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Stepping up the pace on HIV Vaccine: what needs to be done?

Stepping up the pace on HIV Vaccine: what needs to be done?. Antonio Lanzavecchia Institute for Research in Biomedicine, Bellinzona Institute of Microbiology, ETH Zürich.

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Stepping up the pace on HIV Vaccine: what needs to be done?

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  1. Stepping up the pace on HIV Vaccine:what needs to be done? Antonio Lanzavecchia Institute for Research in Biomedicine, Bellinzona Institute of Microbiology, ETH Zürich Thanks to: Dennis Burton, Michel Nussenzweig, WayneKoff, Peter Kwong, Giuseppe Pantaleo and Stanley Plotkin

  2. N° of cases (year) N° cases in 2001 Decrease Smallpox 48,164 (1901-1904) 0 100% Polio 21,269 (1952) 0 100% Diphtheria 206939 (1921) 2 99.99% Measles 894134 (1941) 96 99.99% Rubeola 57686 (1969) 19 99.78% Mumps 152209 (1968) 216 99.86% Pertussis 265269 (1934) 4788 98.20% H. influenzae 20000 (1992) 242 98.79% Tetanus 1560 (1923) 26 98.44% Vaccination campaigns eradicated lethal diseases

  3. Low- and high-hangingfruits Vaccine available Vaccine notavailable Koff et al Science 2013

  4. Vaccination and immunologicalmemory IMMEDIATE PROTECTION “Effectormemorycells” Long-lived plasma cellssecrete antibodiescontinuously Tissue-residentmemory T cellsconferimmediate protection in tissues RECALL RESPONSE “Central memorycells” Memory B and T cellsuponantigen re-encounter generate large numbers of killer T cell, plasma cells and antibodieswithin a fewdays Sallusto, Ahmed, Radbruch, Heath & Carbone

  5. A narrowwindow to prevent HIV infection HIV-1 spreads rapidly from mucosal sites and establishes a latent reservoir • An HIV vaccine should induce effector memory cells: • Long lived plasma cells producing neutralizing antibodies • Tissue resident effector T cells

  6. Additionalproblemsrelating to a HIV vaccine • Extreme strainvariation, even in the sameindividual • Aglycanshieldthatpreventsantibodyaccess to the viralspike • Neutralizingantibodiesdevelop late • Immune escape, class I downregulation, immunosuppression • No naturalrecovery from chronicinfection • Undefinedbiomarkers of protection • Lack of an idealanimal model

  7. Timeline of HIV vaccine trials • Vaxgen: HIV gp120 • Merck/NIAID STEP trial: rAdenovirus 5 (gag T cells) • Sanofi/MHRP/NIAID/ThaiRV-144 trial: canarypoxvector + gp120 • HVTN 505: NIAID-VRC: DNA + rAdenovirus5

  8. Whywas the Thai trial successful? • No association with: • Neutralizing Abs • Cellular immune responses • Decreased risk associated with: • IgGAbresponses to the V1/V2 loop (mainly non neutralizing) • ADCC activity mostly to the C1 region of Env • Low IgA Ab responses • But: • Efficacywas in a low-riskpopulation and fadedwith time 1Rerks-Ngarm et al. New Engl J Med 2009, 361:2209-2220. 2Haynes et al.New Engl J Med 2012;366(14):1275-86. 3Bonsignori et al. J Virol 2012; 86(21):11521-32. How to build on the modestefficacy of the RV144 trial?

  9. Serumneutralizingantibodies can preventmucosalinfection in macaques But none of the vaccinestested so far elicitedneutralizingantibodies

  10. An international collaborative effort to identify broadly HIV neutralizing antibodies (bNAbs) Nature Immunology 2004

  11. Sera with broad HIV neutralizing activity are common Doria-Rose et al. JV, 2010 … buttheseantibodies are producedonlyafteryears of chronicinfection … and HIV continues to escape(Richman PNAS 2009)

  12. Sera with broad HIV neutralizing activity are common Doria-Rose et al. JV, 2010 • Is the neutralizingactivity due to multiple antibodieseachspecific for a single virus or to single antibodies with broadneutralizingcapacity? • How manydifferentsites can be recognized by neutralizingantibodies?

  13. Multiple approaches to isolate bNAbs Key: donorselection and bettermethods to isolate antibodies

  14. Broadly neutralizing antibodies against HIV-1 1981 - 2009 Neutralizing breadth Antibody (mg/ml) Neutralizing potency (IC50)

  15. Broadly neutralizing antibodies against HIV-1 Today Neutralizing breadth Mouquetet al., PNAS 2012 Scheidet al., Science 2011 Diskinet al., Science 2011 Walker et al., Nature 2011 Wu et al., Science 2010 Walker et al., Science 2009 Antibody (mg/ml) Neutralizing potency (IC50)

  16. The sites recognized by best in class antibodies From Klein et al. Science 2013

  17. The evolution of broadly neutralizing antibodies • Antibodies to CD4bshave a long developmentalpathwayconcomitant with viralevolution (Liao et al Nature 2013) • Antibodies to V1V2 can develop more rapidlythroughinitialselection of rare naiveB cells with a long CDRH3 followed by limitedsomaticmutations (Doria-Rose et al Nature 2014) See also: Wu et al Science 2011 Klein et al Cell 2013 Gitlinet al Nature 2014

  18. What we learned that can help vaccine design • Broad neutralization can be achieved by combinations of antibody clones or by individual clones • There are several different epitopes that can elicit broad and potent antibodies and glycanscan be part of the epitope • Broadly neutralizing antibodies are rare • Some use common VH (VH1-2 and VH1-46) but require up to 100 mutations over 300 nucleotides in CDR and framework regions • Some have unusually long CDRH3 (20-35 AA) and derive from rare naïve B cells

  19. Immunogen design to guide antibody evolution Jardineet al Science 2013 Prime-booststrategyusingimmunogensthatrecapitulate the developmentalpathwaystartingformnaive B cellsthusmimickingantibody-viral co-evolution

  20. The structure of the HIV envelope trimer Crystal structure of a soluble cleaved HIV-1 envelope trimer Julien et al. Science 2013 The BG505 SOSIP.664 gp140 trimer was crystallized with PGT122, a bNAb which binds to the glycan-dependent N332 epitope on gp120

  21. bNAbs in prophylaxis and therapy Prophylaxis Fewinfectingviruses Therapy Hugenumber of differentviruses plus a hiddenreservoire

  22. Proof of concept: prophylaxisusingbNAbs • bNAbsprotect: • in the SHIV macaque model (Pegu et al. Sci. Trasl. Med. 2014) • in the humanized HIV-1 model (Pietzsch et al. PNAS 2012) • Potentialimprovements: • engineeringto extendhalflife and increaseADCC • vectoredimmunoprophylaxisusing AAV vectorsengenderslong-livedneutralizingactivity and protection in monkeys and humanized mice (Johnson et al NatMed 2009; Balasz et al NatMed 2014)

  23. An unexpected finding: the new bNAbs can be effective therapeutically Studies with first generation bNAbsshowedpoor control of viremia and rapidemergence of resistantvariants. • Two independent groups treated 27 macaques infected for 1-3 years • All macaques responded in 7-10 days. 25/27 to undetectable levels • A single antibody was sufficient • Only 2/27 showed viral escape • Viremiaremained undetectable for as long as antibody levels remained therapeutic andin 3/18 macaques viremia remained undetectable undetectable after 100-200 days. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia Shingai et al. Nature 2013 Therapeutic efficacy of potent neutralizing HIV-1-specific antibodies in SHIV-infected rhesus monkeys Barouch et al. Nature 2013 A clinical trial with 3BNC117 (to CD4bs) isongoing in humans (M. Nussenweig)

  24. A role for non-neutralizing antibodies? Fcreceptorbutnotcomplementbindingisimportant in antibodyprotectionagainst HIV Hessel et al. Nature 2007 Neutralizationis the mainmechanism of protection, butantibodies can be effectivealso via ADCC, complement and opsonization. Non neutralizingantibodiesshow some in vivo efficacy (alsosuggestedby the Thai trial) Limited or no protection by weakly or nonneutralizingantibodiesagainstvaginal SHIV challenge of macaquescompared with a stronglyneutralizingantibody Burton et al. PNAS 2007

  25. Towards an antibody-based HIV vaccine • Aim: • To stimulate the appropriate naive B-cells and promote affinity maturation leading to bNabs • To induce long-lived plasma cells and durable bNAbresponses • New tools and approaches: • Intact soluble trimers and epitope scaffolds • Prime-boost strategies • Antigen-guided B cell development • Multimerizationon nanoparticles • New adjuvants and formulations

  26. Antibodies and T cells? • Replicatingviralvectorsconferdurableprotectiveimmunity • Phase I: Sendai, measles, VSV, Pox, Ad4 • Preclinical: CMV • Conserved and mosaicantigensfocus immune responsesto conservedregions and provideoptimalcoverage of HIV epitopes

  27. Tissue resident memory CD8 T cells Immune surveillance by CD8aa skin-resident T cells in human herpes virus infection Zhu et al. Nature 2013 The prompt CD8 responseat the site of virus release duringasymptomatic HSV reactivationis in sharpcontrast to the delayedCD8 T-cellinfiltrationduring a lesion-formingherpes recurrence The roleof effectormemory T cells in HIV-1 infectionshouldbe explored

  28. A CMV vector as an effector memory T cell vaccine Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine Hansen et al. Nature 2011 • Rhesus CMV carrying SIV genesinducedeffector T cellresponsesagainstSIV • 50% of monkeyswereprotected from challenge • Theywereinfectedbutcontrolled and aborted SIV so thatitwasundetectable • The vectorelicitsMHC classII-restrictedCD8+ T cells, greatlyexpanding the breadth of the T cellresponse. Immune clearance of highly pathogenic SIV infection Hansen et al. Nature 2013 Cytomegalovirus Vectors Violate CD8+ T Cell Epitope Recognition Paradigms Hansen et al. Science 2013

  29. Innovative trials in humans can accelerate vaccine development Given the limitations of animal models in predicting vaccine-induced immune responses and vaccine efficacy in humans it is important to develop: • rapid, small, hypothesisdrivenclinicalresearch trials (adaptive trials) to test multiple candidates in Phase I/IIb • real-time assessment of immune responses • efficacystudies in high riskpopulations • integrationwith vaccine developmenteffortsagainstotherdiseases (adjuvantsetc) Corey et al Sci TranslMed 2011

  30. A new paradigm for vaccine development (can we do better than nature?) A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins Corti et al. Science 2011 Cross-neutralization of four paramyxovirusesby a human monoclonal antibody Corti et al. Nature 2013 Structure-based design of a fusion glycoprotein vaccine for respiratorysyncytialvirus McLellan et al. Science 2013 Courtesy of Peter Kwong

  31. HIV vaccine: the way forward Antibody discovery and developmental pathways Structuralstudies and antigen design Novelvaccine platforms (VLP, nanoparticles, RNA vaccines) Adjuvants and immunizationschedules Immune monitoringand experimantalvaccine clinicaltrials

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