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HKU Discovers a Novel AIDS DNA Vaccine Dr Chen Zhiwei Director and Principal Investigator Dr Allen Cheung Ka-loon Post-doctoral Fellow Ms Zhou Jingying PhD Candidate AIDS Institute The University of Hong Kong Li Ka Shing Faculty of Medicine Updated Pandemic of HIV/AIDS by 2011 •An estimated 5 million people in Asia were living with HIV up till now. (Source: UNAIDS 2013) HIV/AIDS epidemic in Hong Kong • • • 97.7% of HIV / AIDS cases were due to sexual transmission 4% prevalent rate was found among MSM (Men who have sex with men) in 2012. With the increasing number of HIV / AIDS cases, an effective vaccine is necessary for AIDS prevention and immunotherapy. (Source: Virtual AIDS Office of Hong Kong 2013) Current challenges against HIV/AIDS • Lack of a Therapeutic Cure: • • ssRNA, Reverse transcriptase CCR5 CD4 RNA-DNA hybrid HAART (Highly active antiretroviral therapy, or called cocktail therapy) suppresses patients’ HIV load, extends patients’ life and reduces secondary HIV spread. Yet, issues of drug toxicity, drug resistance and failure of eliminating HIV remain unsolved. Integrase dsDNA Provirus LTR mRNA ssRNA Protease Precursors • Lack of an Effective Vaccine: • Current vaccines are rather weak and poorly immunogenic. Proteins Illustration of HIV life cycle and drug target Role of CD8+ T cells in controlling HIV infection • CD8+ T cells belong to a group of white blood cells known as cytotoxic lymphocytes or killer T cells. • They play a central role in cell-mediated immunity by killing HIV-infected cells and cancer cells. • The are well-known for their critical role of suppressing HIV replication and eliminating latent reservoir in the body. Unknown to Scientists How to induce a high frequency of protective HIV-specific CD8+ T cells for both preventive vaccine and therapeutic cure? HKU’s Discovery 1) We have discovered a novel AIDS DNA vaccine that induces a high frequency of broadly reactive, poly-functional and protective CD8+ T cells against HIV. 2) This new vaccine works by targeting HIV antigen to dendritic cells via the PD1/PDL binding, which results in the distinct and robust CD8+ T cell immunity. Structure of HIV Novel AIDS DNA Vaccine Design - PD1-guided delivery of p24 to dendritic cell Counts Dendritic Cell More effective to induce robust CD8+ T cells. p24fc sPD1-p24fc sΔPD1-p24fc PD-L1 p24 PD-L2 Anti-rabbit Fc Experimental Schedule Antibody & T-cell responses Immunization 0 (weeks) 3 6 8 Memory Response 30 TERESA-Gene Delivery Device for in vivo electroporation (EP) EP efficiently delivers DNA Vaccine Novel AIDS DNA Vaccine Greatly Intensified CD8+ T cells in a Dose-Dependent Way ELIspot Assay IFN-γ+/CD + Elispots / Splenocytes 2000 *** 1600 1200 ** 600 400 8 6 10 sPD1 sIgV-PD1 -p24-fc -p24-fc 20μg sPD1 sIgV-PD1 -p24-fc -p24-fc PBS 100μg -Kd- AMQMLKDTI tetramer Tetramer Assay sPD1-p24-fc 21.2 sIgV-PD1-p24-fc 0.6 PBS 0.2 H 2 CD8 Long Term Memory CD8+ T cells Response 30 weeks post-vaccination p24fc 2.36% sPD1-p24fc 29.3% sΔPD1-p24fc 1.42% PBS 1.85% Positive control 31.8% The novel AIDS DNA Vaccine induces long lasting anti-HIV memory CD8+ T cells as compared with control vaccines. Significant Protection against Lethal Viral Challenges in Mice 100 90 *** 80 70 60 p24fc sPD1-p24fc sIgV-PD-1-p24fc PBS 0 1 2 3 4 5 6 7 8 Days after challenge • (Left) The line with circle illustrates that the new vaccine significantly increases the body weight of mice as compared with control vaccines WR-gagpol Titer (x103 PFU)/ml Body weight (%) Virulent vaccinia WR-gag Challenge 10 8 ** 6 4 2 sPD1 sIgV-PD1 -p24-fc -p24-fc PBS • (Right) The number of lethal virus has remarkably decreased after vaccination. IL-12 on CD11c+ DCs (%) IFN-γ+/CD + Elispots/ splenocytes Direct Comparison of Two Methods of Antigen-Targeting to DCs 2000 * 1500 1000 500 8 6 10 p24fc sPD1 α-DEC205 p41 -p24fc -p41 PBS * * 3.0 2.0 1.0 p24fc sPD1 α-DEC205 PBS -p24fc -p41 Early DNA vaccine (α-DEC205-p41) •a vaccine published in JCI 2008 by Prof R. Steinman (2011 Nobel Prize in Medicine). •DC-targeting: through DEC205 New AIDS DNA vaccine (sPD1-p24fc) •New discovery by HKU •DC-targeting: through PD1/PD-L interaction to induce a high frequency of CD8+ T cells (left) and IL-12 releasing DCs (right). •New vaccine is more effective in inducing higher frequency of CD8+ T cells Mechanism of Novel AIDS DNA vaccine Dendritic Cells sPD1-p24 DC-targeting α-DEC205-p24 cross-presentation PD-L1/L2 DEC205 Rab14 MHC I Rab5 CD40 Th1 cytokines p24 Rab7 IL-12 CD8 Non-DC-targeting IFN-γ Rab9 Lamp1 New discovery by HKU Early finding by Prof Steinman’s team Traditional vaccines Cytokines Cytotoxicity Cytokines Cytotoxicity MHC II CD40 CD4 B Antibodies (IgG1/IgG2a) Importance of the findings • Our findings shed light on how to induce a high frequency of protective HIV-specific CD8+ T cells - important for an effective vaccine to either prevent or cure AIDS. • The study obtained the international patent, implying that Hong Kong researchers have capability to invent novel AIDS vaccine • Our results provide new insights on how immune system works in regulating CD8+ T cell responses. • Besides against HIV/AIDS, our new technique can be used for making vaccines for prevention and immunotherapy against other diseases (e.g. TB, Malaria and Cancer). Questions and Answers AIDS vaccine is the ultimate solution