-p24 mAb or gag-p24 protein, or one dose of control-Ig gag-p24, and boosted with the same condition 6 weeks later. Here 1.25 μg of gag-p24 within anti-DEC mAb corresponds to 5 μg of anti-DEC-gag-p24 mAb. One week after boost, IFN-γ in spleen CD3+CD4+ T cells was measured in response to stimulation with HIV gag-p24 reactive peptide mix or non-reactive HIV gag-p17 peptide mix.

Fig. 2

Targeting of antigen to DEC receptor allows for cross-presentation on MHC class I and expansion of adoptively transferred, gag-primed, CD8+ T cells. Cross presentation refers to the capacity of nonreplicating protein to be presented on MHC class I. To show that DEC targeting of an antigen is able to greatly facilitate cross-presentation the following adoptive transfer experiment was done. (A) CxB6 F1 Thy 1.2+ mice were primed and boosted with adenovirus-gag-p24. Two weeks after the booster immunization, T cells from adenovirus-gag immunized spleens were enriched by negative selection, labeled with CFSE and one spleen equivalent was adoptively transferred into each CxB6 F1 Thy 1.1+ mouse. The following day, mice were challenged with different targeting mAbs given along with adjuvant. Four days later, the transferred T cells were evaluated for proliferation by CFSE dilution and cytokine production. (B) Adoptively transferred, gag-primed, enriched Thy 1.2+ CD3+ CD8+ T cells were challenged with 5 μg anti-DEC-gag-p24 or the other indicated fusion mAbs along the top, given along with 25 μg anti-CD40 that is essential to observe immune boosting. Four days after antibody inoculation, IFN-γ production and proliferation of the transferred T cells was assessed in a 6 hr in vitro re-stimulation assay in the presence of HIV gag-p24 reactive peptide mix, with HIV gag-p17 mix as negative control.