医学免疫学课件：HIV疫苗的最新研究进展

1、Recent Advances in HIV Vaccine DevelopmentContentI. IntroductionII. Several human trialsIII. Antibodies inducing strategy bNAbs (broadly neutralizing antibodies) HIV Env trimer Epitope-based immunogen designsIV. T cell response strategy Multivalent mosaic proteins Conserved elements immunogens CMV v

2、ector: atypical CD8 responseI. IntroductionHighly active anti-retroviral therapy (HAART)Immune escape: Attack CD4+ T cell Highly antigenic variation ProvirusStructure : ImmunogenCr: WikipediaCr: WikipediaII. Several human trials1. Whole inactivated viruses & Live attenuated virusesSecurity: Cause in

3、fectiousEfficiency： No evidenceDelete genes related to duplicate： No advance2. Subunit vaccineMembrane proteinMonomer or polypeptideSecurity: noninfectiousEfficiency： Highly variable Neutralizing antibody spectrum is narrowVax Gen：gp120 vaccine No vaccine efficacy3. Vector virus vaccineT cell immuni

4、ty to HIVPox viruses & Adenoviruses(Ad5)MRKAd5 HIV-1 Gag/Pol/Nef Poor efficacy Risk of viral acquisition increasedRV-144：Canarypox vector （Gag/Pol/Env）/gp120Prime-BoostCombined vaccination31.2% vaccine efficacy (at 42 months)The importance of Abs： IgG：inversely correlated with risk of acquisition Ig

5、A: positive correlation nNAbs（non-neutralizing antibodies): Neither bNAbs，nor CTL ADCC4. DNA vaccineHVTN 505Prime： DNA vaccine Clade B-Gag/Pol/Nef Clade A/B/C-EnvBoost：Ad5 Clade B-Gag/Pol Clade A/B/C-Env No efficacyThe HIV vaccine efficacy trials6 So Youn Shin. Recent update in HIV vaccine developme

6、nt. Cin Exp Vaccine Res.2016;5:6-11III. Antibodies inducing strategybNAbs (broadly neutralizing antibodies)Neutralize most prevalent HIV strains VRC01、PGT13510%-30%：2-4 years after infectionEfficacy in preventing infection Decrease the load of vival Bind to Env trimerThe broad neutralization capabil

7、ity of VRC019 Peter D K, John R M, Gary J N. The changing face of HIV vaccine research. Journal of the international AIDS society 2012,15:17407HIV glycoprotein spike7 Barton F. Haynes. New approaches to HIV vaccine development. Curr Opin Immuno. 2015. 35:39-47.Characteristics of bNAbs10%-30%： Higher

8、 frequency of T follicular helper cellHigh degree of somatic mutationbNAbs are disfavored: Poly- and auto-reactivity Immune tolerance controlMaturation of broadly neutralizing HIV-1 immunity9 Peter D K, John R M, Gary J N. The changing face of HIV vaccine research. Journal of the international AIDS

9、society 2012,15:17407Antibody-virus co-evolution10Liao HX, Lynch R, Zhou T, et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. 2013; 496(7446):469476. How to induce bNAbs 1）Target bNAbs B cell lineages： Activation of B-cell lineage to yield bNAbs VRC01：Break the

10、glycosylation cite2）Epitope-based immunogen designs： HIV Env trimer2. HIV Env trimerNative HIV Env trimer： Antigenic diversity Consealing critical epitope Somatic hypermutation Effective immunogenEpitope-based immunogen designs： Stable Mimics the native trimer of bNAbs epitopes Expose as many bNAb e

11、pitopes as possibleEpitope-based immunogen designsBG505 SOSIP. 664 gp140Highly stableClosely resemble native virus spikesMultiple neutralizing epitopes were highly reactive with theBG505Biophysical characterization of BG505 SOSIP.664 gp140 trimers3 Rogier W. A Next-Generation Cleaved, Soluble HIV-1

12、Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies. PLoS Pathog. 2013.9(9): e1003618. BG505 SOSIP.664 gp140 trimer antigenicity by negative stain EM.3 Rogier W. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.6

13、64 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies. PLoS Pathog. 2013.9(9): e1003618. BG505.T332N virus neutralization and ELISA binding to BG505 SOSIP.664 gp140 trimers by bNAbs or non-NAbs.3 Rogier W. A Next-Generation Cleaved, Soluble HIV-1 Env Trim

14、er, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies. PLoS Pathog. 2013.9(9): e1003618. IV. T cell response strategyCD8+ T cell： Kill HIV-infected T cellDifficulties： Variability CTL escape mutant3 strategies： Multivalent mosaic proteins

15、 Conserved-epitopes CMV vector1. Multivalent mosaic proteinsMaximize the coverage of potential T cell epitopesMosaic HIV-1 Gag/Pol/Env （rAd26 vector）Expand both the breadth and depth of T cell responses Breadth and magnitude of epitope-specific T lymphocyte responses to PTE peptides.1Barouch D H. Mo

16、saic HIV-1 vaccines expand the breath and depth of cellular immune responses in rhesus monkeysJ. Nat Med,2010,16(3):319-232. Conserved-epitopesTarget the most conserved region of HIVNYVAC vector: Consensus Env Trivalent mosaic Env proteinAverage coverage of 9-mers by three HIV-1 Env immunogens.8 Hul

17、ot S.L。 Comparison of immunogenicity in rhesus macaques of transmitted-founder, HIV-1 Group M consensus, and trivalent mosaic envelope vaccines formulated as a DNA prime, NYVAC, and envelope protein boos. Journal of Virology 2015 3. CD8+T cell：CMV vectorsRhesus cytomegalovirus (rhCMV) vectors Geneti

18、cally programmed： Absence of the Rh157.5, Rh157.4, and Rh157.6CD8+Tcellepitoperecognition： Promiscuous MHC class I- and class II-restricted CD8+ T cell responses CD8-MHC class II cytotoxic T cell responseV. References1Barouch D H, Obrien K L, Simmons N L, et al. Mosaic HIV-1 vaccines expand the brea

19、th and depth of cellular immune responses in rhesus monkeysJ. Nat Med,2010,16(3):319-232 N. Borthwick, T. Ahmed, B. Ondondo et al.Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Molecular Therapy, 2014,22(2), 464753 Rogier W. Sanders, Ronald Derking, Albert Cupo,

20、et al. A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies. PLoS Pathog. 2013.9(9): e1003618. doi:10.1371/journal.ppat.10036184 Hansen SG, Sacha JB, Hughes CM, et al. Cytomegalovirus vect

21、ors violate CD8+ T cell epitope recognition paradigms. Science. 2013; 340 (6135) : 1237874. 5 Sanders RW, van Gils MJ, Derking R, et al. HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by nativelike envelope trimers. Science 2015;349:aac4223.6 So Youn Shin. Recent update in HIV vaccine development. Cin Exp Vaccine Res.2016;5:6-117 Barton F. Haynes. New approaches to HIV vaccine development. Curr Opin