Stepping up the pace on HIV Vaccine: what needs to be done?
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www.aids2014.org 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, Wayne Koff, Peter Kwong, Giuseppe Pantaleo and Stanley Plotkin
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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. - PowerPoint PPT Presentation
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Stepping up the pace on HIV Vaccine:what needs to be done?
Antonio Lanzavecchia
Institute for Research in Biomedicine, BellinzonaInstitute of Microbiology, ETH Zürich
Thanks to: Dennis Burton, Michel Nussenzweig, Wayne Koff, Peter Kwong, Giuseppe Pantaleo and Stanley Plotkin
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Vaccination campaigns eradicated lethal diseases
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%
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Low- and high-hanging fruits
Koff et al Science 2013
Vaccine available Vaccine not available
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Vaccination and immunological memory
Sallusto, Ahmed, Radbruch, Heath & Carbone
IMMEDIATE PROTECTION“Effector memory cells”
Long-lived plasma cells secrete antibodies continuouslyTissue-resident memory T cells confer immediate protection in tissues
RECALL RESPONSE“Central memory cells”
Memory B and T cells upon antigen re-encounter generate large numbers of killer T cell, plasma cells and antibodies within a few days
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A narrow window 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
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Additional problems relating to a HIV vaccine
Extreme strain variation, even in the same individual A glycan shield that prevents antibody access to the viral spike Neutralizing antibodies develop late Immune escape, class I downregulation, immunosuppression No natural recovery from chronic infection Undefined biomarkers of protection Lack of an ideal animal model
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Timeline of HIV vaccine trials
Vaxgen: HIV gp120 Merck/NIAID STEP trial: rAdenovirus 5 (gag T cells) Sanofi/MHRP/NIAID/Thai RV-144 trial: canarypox vector + gp120 HVTN 505: NIAID-VRC: DNA + rAdenovirus 5
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Why was the Thai trial successful?
No association with: Neutralizing Abs Cellular immune responsesDecreased risk associated with: IgG Ab responses to the V1/V2 loop (mainly non neutralizing) ADCC activity mostly to the C1 region of Env Low IgA Ab responsesBut: Efficacy was in a low-risk population and faded with time1Rerks-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 modest efficacy of the RV144 trial?
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Serum neutralizing antibodies can prevent mucosal infection in macaques
But none of the vaccines tested so far elicited neutralizing antibodies
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Nature Immunology 2004
An international collaborative effort to identify broadly HIV neutralizing antibodies (bNAbs)
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Sera with broad HIV neutralizing activity are common
… but these antibodies are produced only after years of chronic infection
… and HIV continues to escape (Richman PNAS 2009)
Doria-Rose et al. JV, 2010
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Sera with broad HIV neutralizing activity are commonDoria-Rose et al. JV, 2010
Is the neutralizing activity due to multiple antibodies each specific for a single virus or to single antibodies with broad neutralizing capacity?
How many different sites can be recognized by neutralizing antibodies?
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Multiple approaches to isolate bNAbs
Key: donor selection and better methods to isolate antibodies
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Broadly neutralizing antibodies against HIV-1
1981 - 2009
Neutralizing potency (IC50)
Neu
traliz
ing
brea
dth
Antibody (mg/ml)
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Broadly neutralizing antibodies against HIV-1
Neutralizing potency (IC50)
Neu
traliz
ing
brea
dth
Today
Mouquet et al., PNAS 2012Scheid et al., Science 2011Diskin et al., Science 2011Walker et al., Nature 2011Wu et al., Science 2010Walker et al., Science 2009
Antibody (mg/ml)
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The sites recognized by best in class antibodies
From Klein et al. Science 2013
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The evolution of broadly neutralizing antibodies
See also:Wu et al Science 2011Klein et al Cell 2013Gitlin et al Nature 2014
Antibodies to CD4bs have a long developmental pathway concomitant with viral evolution (Liao et al Nature 2013)
Antibodies to V1V2 can develop more rapidly through initial selection of rare naive B cells with a long CDRH3 followed by limited somatic mutations (Doria-Rose et al Nature 2014)
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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 glycans can 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
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Prime-boost strategy using immunogens that recapitulate the developmental pathway starting form naive B cells thus mimicking antibody-viral co-evolution
Immunogen design to guide antibody evolution
Jardine et al Science 2013
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The BG505 SOSIP.664 gp140 trimer was crystallized with PGT122, a bNAb which binds to the glycan-dependent N332 epitope on gp120
The structure of the HIV envelope trimerCrystal structure of a soluble cleaved HIV-1 envelope trimer Julien et al. Science 2013
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bNAbs in prophylaxis and therapy
Prophylaxis
Few infecting viruses
Therapy
Huge number of different viruses plus a hidden reservoire
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Proof of concept: prophylaxis using bNAbs
bNAbs protect:
in the SHIV macaque model (Pegu et al. Sci. Trasl. Med. 2014)
in the humanized HIV-1 model (Pietzsch et al. PNAS 2012)
Potential improvements:
engineering to extend halflife and increase ADCC
vectored immunoprophylaxis using AAV vectorsengenders long-lived neutralizing activity and protection in monkeys and humanized mice (Johnson et al Nat Med 2009; Balasz et al Nat Med 2014)
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An unexpected finding: the new bNAbs can be effective therapeutically
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 Viremia remained undetectable for as long
as antibody levels remained therapeutic and in 3/18 macaques viremia remained undetectable undetectable after 100-200 days.
Therapeutic efficacy of potent neutralizing HIV-1-specific antibodies in SHIV-infected rhesus monkeysBarouch et al. Nature 2013
Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemiaShingai et al. Nature 2013
Studies with first generation bNAbs showed poor control of viremia and rapid emergence of resistant variants.
A clinical trial with 3BNC117 (to CD4bs) is ongoing in humans (M. Nussenweig)
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A role for non-neutralizing antibodies?
Neutralization is the main mechanism of protection, but antibodies can be effective also via ADCC, complement and opsonization.
Non neutralizing antibodies show some in vivo efficacy (also suggested by the Thai trial)
Fc receptor but not complement binding is important in antibody protection against HIVHessel et al. Nature 2007
Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibodyBurton et al. PNAS 2007
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Aim: To stimulate the appropriate naive B-cells and promote affinity
maturation leading to bNabs To induce long-lived plasma cells and durable bNAb responses
New tools and approaches: Intact soluble trimers and epitope scaffolds Prime-boost strategies Antigen-guided B cell development Multimerization on nanoparticles New adjuvants and formulations
Towards an antibody-based HIV vaccine
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Antibodies and T cells?
Replicating viral vectors confer durable protective immunity Phase I: Sendai, measles, VSV, Pox, Ad4 Preclinical: CMV
Conserved and mosaic antigens focus immune responses to conserved regions and provide optimal coverage of HIV epitopes
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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 response at the site of virus release during asymptomatic HSV reactivation is in sharp contrast to the delayed CD8 T-cell infiltration during a lesion-forming herpes recurrence
The role of effector memory T cells in HIV-1 infection should be explored
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A CMV vector as an effector memory T cell vaccine
Rhesus CMV carrying SIV genes induced effector T cell responses against SIV
50% of monkeys were protected from challenge
They were infected but controlled and aborted SIV so that it was undetectable
The vector elicits MHC class II-restricted CD8+ T cells, greatly expanding the breadth of the T cell response.
Immune clearance of highly pathogenic SIV infectionHansen et al. Nature 2013
Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine Hansen et al. Nature 2011
Cytomegalovirus Vectors Violate CD8+ T Cell Epitope Recognition Paradigms Hansen et al. Science 2013
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Innovative trials in humans can accelerate vaccine development
rapid, small, hypothesis driven clinical research trials (adaptive trials) to test multiple candidates in Phase I/IIb
real-time assessment of immune responses
efficacy studies in high risk populations
integration with vaccine development efforts against other diseases (adjuvants etc)
Given the limitations of animal models in predicting vaccine-induced immune responses and vaccine efficacy in humans it is important to develop:
Corey et al Sci Transl Med 2011
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A new paradigm for vaccine development(can we do better than nature?)
Courtesy of Peter Kwong
A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutininsCorti et al. Science 2011
Cross-neutralization of four paramyxoviruses by a human monoclonal antibody Corti et al. Nature 2013
Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virusMcLellan et al. Science 2013
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HIV vaccine: the way forward
1. Antibody discovery and developmental pathways
2. Structural studies and antigen design
3. Novel vaccine platforms (VLP, nanoparticles, RNA vaccines)
4. Adjuvants and immunization schedules
5. Immune monitoring and experimantal vaccine clinical trials
