医学免疫学课件：HIV-1 疫苗研究进展

1、Development of HIV-1 VaccineHIV-1 疫苗研究进展ContentsPart BackgroundPart Introduction of HIV-1Part HIV-1 Vaccine Efficacy TrialsPart Directions of HIV-1 VaccineIn 1984, HHS Secretary Margaret Heckler expressed hope that a vaccine against AIDS could be produced within two years.(/nihinownwords/docs/page_2

2、9.html)In1992, candidate Bill Clinton asserted, “When it comes to AIDS, there should be a Manhattan Project.”(/1993/12/03/opinion/a-renewed-urgency-on-aids.html)Part Background()Part Introduction of HIV-1HIV-1 structureHIV-1 genomeProvirusError-prone RT (Cold Spring Harb Perspect Med. 2012 Aug; 2(8)

3、: a006866)Envelope spike (Env)Gp120Conserved regions, C1-C5Variable surface exposed regions, V1-V5Gp41External domainTransmembrane domainCytoplasmic tailHypervariable epitopesFew conserved epitopes Heavily glycosylatedNot fixed conformation of EnvLimited number of Env spikes on virions surfaceEnv &

4、Immune escapeChange & HidePart HIV-1 Vaccine Efficacy TrialsAntibody-mediated immune responseCell-mediated immune responseStage oneStage twoStage three(Muni Rubens, “HIV-1 vaccine:Recent Advances, Current Roadblocks, and Future Directions ”. Journal of Immunology Research, Volume 2015, Article ID 56

5、0347)Antibody-mediated immune responseNeutralizing antibody (NAb)Non-neutralizing antibody (nNAb) Neutralization: usually measured by prevention of cultured cells infection(Bin Su, Christiane Moog, “Which antibody functions are important for an HIV vaccine? ”. Frontiers in Immunology, June 2014, Vol

6、ume 5, Article 289)Components AIDSVAX B/B gp120 with alumSites USA and NetherlandsResultsThe level and breadth of elicited NAb were not sufficient for protectionGp120-binding IgG and IgA produced in vagina lavage, gingival secretionsVax004Vax003Components AIDSVAX B/E gp120 with alumSites ThailandRes

7、ultsThe level and breadth of elicited NAb were not sufficient for protection ComponentsPrime: recombinant canarypox vectorBoost: recombinant gp120 with alum used in Vax003Community-based phase efficacy trialHeterosexual HIV-uninfected 18-30-year-old men and women With “community risk” in Rayong and

8、Chon Buri provinces in ThailandResultsNon-durable efficacy: 60% at 12 months, 44% at 18months, 31.2% at 42 months RV144Prime-boost conceptPriming with a recombinant vector or DNA plasmids expressing HIV-1 proteinsBoosting with soluble HIV-1 proteins or with another vector expressing HIV-1 proteinsAD

9、CC (antibody-dependent cell-mediated cytotoxicity) ADCVI (antibody-dependent cell-mediated virus inhibition)EvidencesSelective inducing of highly functional IgG3 Positive association between the FcRIIC polymorphism and vaccine efficacyFc-mutated nNAbs passive transfer studies in macaqueCell-mediated

10、 immune responseHVTN502/HVTN503Components MRKAd5 HIV-1 gag/pol/nef trivalent vaccineSites HVTN502: North and South America, Australia HVTN503: South Africa HVTN505Components6-plasmid DNA vaccine prime and rAd5 vector boostSites USA Two competing activities(Anthony S. Fauci, Mary A. Marovich, Carl W.

11、 Dieffenbach, “Immune Activation with HIV Vaccines”. Science, April 2014, Volume 344)Activate CD4+ T cells: More susceptible to HIV-1 infection Lessons Assessing viral vectorsEvaluate the amounts and distribution of both vector and insert responses in target tissues where HIV-1 acquisition is known

12、to occurBetter understanding of mucosal immune responsesEvidence in HVTN502/503/505HVTN502/503High titers of preexisting antibodies against Ad5Increased risksHVTN505Restricted enrollment to MSM who lacked preexisting antibodies to Ad5Halted prematurely, no evidence of increased risk of HIV-1 infecti

13、onPart Directions of HIV-1 VaccineBroadly neutralizing antibodyMucosal vaccineStimulation of CD8+ T cell immune responsesDelivery systems and adjuvantDiscovery20-30% of HIV-1 infected individualsAfter two years of infectionFunction Against a wide range of different virus isolatesPatients do not bene

14、fit from their own bNAbsBroadly neutralizing antibody (bNAb)bNAbs targets (Bin Su, Christiane Moog, “Which antibody functions are important for an HIV vaccine? ”. Frontiers in Immunology, June 2014, Volume 5, Article 289)Properties Identification of conserved epitopesShort CDRH3Undergoing extensive

15、somatic hypermutationPolyreactive or autoreactiveCoevolutionViral escapeNAb renewSomatic hypermutationPrime: germline-targeting immunogenBoost: a sequence of native-like antigens Mimicking the bNAbs maturation pathway(Joseph Jardine, “Rational HIV Immunogen Design to Target Specific Germline B Cell

16、Receptors ”. Science, May 2013, Volume 340)Poor understanding of somatic hypermutation Native Env cannot induce bNAbs easilyCompetition between B cells with different targetsAutoreactive B cells tend to be deleted ChallengesMucosal vaccine(Bin Su, Christiane Moog, “Which antibody functions are impor

17、tant for an HIV vaccine? ”. Frontiers in Immunology, June 2014, Volume 5, Article 289)Example Mucosal prime: MVTT(SIVgpe)Intramuscular boost: Ad5(SIVgpe)Proved protection in rhesus monkeys (Sun C, Zhang L, Chen Z, “Mucosal priming with a replicating-vaccinia virus-based vaccine elicits protective im

18、munity to simian immunodeficiency virus challenge in rhesus monkeys”. J Virol, May 2013, 87(10)Two strategiesMaximizing the incorporation of variable viral epitopes or mosaicsIncorporating only conserved regionsOthers Vaccines targeting effector memory T cellsVectors induce uninterrupted, powerful a

19、nd long-term antiviral immune surveillanceCombination of different vectorsStimulation of CD8+ T cell immune responseDelivery systems and adjuvantPotential suitable delivery systemsLiposomesInorganic nanoparticles VLPsSelf-assembling protein-based nanoparticlesMicrocapsulePotent adjuvant candidatesMF

20、59AS02VirosomesBreadth, magnitude and durability Focusing on individual epitopes or a combination of multiple epitopesMechanism for the production of effective CD8+ T cell responsesRight sequence of somatic hypermutationPhylogenetic differences between simian and human immunodeficiency virusRapid an

21、d continuous evolution of innumerable number of quasi-species of HIV-1 Future challenges Summary Conventional strategiesNovel strategiesSequential vaccinationbNAbsCocktail vaccinationFrequentmutationAttack CD4+T cell1 M Rubens, V Ramamoorthy, A Saxena, et al. “HIV-1 vaccine: Recent Advances, Current

22、 Roadblocks, and Future Directions ”. Journal of Immunology Research, Volume 2015, Article ID 5603472 Bin Su, Christiane Moog, “Which antibody functions are important for an HIV vaccine? ”. Frontiers in Immunology, June 2014, Volume 5, Article 2893 Anthony S. Fauci, Mary A. Marovich, Carl W. Dieffen

23、bach, “Immune Activation with HIV Vaccines”. Science, April 2014, Volume 3444 Joseph G. Jardine et al. “Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors ”. Science, May 2013, Volume 3405 Sun C, Zhang L, Chen Z, “Mucosal priming with a replicating-vaccinia virus-based vaccine elicits protective immunity to simian immunodeficiency virus challenge in rhesus