Immune Approaches to PreventionPortia Hunidzarira

University of Zimbabwe College of Health Sciences-Clinical Trials Research Centre

Potential Conflicts and Financial Disclosures

• I have no actual or potential conflicts to declare in relation to this programme and presentation

• Grant/Research support: US National Institutes of Health, Bill and Melinda Gates Foundation, USAID

The need for more HIV Prevention approaches has not changed

• HIV epidemic continues to surge even in countries with longstanding ART

• In eastern and southern Africa, in 2015 there were 19 million people living with HIV, 960,000 new infections and 470,000 AIDS-related deaths (UNAIDS)

• Under status quo, 49 million new infections predicted worldwide 2015-2035(Medlock et al., PNAS, 2017)

Immune approaches to prevention

• For the global community to achieve elimination of new HIV infections, innovative approaches need to be explored.

• Immune‐based approaches to prevention HIV infection may help fill some of the remaining gaps and provide new opportunities to eliminate the pandemic.

• These Immune‐based interventions to prevent HIV may include active immunization with HIV vaccines and passive immunization approaches with monoclonal antibodies.

Active Immunization Passive Immunization

Vaccination to stimulate antibodies previously shown to correlate with reduced risk of HIV infection. This is being tested in HVTN 702 &705

Pre-formed broadly neutralizing antibody VRC01 is infused to provide protection against HIV infection. This is being tested in the HVTN 703/HPTN081, HVTN704/085 (AMP trial) Nono Mkhize,2017

Novel Immune strategies 2016/2017

Effi

cacy

stu

die

s

Building on RV144 ,a P5 “Clade C” approach using ALVAC & gp120/MF59

(HVTN 702)

Neutralizing antibody approach using VRCO1

(AMP Trial: HVTN703/HPTN081 & HVTN 704/HPTN 085 )

Multi-clade Prime/Boost Ad26/gp140

(HVTN705)

RECENT HIV VACCINE RESEARCH

Active Immunization

Vaccine and Related* Designs

8

9

HVTN 705/HPX2008

• Phase 2b Efficacy trial called “Imbokodo” meaning “Rock”

• “Imbokodo” originates from a popular South African proverb which says : “You Strike the Women, You Strike the Rock”!

• Test/Proof of Concept:

• Study to see if the vaccine regimen can work in the most vulnerable groups of people at risk – women in sub-Saharan Africa

• Not for licensure

10

Study Vaccines used in HVTN 705

• HVTN 705 is testing 2 experimental vaccines against HIV

• The study vaccines are called Ad26.Mos4.HIV and Clade C gp140Ad26.Mos4.HIVthis is a cold-like virus that

has been altered to produce

tiny pieces of the HIV virus

envelope

Clade C gp140This is a tiny piece of the outside of

the HIV virus

Placebo

11

HIV-1 Diversity

Worldwide

A

B

C

D

F, G, H, J, K

CRF01_AE

other

CRF02_AG

CRF03_AB

Subtype

HVTN 705 : Adenovirus 26 Mosaic Inserts Trivalent subtype C +alum

12

Schema

• Total: 2600 females in sub-Saharan Africa• Anticipated enrollment: 14 months, 24-36 months of follow-up• Primary Objective

• To evaluate vaccine efficacy (Months 7-24)• To evaluate the safety and tolerability of this vaccine regimen

• Trial is co-funded by the US National Institutes of Health, the Bill and Melinda Gates Foundation and Janssen Vaccines & Prevention B.V.

Group N Month 0 Month 3 Month 6 Month 12

Prime Boost

1 1300 Ad26.Mos4.HIV Ad26.Mos4.HIV

Ad26.Mos4.HIV

+

Clade C gp140 (250 mcg +

adjuvant)

Ad26.Mos4.HIV

+

Clade C gp140 (250 mcg +

adjuvant)

2 1300 Placebo Placebo

Placebo

+

Placebo

Placebo

+

Placebo

13

13

Bloemfontein

Sites: HVTN efficacy trial enrollment

Mamelodi

Ndola

Isipingo

Elansdoorn

Cape Town-

Emavundleni

Lilongwe

Maputo

Seke South

Lusaka -Matero

Klerksdorp

Soweto – Kliptown

Mthatha

Soshanguve

Medunsa

Tembisa

Rustenburg

Ladysmith

Masiphumelele

Legend:

705, only (6)

702 &705 (10)

702, 703/081, 705 (5)

703/081 & 705 (7)

Soweto – Baragwanath

Chatsworth

eThekwini

Lusaka -ZEHRP

Cape Town-

Khayelitsha

Verulam

Tongaat

HPTN 084 (6) St Mary’s

bb

Study updateMarch 2018 128 out of 2600 (~5%) enrolled.

Zimbabwe enrolled 1st

participant 26 Feb 2018, 20 out of 350 now enrolled

No serious Adverse events

14

Future Research designs • If HVTN 705 succeeds, a Phase 3 global efficacy trial will be performed

to determine if this regimen can sufficiently prevent infection globally with HIV-1 of multiple clades.

• Future studies will then include men and women from other parts of the world

• Other HIV vaccine strategies are still under development with newer promising concepts such as use of replicating viral vectors, mRNA and virus like particles .

• However, there is still no HIV vaccine licensed for use.

Broadly neutralizing monoclonal antibodies (bnAbs)

Passive immunization

There is a long history of using

antibodies to prevent viral infections.

VIRUS PRODUCT DESCRIPTION INDICATION

Measles Concentrated human gamma globulin Prevention

Polio Concentrated human gamma globulin Prevention

CMV Cytomegalovirus Immune Globulin Prevention

Hepatitis A Immune serum globulin (ISG) Prevention (travel)

Hepatitis B Hepatitis B Immune Globulin Post Exposure

Rabies Rabies Immune Globulin Post Exposure

RSVmAb (palivizumab) for prophylaxis of

high risk infantsPrevention in High Risk

Infants

VZ Varicella Zoster Immune Globulin Post Exposure

And, most effective vaccines induce antibodies that neutralize the pathogen.Thanks to John Mascola for this slide.

v1 1Aug16

Neutralizing Antibodies Preventing HIV Infection

Video goes here

17v1 1Aug16

The AMP Study:

Filling the Gap

• This is the idea of using an antibody made by scientists

and giving it to people directly, i.e. using an intravenous (IV)

infusion, to prevent HIV infections.

• This is the first efficacy trial to assess if antibodies can be

used to prevent HIV infection , similar to how antibodies

are used to prevent other infectious diseases

18

AMP = Antibody Mediated Prevention

v1 1Aug16

VRC01: The AMP Study Antibody

Broadly Neutralizing (“bnAb”)

Monoclonal antibody (“mAb”)

Discovered by scientists at the US NIH

In the lab, it has been able to block HIV in about 90% of the different types of HIV that it has been tested against.

19

Photo: NIAID/NIH Vaccine Research Center (VRC)

Gray: gp120

Red: CD4 binding site (CD4bs)

Purple & Green: VRC01 attached to the CD4bs

v1 1Aug16

What is a Monoclonal Antibody (mAb) to HIV?

20

V1V2 Glycan:

PG6, PG16, CH01-04, PGT141-45,

CAP256-VRC26

CD4 Binding Site:

VRC01, PG04, CH31,

VRC07, 3BNC117,

12A12, CH103

N332 Glycan Supersite:

PGT121, PGT128

10-1074

Trimer (gp120/41)

8ANC195, PGT151, 35022

Thanks to the Subramaniam, Kwong, and Wilson groups.

A single type (“clone”) of antibodies often found in the blood of

long-term non-progressors, then made in a lab

Bind to different parts of the HIV gp120 envelope protein

gp41 MPER:

2F5, 4E10, 10e8

v1 1Aug16

AMP Study Design

21

REGIMENMSM & TG in the

Americas

Women in

sub-Saharan AfricaTOTAL

VRC01 10 mg/kg 900 634 153410 infusions total

&

Infusions every 8 weeks

Study duration:

~24 months

VRC01 30 mg/kg 900 634 1534

Control 900 634 1534

Total 2700 1900 4600

v1 1Aug16

HVTN 703/HPTN 081 HVTN 704/HPTN 085

Study update (Feb 2018)

703/081

African Women

1487* enrolled

95% retention through 13,700

clinic visits

99% adherence to 7126 infusions

704/085

MSM & TGM

2138 enrolled

94% retention through 23,133

clinic visits

100% adherence to 1162 infusions

22

* 334 (22%) from

Zimbabwean sites

Seke South,

Spilhaus and

Parirenyatwa CRSs

Future research for Monoclonal antibodies• If virus is targeted by multiple bNAbs, then escape is difficult.

• Future studies will use combinations of mAbs to improve efficacy through both better coverage and higher potency

• The goal of these studies is to identify what are the best regimens for moving to a licensure trial

Sept. 2018 Dec. 2018 Jan. 2019 March 2019

VRC07-523LS

+

PGT121 V3 loop

+

PDM1000

Tri-specific VRC07-523LS

+

10E8LS

VRC07 -523LS

+

PGT 121 LS

Dan

Barouch/IAVI/VRCSanofi VRC

Dan Barouch/IAVI/VRC

Larry CoreyHVTN Regional Meeting RSA 2018

In conclusion,

• On a global scale, immune‐based approaches to prevention HIV infection may help fill some of the remaining gaps that will finally stop the pandemic.

• Currently there are no HIV vaccines licensed for use and clinical research is still ongoing

• Use of monoclonal antibodies (mAbs) for HIV prevention is a promising new approach

• Plans are underway to begin research in combination mAbs which will have a higher coverage and potency to prevent HIV .

Acknowledgements• UZ-CHS-CTRC

• Clinic staff, recruiters and investigators

• Study participants and Community

• Sponsors and collaborators