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)

5th CSIR Conference, CSIR ICC, Pretoria. 8-9 Oct 2015

OverviewOverview

• 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

~5,500 new HIV infections every day

~4,000 AIDS deaths every day

The Global HIV Pandemic

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

HIV prevalence in young pregnant women in rural Vulindlela, South Africa

(2009-2012)

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)

0.010

0.008

0.006

0.004

0.002

0.000

Pro

bab

ilit

y o

f In

fect

ion

B10000

1000

100

10

0

MF

I

Low Medium HighUninfected Vaccine

UninfectedPlacebo

A

PlaceboLowMediumHigh

3624120

Time since Week 26 visit (months)

Non-neutralizing antibodies to V1V2 correlated with protection in the RV144 vaccine trial

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 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.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 next-generation 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

Years of Infection

Breadth

UCA (Unmutated

common ancestor )

Understanding how broadly neutralizing antibodies develop in HIV infection

Strain-specific antibodies

Creation of bNAb epitopes through viral escape

Broadly neutralizing antibodies

Exposure of bNAb epitopes through viral escape

Generation 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 2015

Years of Infection

Escape from autologous antibodies creates a V3/glycan bNAb epitope

Penny Moore et al., Nature Medicine, 2012

+332 glycan

Breadth

Infecting virus

Viral escape through glycan

shielding

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

169R

Years of Infection

Breadth

Sequential immunization strategies

Malherbe et al, 2011; Haynes et al., 2012; Moore et al, 2012; Liao et al, 2013

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

... .

CD4bsCH103

CD4 binding site antibodies develop through a process of extensive somatic hypermutation

Nature 2013

V1V2/glycan

CAP256-VRC26

V1V2 antibodies with long CDRH3 regions are selected during the initial recombination event

... .

Nature 2014

Rapid development of neutralization breadth within the CAP256-VRC26 lineage

00

2.1%1.1%

6.3%2.1%

8.3%3.9%

Mutations (nt)HeavyLight

Doria-Rose, Schramm, Gorman, Moore et al., Nature 2014

UCA

Ab

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 2014

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 lineage

Active versus Passive/Vector-based Immunoprophylaxis (VIP)

Vaccination

Stimulating an antibody response

Passive “vaccination”

Infusion with protective antibodies

Production of antibodies by vector

VIP

No HIV vaccine is able to

stimulate bNAbs

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

Doria-Rose et al., J Virology in press

CAP256-VRC26.25 IgG

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)

 

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-of-concept for bNAb-mediated protection

NICD HIV ANTIBODY GROUP

Collaborators and FundersDuke/CHAVI-IDBarton HaynesTony MoodyLarry LiaoGeorgia TomarasDavid Montefiori

HVTNGlenda GrayLarry CoreyJulie McElrath John Hural

CAPRISASalim Abdool KarimQuarraisha Abdool KarimNigel Garrett Carolyn Williamson

VRCJohn MascolaPeter KwongNicole Doria-RoseJay Gorman

ColumbiaLarry ShapiroChaim Schramm