Is a preventative HIV vaccine possible? 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) 6th FIDSSA Congress 2015; Drakensburg, KZN, SA

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

Why don’t we have a vaccine against HIV? • • • • •

No-one has ever recovered from HIV infection HIV mutates rapidly HIV integrates into human DNA HIV envelope glycoprotein is a complex target 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 V1V2 antibodies correlated with a reduced risk of infection 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

11

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 B cell

Infecting virus

UCA (Unmutated common ancestor )

Northern Province

Gauteng

Mpumalanga

North West

Free State

KwaZulu Natal

Vulindlela

Northern Cape

Durban Eastern Cape Western Cape

Elin Gray et al J Virol. 2011

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 i2015

Escape from autologous antibodies creates a V3/glycan bNAb epitope Viral escape through glycan shielding

+332 glycan

Infecting virus

V3 glycan bNAb CAP177 & CAP314

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

V1V2 bNAb Years of Infection Jinal Bhiman et al., Nature Medicine, 2015

Sequential immunization strategies Breadth

Years of Infection

Malherbe et al, 2011; Haynes et al., 2012; Moore et al, 2012; Liao et al, 2013; Bhiman et al., 2015

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

..

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

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

An HIV vaccine is an achievable goal • RV144 has provided immune correlates that are being pursued in large scale efficacy trials • Availability of HIV envelope trimer immunogens • Identified critical factors in bNAb induction; although significant challenges remain in translating these into an HIV vaccine • Passive immunization studies will provide proofof-concept for bNAb-mediated protection

NICD HIV VACCINE RESEARCH 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