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
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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?
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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