1、HIV Vaccine: Recent Advances, Current Roadblocks,and Future DirectionsContentHIV BasicsStructure、Genome、Life cycle、EpidemiologyHIV Vaccine BasicsTrials、Challenges、Future perspectiveStructure & Genome三個(gè)主要基因：gag、pol、env。六個(gè)輔助基因：tat、rev、vif、vpr、vpu、nefHIV BasicsCoded by envgp 120 CD4 bindingVariable reg

2、iongp 41fusionLife CyclePhase I. Free statePhase II. AttachmentPhase III. PenetrationPhase IV. UncoatingPhase V. ReplicationPhase VI. AssemblingPhase VII. ReleasingEpidemiologySince the first recognized cases of the Acquired Immuno-deficiency Syndrome (AIDS) came to light in the early 1980s and the

3、discovery of the human immunodeficiency virus (HIV) soon after, HIV/AIDS has become a leading cause of mortality and morbidity worldwide.GLOBAL STATISTICSNew HIV infections have fallen by 41% since 2001.AIDS-related deaths have fallen by 50% since the peak in 2005.In 2013, around 12.9 million people

4、 living with HIV had access to antiretroviral therapy.Since the advent of antiretroviral medications, HIV infection has become a chronic disease with decreasing incidence and increasing prevalence.Vaccine: Necessary ?Vaccine Basics: GoalsThe first goal of an HIV-1 vaccine would be to prevent HIV-1 i

5、nfection and provide sterilizing immunity.RV144An estimated efficacy of 31% against HIV-1 acquisitionVaccine Basics: GoalsA second goal would be to reduce peak and set point viral load by controlling viral replication and to stop progression to clinical disease in vaccine recipients who became infec

6、ted.Complementary to the first goal Efficacy TrialsFrom: Jean-Louis Excler, Merlin L Robb & Jerome H Kim (2014) HIV-1 vaccines, Human Vaccines & Immunotherapeutics, 10:6, 1734-1746, DOI: 10.4161/hv.28462Trials DevelopmentAntibody-inducing VaccinesVAX004 & VAX003 in 2005 & 2006Cell-mediated Immune Re

7、sponse-inducing VaccinesStep (HVTN 502/Merck 023) and Phambili (HVTN503) vaccinePrime-boostRV144 HVTN 505VAX004 & VAX003Vaccine: AIDSVAX B/B gp120 in alumMonomeric gp120 HIV-1 envelope proteins aloneVolunteers: High-risk populationsMSM and women at high risk & Injecting drug usersStrategy: Antibody-

8、inducingFailure of VAX TrailsThe vaccine did not prevent HIV-1 acquisition nor did it affect HIV-1 disease progression. Hypotheses that level and breadth of NAb were not sufficient for protection. Antibody PathwayIn natural infectionMonoclonal type antibody responseNonconventional bnAbsHigh level of

9、 protectionShortcomingsRarely producedTime-consumingMechanism unknownPolyreactive or AutoreactivePathway elaborated by Kwong et al. Broadly neutralizing antibodies and the search for an HIV-1 vaccine : the end of the beginning. Nat Rev Immunol 2013;13:693-701The B-Cell Pathway in an HIV VaccineTrial

10、s DevelopmentAntibody-inducing VaccinesVAX004 & VAX003 in 2005 & 2006Cell-mediated Immune Response-inducing VaccinesStep (HVTN 502/Merck 023) and Phambili (HVTN503) vaccinePrime-boostRV144 HVTN 505HVTN 502 & HVTN503Vector: adenovirusesGenes: gag/pol/nefStrategy: Eliciting cell mediated immune (CMI)

11、responses. (CTL-based)Hypotheses: prevent HIV infection, and would lower viral loads in that became infected.Failure of STEP Trial (HVTN502)But the results are: It can not protect people from HIV, and lack of viremia reduction in the infected.In contrast, vaccinated people have a higher risk of acqu

12、iring HIV，especially in uncircumcised men with pre-existing Ad5-NAbThis failure lead to HVTN503 trial halted.WHY STEP FailsPre-existing Ad5 antibody may induce Ad5-specific T cellsCTL-mediated mutationsTrials DevelopmentAntibody-inducing VaccinesVAX004 & VAX003 in 2005 & 2006Cell-mediated Immune Res

13、ponse-inducing VaccinesStep (HVTN 502/Merck 023) and Phambili (HVTN503) vaccinePrime-boostRV144 & HVTN 505HVTN 505Aiming at inducing both functional antibodies and cell-mediated responsesA regimen with DNA vaccine prime and replication-defective rAd5 vaccine boostFailureThe Phase IIB trial (HVTN 505

14、) was recently stopped for futility, showing no efficacy and no statistically significant effect on viral load and a non-significant excess of HIV infection in the vaccinated group. Further analysis is ongoing.RV144Four priming injections: recombinant canarypox vector vaccine (ALVAC-HIV)Two booster

15、injections: recombinant gp120 subunit (AIDSVAX B/E).Result: the vaccine efficacy was 31.2%.Result AnalysisPost hoc analysis of the interaction of risk status and acquisition efficacy was significant with greater benefit in low-risk individuals. Vaccine efficacy appeared to be higher (60%) at 12 mo p

16、ost first vaccination, suggesting an early, but nondurable, vaccine effect. There was no effect on early post-infection HIV-1 RNA VL or CD4+ T-cell count. Vaccination did not affect the clinical course of HIV-1 disease after infection, though there was evidence of reduction in seminal fluid viral lo

17、ad. Some problemsEfficacy50%. (74 VS 51)The population was made up largely of persons at low risk (47.5%) or moderate risk (28.4%) for HIV infection, rather than those at high risk.The viral load in the infected people injected with vaccine was not lower than that with placebo.Correlates of Protecti

18、onReference:Jean-Louis Excler, Merlin L Robb & Jerome H Kim (2014) HIV-1 vaccines, Human Vaccines & Immunotherapeutics, 10:6, 1734-1746, DOI: 10.4161/hv.28462Lessons LearnedChallenges from the level of bnAbs inducedMechanism unknownTime-consumingT-cell responses alone will not be sufficient for effe

19、ctive protective efficacyCD8 T cells destroy viruses and infected cells thereby helping in the process of convalescence in any viral infection. This mechanism does not work with HIV because CD8 T cells control the viremia but cannot eliminate it.Recent T cell strategyIncorporating the near complete

20、gene sequences of several proteinsAvoiding all variable viral epitopes and incorporating only conserved regionsConsensusCountering HIV variability remains one of the main hurdles for HIV-1 vaccines.Broadly neutralizing antibodiesADCC and ADCVIT Cells Immune Responses Reference: S. G. Hansen, M. Piat

21、ak Jr., A. B. Ventura et al., “Immune clearance of highly pathogenic SIV infection,” Nature, vol. 502, no. 7469, pp. 100104, 2013.Viral Vectors, Alternative Delivery Systems, and Costimulatory MoleculesQuestions unansweredWhether vaccines should focus on individual epitopes or a combination of multi

22、ple epitopesThe right sequence of somatic hypermutations to derive effectively neutralizing bnAbs.With regard to stimulation of cytotoxic T cells, the exact mechanism for the production of effective CD8 T cell responses needs to be researched and understood.More trialsNew PerspectiveConstruction of

23、novel live-attenuated HIV vaccine through genetic code expansion. UAA*, unnatural amino acid.HIV vaccine in ChinaCAVI(中國(guó)艾滋病疫苗聯(lián)盟)，2009年3月成立于北京Clinical trial in Guangxi1st HIV vaccine that undertaken clinical trial.Project began in 1996phase began on 2005-3-12, finished on 2006-6 phase began on 2009-3

24、-21now it goes well.Primer: BC subtype DNA Booster: MVA vectorGetting to ZeroMain ReferencesJean-Louis Excler, Merlin L Robb & Jerome H Kim (2014) HIV-1 vaccines, Human Vaccines & Immunotherapeutics, 10:6, 1734-1746, DOI: 10.4161/hv.28462Rubens, Muni et al. “HIV Vaccine: Recent Advances, Current Roadblocks, and F