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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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
Vaccine available
Koff et al Science 2013
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Vaccine not available
Vaccination and immunological memory
IMMEDIATE PROTECTION
“Effector 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
Long-lived plasma cells secrete
antibodies continuously
Tissue-resident memory T cells
confer immediate protection in tissues
Serum IgG ter
RECALL RESPONSE
“Central memory cells”
Memory B
cells
wks-mos
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Short-lived
Plasma Cells
mos - few years
Long-lived Plasma Cells
> 3 years
Sallusto, Ahmed, Radbruch, Heath & Carbone
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
negative effect




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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
Why was the Thai trial successful?
No association with:
 Neutralizing Abs
 Cellular immune responses
Decreased 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 responses
But:
 Efficacy was in a low-risk population and faded with time
1Rerks-Ngarm et
al. New Engl J Med 2009, 361:2209-2220.
et al. New Engl J Med 2012;366(14):1275-86.
3Bonsignori et al. J Virol 2012; 86(21):11521-32.
2Haynes
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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An international collaborative effort to identify
broadly HIV neutralizing antibodies (bNAbs)
Nature Immunology 2004
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Sera with broad HIV neutralizing activity are common
110 HIV+ sera tested against panel of 20 viruses
Doria-Rose et al. JV, 2010
… but these antibodies are produced only after years of chronic infection
… and HIV continues to escape (Richman PNAS 2009)
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Sera with broad HIV neutralizing activity are common
110 HIV+ sera tested against panel of 20 viruses
Doria-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
Neutralizing
neutralizing breadth
breath
1981
- 2009
1994
1.0
1.0
2F5
4E10
b12
2G12
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.001
0.01
0.1
1
10
100
0.0
2F5
4E10
b12
2G12
PG9
PG16
0.001
0.01
Antibody (mg/ml)
Neutralizing potency (IC50)
2010
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ath
1.0
0.8
2F5
4E10
b12
1.0
0.8
2F5
4E10
b12
45
10
45
10
100
0.0
0.01
0.1
1
10
100
Broadly 0.001
neutralizing
antibodies
against
HIV-1
Neutralizing breadth
Today
2011
10
100
(IC50)
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1.0
0.8
0.6
0.4
45-46G54W
2F5
4E10
10-1074
b12
45-46
2G12
PG9
PG16
VRC01
3BNC117
PGT128
Mouquet et al., PNAS 2012
Scheid et al., Science 2011
Diskin et al., Science 2011
Walker et al., Nature 2011
Wu et al., Science 2010
Walker et al., Science 2009
0.2
0.0
0.001
0.01
0.1
1
Antibody (mg/ml)
10
100
Neutralizing
potency
Neutralizing
potency
(IC50(IC
) 50)
The sites recognized by best in class antibodies
From Klein et al. Science 2013
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The evolution of broadly neutralizing antibodies
 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)
The transmittedFounder virus
Naïve B cells
autologous
neutralization
Escape virus
Crossneutralization
Breadth
55% viruses
Adapted from Bart Haynes
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See also:
Wu et al Science 2011
Klein et al Cell 2013
Gitlin et al Nature 2014
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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Immunogen design to guide antibody evolution
Jardine et al Science 2013
Prime-boost strategy using immunogens that recapitulate the
developmental pathway starting form naive B cells thus mimicking
antibody-viral co-evolution
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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
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bNAbs in prophylaxis and therapy
Prophylaxis
Therapy
Few infecting viruses
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 vectors
engenders 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
Studies with first generation bNAbs showed poor control of viremia and rapid
emergence of resistant variants.
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
 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.
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 HIV
Hessel et al. Nature 2007
Limited or no protection by
weakly or nonneutralizing
antibodies against vaginal SHIV
challenge of macaques
compared with a strongly
neutralizing antibody
Burton et al. PNAS 2007
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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 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
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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
Profound early control of highly
pathogenic SIV by an effector
memory T-cell vaccine
 Rhesus CMV carrying SIV genes induced
effector T cell responses against SIV
Hansen et al. Nature 2011
 50% of monkeys were protected from
challenge
Immune clearance of highly
pathogenic SIV infection
 They were infected but controlled and
aborted SIV so that it was undetectable
Hansen et al. Nature 2013
Cytomegalovirus Vectors
Violate CD8+ T Cell Epitope
Recognition Paradigms
Hansen et al. Science 2013
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 The vector elicits MHC class II-restricted
CD8+ T cells, greatly expanding the
breadth of the T cell response.
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, 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)
Corey et al Sci Transl Med 2011
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A new paradigm for vaccine development
(can we do better than nature?)
A Characterization of protective responses
elicited by natural infection
B Structural definition of a neutralization-sensitive
site of viral vulnerability
Natural RSV
infection
Potent D25
antibodies
recognize
antigenic site Ø
Potently neutralizing antibodies
Moderately neutralizing antibodies
Corti et al. Science 2011
Weakly neutralizing antibodies
RSV F
glycoprotein
trimer
C Information matrix for structure-based
vaccine design
Design
Cavity filling
Cavity filling
Disulfide
Immunogenicity
D Elicitation of protective responses with a
neutralization-sensitive site immunogen
Antigenic &
physical properties
Antibody
recognition of
homogeneous
trimer
Structure
A neutralizing antibody selected from
plasma cells that binds to group 1 and
group 2 influenza A hemagglutinins
Immunization
with RSV F
optimized to
present the
neutralizationsensitive site
Neutralization-sensitive
site-directed
potently neutralizing
antibodies
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 virus
McLellan et al. Science 2013
Disulfide
Cavity filling
Elicitation of humoral response
Courtesy of Peter Kwong
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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
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