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Towards an antibody-based HIV vaccine Towards an antibody-based HIV vaccine

Towards an antibody-based HIV vaccine - PowerPoint Presentation

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Towards an antibody-based HIV vaccine - PPT Presentation

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

vaccine hiv neutralizing antibodies hiv vaccine antibodies neutralizing v1v2 infection viral passive bnabs nature antibody 2012 years cap256 immunization

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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 Slide5
Slide6

~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