Towards an antibody-based HIV vaccine
Prof Lynn Morris
National Institute for Communicable Diseases, a division of the
National Health Laboratory Service (NHLS) of South Africa,
University of the Witwatersrand, Johannesburg, South Africa
Centre for the AIDS Program of Research in South Africa (CAPRISA)
5th CSIR Conference, CSIR ICC, Pretoria. 8-9 Oct 2015
Overview
• Vaccination as a public health intervention
• HIV vaccine trials and immune correlates
• Roadblocks and roadmaps for inducing
broadly neutralizing antibodies
• The promise of passive immunization
Apart from the provision of clean
water, vaccines have had a more
profound effect on world health,
especially of children, than any
other public health measure.
E Richard Moxon, University of Oxford, UK
Most licensed vaccines work by inducing
neutralizing antibodies that fight virus
infections
The Global HIV Pandemic
~5,500 new HIV
infections every day
~4,000 AIDS deaths
every day
HIV prevalence in young
pregnant women in rural
Vulindlela, South Africa
(2009-2012)
Age Group
(Years)
HIV Prevalence
(N=1029)
≤16
8.4
17-18
18.6
19-20
25.4
21-22
32.8
23-24
44.8
Quarraisha and Salim Abdool Karim
Why don’t we have a vaccine against HIV?
•
•
•
•
No-one has ever recovered from HIV infection
HIV is a rapidly moving target
HIV integrates into human DNA
It is difficult to neutralize HIV (complex surface
envelope glycoprotein)
• Current vaccines are unable to stimulate broadly
neutralizing antibodies
HIV Vaccine Efficacy Trials To Date
No
NOTE: Phambili (HVTN 503) began to explore a regimen similar to STEP in South Africa (not included)
Non-neutralizing antibodies to V1V2 correlated
with protection in the RV144 vaccine trial
A
10000
B
Probability of Infection
0.010
MFI
1000
100
10
Placebo
Low
Medium
High
0.008
0.006
0.004
0.002
0.000
0
0
Uninfected
Placebo
Low
Medium
High
Uninfected Vaccine
12
24
36
Time since Week 26 visit (months)
Haynes et al., 2012
Formation of the P5 Partnership in 2010
(Pox-Protein Public Private Partnership)
Purpose:
To build on RV144 data and
ultimately license a poxprotein based HIV vaccine
with the potential for broad
and timely public health
impact.
Strategy:
Continue to build public-private
partnerships critical for success.
1.Work with host countries to support a
flexible regulatory strategy in target
populations and regions.
2.Generate and incorporate knowledge
from the assessment of nextgeneration vaccine concepts.
Timeline for P5 Efficacy Trial
12
Reasons for Optimism
• Vaccination can alter risk of acquiring HIV infection
• Protection correlated with non-neutralizing V1V2
antibodies that are relatively easy to induce
• However, better vaccine efficacy will likely require the
induction of neutralizing antibodies
• Recent structure of HIV envelope trimer has resulted in
better immunogens
• A large number of potent and broadly neutralizing
monoclonal antibodies have been isolated from HIV
infected individuals
Understanding how broadly neutralizing
antibodies develop in HIV infection
Breadth
Years of Infection
UCA
(Unmutated
common ancestor )
Viral mechanisms for stimulating bNAbs
Moore, Williamson and Morris, Trends in Microbiology 2015
Viral diversity
Creation of bNAb epitopes
through viral escape
Exposure of bNAb epitopes
through viral escape
Strain-specific
antibodies
Broadly
neutralizing
antibodies
Generation of epitope
variants (immunotypes)
through viral escape
Moore et al., Nat Med 2012; Liao et al., Nature 2013; Wibmer et al., PLoS Path 2013; Gao et al., Cell 2014;
Doria-Rose et al., Nature 2014; Bhiman et al., Nat Med in press
Escape from autologous antibodies
creates a V3/glycan bNAb epitope
Viral escape
through glycan
shielding
+332 glycan
Infecting virus
Breadth
Years of Infection
Penny Moore et al., Nature Medicine, 2012
bNAbs are able to tolerate multiple
immunotypes (toggling escape mutations)
169K
Epitope variants
(immunotypes)
through viral escape
169I
169R
169Q
Breadth
Years of Infection
Jinal Bhiman et al., Nature Medicine, in press
Sequential immunization strategies
Breadth
Years of Infection
Malherbe et al, 2011; Haynes et al., 2012; Moore et al, 2012; Liao et al, 2013
HIV-1 bNAbs display unusual properties that present
significant challenges for vaccine development
..
..
V1V2/glycan
Long CDRH3
(>25 aa)
CD4bs
Heavily mutated
(up to 30%)
Modified from Burton et al., Science 2012
CD4 binding site antibodies develop through a
process of extensive somatic hypermutation
Nature 2013
CD4bs
CH103
V1V2 antibodies with long CDRH3 regions are
selected during the initial recombination event
..
V1V2/glycan
CAP256-VRC26
Nature 2014
..
Rapid development of neutralization breadth within
the CAP256-VRC26 lineage
UCA
Ab
% Neutralization
CAP256-VRC26-UCA
100
80
60
CAP256-VRC26-I2
CAP256-VRC26.01
100
100
80
80
80
60
60
60
40
40
40
40
20
20
20
20
0
0.01
Mutations (nt)
Heavy
Light
CAP256-VRC26-I1
100
0.1
1
mg/mL
0
0
10
100
0
0.01
SU
0.1
1
mg/mL
2.1%
1.1%
10
100
0
0.01
0.1
1
mg/mL
6.3%
2.1%
10
100
0
0.01
SU
ZM53.12
ZM197
KER2018
KER2008
CM244
CAP210
30163v5.c45
0.1
1
10
100
mg/mL
8.3%
3.9%
Doria-Rose, Schramm, Gorman, Moore et al., Nature 2014
Different routes to neutralization breadth
Unmutated common
Ancestor (UCA)
MONTHS
YEARS
+
+
+
+
+
CD4bs lineage
Binding to autologous Env
Strain-specific neutralization
Broad neutralization
+
..
..
V1V2 lineage
Binding to autologous Env
Strain-specific neutralization
Broad neutralization
+
+
+
+
+
Derdeyn, Moore and Morris. COHA 2014
Which pathway is more amenable to
HIV vaccine design?
..
..
V1V2 lineage
CD4bs lineage

Requires engagement with rare B
cells with long CDRH3 which are
often deleted

No requirement for long CDRH3
but may need to engage
particular germline alleles

Once stimulated, V1V2 bNAbs
can develop within months, not
years

Needs high levels of affinity
maturation - which may be hard
to achieve through vaccination
Active versus Passive/Vector-based
Immunoprophylaxis (VIP)
Vaccination
Stimulating
an antibody
response
Passive “vaccination”
Infusion
with
protective
antibodies
VIP
Production of
antibodies by
vector
Highly potent bNAbs are being
tested as “drugs” to
prevent HIV
Passive Immunization – shortcut to an
HIV vaccine?
• Passive immunization tests the role of neutralizing
antibodies in the absence of other vaccine immune
responses
• Such studies wont provide information on the
immunological roadblocks to inducing bNAbs
• Efficacy data for prevention of sexual transmission
will not be available for a number of years
• Prospects for using bNAbs for prevention at a
population-level still need to be assessed
The Promise of Passive Immunization
• Provide proof-of-principle that bNAbs can
prevent HIV infection in humans
• Determine the minimal dose of antibody
(including levels at mucosal surfaces)
• Identify the best viral epitopes to target
• Assess the importance of antibody isotypes
• Provide additional correlates of protection
CAP256-VRC26.25 mAb
• Broadly neutralizing mAb isolated from CAPRISA donor,
CAP256
• Targets the V1V2 region of the HIV-1 envelope, in
particular the K169 residue which is more common in
subtype C viruses
• Unlike other members of this class, neutralization does
not depend on binding to key glycans
• Neutralises 72% of clade C panel (63% of all subtypes)
and is exceptionally potent so may require less antibody
to achieve inhibitory concentrations
Breadth and potency of CAP256-VRC26 against
HIV-1 clade C isolates
0.00001
IC50 (ug/ml)
0.0001
0.001
0.01
0.1
1
10
100
CAP256.08 CAP256.25 PGDM1400
PG9
CH01
PGT121
PGT151
VRC01
10E8
Doria-Rose et al., J Virology in press
Development plan for CAP256-VRC26.25
for passive immunization
• Manufacture GLP lot

• Monkey challenge study
• Sub-cutaneous formulation
• GMP lot manufacture and formulation for
human trials and stability studies
• Pre-clinical studies
• Regulatory filing of IND
• Phase I/II safety & proof-of-concept trial
(CAPRISA 012)
CAP256-VRC26.25 IgG
Prospects for an antibody-based HIV vaccine
• An HIV vaccine is an achievable goal
• RV144 has provided immune correlates that are
being pursued in large scale efficacy trials
• Studies in HIV infection have identified critical
factors in bNAb induction; although significant
challenges remain in translating these into an
HIV vaccine
• Passive immunization will provide proof-ofconcept for bNAb-mediated protection
NICD HIV ANTIBODY GROUP
Collaborators and Funders
CAPRISA
Salim Abdool Karim
Quarraisha Abdool Karim
Nigel Garrett
Carolyn Williamson
VRC
John Mascola
Peter Kwong
Nicole Doria-Rose
Jay Gorman
Columbia
Larry Shapiro
Chaim Schramm
Duke/CHAVI-ID
Barton Haynes
Tony Moody
Larry Liao
Georgia Tomaras
David Montefiori
HVTN
Glenda Gray
Larry Corey
Julie McElrath
John Hural