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 ID: 641960
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Slide1
Towards an antibody-based HIV vaccine
Prof Lynn MorrisNational 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)
5
th
CSIR Conference, CSIR ICC, Pretoria. 8-9 Oct 2015Slide2
Overview
Vaccination as a public health intervention HIV vaccine trials and immune correlatesRoadblocks and roadmaps for inducing broadly neutralizing antibodiesThe promise of passive immunization Slide3
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, UKSlide4
Most licensed vaccines work by inducing
neutralizing antibodies that fight virus infections Slide5Slide6
~5,500 new HIV infections every day
~4,000 AIDS deaths every day The Global HIV Pandemic Slide7
Age Group
(Years)
HIV Prevalence
(N=1029)
≤168.4
17-18
18.6
19-20
25.4
21-22
32.8
23-24
44.8
HIV prevalence in young pregnant women in rural Vulindlela, South Africa
(
2009-2012)
Quarraisha and Salim Abdool Karim Slide8
Why don’t we have a vaccine against HIV?
No-one has ever recovered from HIV infection HIV is a rapidly moving targetHIV integrates into human DNAIt is difficult to neutralize HIV (complex surface envelope glycoprotein) Current vaccines are unable to stimulate broadly neutralizing antibodiesSlide9
HIV Vaccine Efficacy Trials To Date
NoNOTE: Phambili (HVTN 503) began to explore a regimen similar to STEP in South Africa (not included)Slide10
0.010
0.008
0.006
0.004
0.0020.000Probability of InfectionB
10000
1000
100
10
0
MFI
Low
Medium
High
Uninfected Vaccine
Uninfected
Placebo
A
Placebo
Low
Medium
High
36
24
12
0
Time since Week 26
v
isit (months)
Non-neutralizing antibodies to V1V2 correlated
with protection in the RV144 vaccine trial
Haynes et al., 2012Slide11
Formation of the P5 Partnership in 2010(Pox-Protein Public Private Partnership)
Purpose:
To build on RV144 data and ultimately license a pox-protein based HIV vaccine with the potential for broad and timely public health impact.
Strategy:
Continue to build public-private partnerships critical for success.
Work with host countries to support a flexible regulatory strategy in target populations and regions.
Generate and incorporate knowledge from the assessment of next-generation vaccine concepts.Slide12
Timeline for P5 Efficacy Trial
12Slide13
Reasons for Optimism
Vaccination can alter risk of acquiring HIV infectionProtection correlated with non-neutralizing V1V2 antibodies that are relatively easy to induceHowever, better vaccine efficacy will likely require the induction of neutralizing antibodiesRecent structure of HIV envelope trimer has resulted in better immunogensA large number of potent and broadly neutralizing monoclonal antibodies have been isolated from HIV infected individuals Slide14
Years of Infection
Breadth
UCA
(Unmutated common ancestor )
Understanding how broadly neutralizing antibodies develop in HIV infectionSlide15
Strain-specific antibodies
Creation of bNAb epitopes through viral escape
Broadly neutralizing antibodies
Exposure of
bNAb epitopes through viral escapeGeneration of epitope variants (immunotypes) through viral escape
Viral diversity
Viral mechanisms for stimulating
bNAbs
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
Moore, Williamson and Morris,
Trends in Microbiology
2015Slide16
Years
of Infection Escape from autologous
antibodies creates a V3/glycan bNAb
epitope Penny Moore et al., Nature Medicine, 2012
+332 glycanBreadth
Infecting virus
Viral escape through glycan shieldingSlide17
bNAbs are able to tolerate multiple
immunotypes (toggling escape mutations) Epitope variants (immunotypes) through viral escape169K
Years of Infection
Breadth
Jinal Bhiman et al., Nature Medicine, in press
169I
169Q
169RSlide18
Years of Infection
Breadth
Sequential immunization strategies
Malherbe et al, 2011; Haynes et al., 2012; Moore et al, 2012; Liao et al, 2013Slide19
V1V2/glycan
CD4bs
Modified from Burton
et al., Science
2012
Long CDRH3 (>25
aa
)
Heavily mutated
(up to 30%)
HIV-1
bNAbs
display unusual properties that present significant challenges for vaccine development
.
.
.
.Slide20
CD4bs
CH103
CD4 binding site antibodies develop through a process of extensive somatic
hypermutation
Nature 2013Slide21
V1V2/glycan
CAP256-VRC26
V1V2 antibodies with long CDRH3 regions are selected during the initial recombination event
.
.
.
.
Nature 2014Slide22
Rapid development of neutralization breadth within the CAP256-VRC26 lineage
002.1%
1.1%6.3%2.1%
8.3%3.9%
Mutations (nt)HeavyLight Doria-Rose, Schramm, Gorman, Moore et al., Nature 2014
UCA
AbSlide23
Different routes to neutralization breadth
Unmutated commonAncestor (UCA)
CD4bs lineageBinding to autologous
EnvStrain-specific neutralizationBroad neutralization+
+++++V1V2 lineageBinding to autologous EnvStrain-specific neutralizationBroad neutralization
+
+
+
+
+
.
.
.
.
MONTHS
YEARS
Derdeyn, Moore and Morris. COHA 2014Slide24
Which pathway is more amenable to
HIV vaccine design?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
...
.
V1V2 lineage
CD4bs lineageSlide25
Active versus Passive/Vector-based Immunoprophylaxis
(VIP)VaccinationStimulating an antibody response
Passive “vaccination”Infusion with protective antibodies
Production of antibodies by vectorVIP
No HIV vaccine is able to stimulate bNAbsHighly potent bNAbs are being tested as “drugs” to prevent HIVSlide26
Passive Immunization – shortcut to an HIV vaccine?
Passive immunization tests the role of neutralizing antibodies in the absence of other vaccine immune responsesSuch studies wont provide information on the immunological roadblocks to inducing bNAbsEfficacy data for prevention of sexual transmission will not be available for a number of yearsProspects for using bNAbs for prevention at a population-level still need to be assessedSlide27
The Promise of Passive Immunization
Provide proof-of-principle that bNAbs can prevent HIV infection in humansDetermine the minimal dose of antibody (including levels at mucosal surfaces)Identify the best viral epitopes to targetAssess the importance of antibody isotypesProvide additional correlates of protection Slide28
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 virusesUnlike other members of this class, neutralization does not depend on binding to key glycansNeutralises 72% of clade C panel (63% of all subtypes) and is exceptionally potent so may require less antibody to achieve inhibitory concentrationsSlide29
Breadth and potency of CAP256-VRC26 against
HIV-1 clade C isolatesDoria-Rose et al., J Virology in pressSlide30
CAP256-VRC26.25 IgG
Development plan for CAP256-VRC26.25 for passive immunizationManufacture GLP lotMonkey challenge studySub-cutaneous formulation GMP lot manufacture and formulation for human trials and stability studies Pre-clinical studiesRegulatory filing of IND Phase I/II safety & proof-of-concept trial (CAPRISA 012)
Slide31
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 trialsStudies in HIV infection have identified critical factors in bNAb induction; although significant challenges remain in translating these into an HIV vaccinePassive immunization will provide proof-of-concept for bNAb-mediated protectionSlide32
NICD HIV ANTIBODY GROUPSlide33
Collaborators and Funders
Duke/CHAVI-IDBarton HaynesTony MoodyLarry LiaoGeorgia TomarasDavid MontefioriHVTNGlenda GrayLarry CoreyJulie McElrath John HuralCAPRISASalim Abdool KarimQuarraisha Abdool Karim
Nigel Garrett Carolyn WilliamsonVRC John MascolaPeter KwongNicole Doria-Rose
Jay GormanColumbiaLarry ShapiroChaim Schramm