1. Nyaradzo Mgodi, MBChB, MMed
Progress in HIV Vaccines and the Road to the Clinic Antibody Mediated Prevention: The AMP Studies
Nyaradzo Mgodi, MBChB, MMed
Co-Chair, The AMP Studies
University of Zimbabwe - University of California San Francisco Collaborative Research Program
19 July 2016

2. Conflict of Interest Disclosures
I have no potential conflict of interest to report

3. Major advances in the path toward novel vaccine designs.
HVTN 704
Gray GE, Laher F, Lazarus E, Ensoli B, Corey L. Approaches to preventative and therapeutic HIV vaccines. Curr Opin Virol. April 2016, 17, 104–9.

4. Passive Immunization
Long history of use of antibodies against viral infections
Passive Antibody Prevention of HIV/SHIV in NHP for over 20 years
NHP studies tell us that physiologically achievable levels of Ab could prevent HIV-1 infection
There are no human data regarding passive protection by HIV-1 monoclonal antibodies
Learn from Proof of Concept in Humans:
What type of Ab response can prevent HIV infection?
What level of Ab is needed to prevent infection?
Convert the mAb levels to serum level of neutralization needed to protect
Provide a benchmark for vaccine development; i.e., what antibody level does a vaccine need to achieve

5. CAN ANTIBODIES BE USED TO PREVENT HIV in humans?

6. The Antibody Response to HIV
In HIV-1 infection, patients develop a strong and persistent immune response characterized by the production of HIV-specific antibodies
Neutralising Abs against the infecting strain appear months later – but are not able to neutralise more divergent viruses
Lack of broadly neutralizing antibodies elicited by the RV144-like regimens is an acknowledged deficiency in their immune profile.

7. VRC01 – Breadth and Potency
Panel of 190 Diverse Viral Isolates
Thanks to Barney Graham and
Wu et al. Rational design of
envelope identifies broadly
neutralizing human monoclonal
Antibodies to HIV. Science. 2010

8. VRC01: NHP Studies

9. VRC01 Protects Against Mucosal SHIV-Challenge in Non-Human Primates
20 mg/kg infusion of VRC01: Challenge with SHIV SF162P3
RECTAL CHALLENGE
VAGINAL CHALLENGE
4/4 protected
4/4 protected
0/4 protected
1/4 protected
Pegu et al. Science Transl Med (2014), Ko et al. Nature (2014), Rudicell et al. J Virol (2014)
9/20/2018

10. VRC01: From NHP Studies to Human Studies
9/20/2018

11. VRC01 in Phase 1 Studies: Safe and Well-tolerated
3 Phase 1 trials: VRC601, VRC602, HVTN 104
Safe and well-tolerated in about 140 participants
No serious adverse events
Mild adverse events only, which included mild lab changes in liver & kidney function that resolved spontaneously

12. AMP = Antibody Mediated Prevention
Can a passively infused monoclonal antibody prevent HIV-1 infection in high risk adults?
Two harmonized protocols:
The AMP Studies:
HVTN 704/HPTN 085
( 2700 MSM and TG in the Americas)
HVTN 703/HPTN 081
( 1500 Women in sub-Saharan Africa)

13. The AMP Studies HVTN 703/HPTN 081, HVTN 704/HPTN 085
AMP = Antibody Mediated Prevention
Defining a new path forward: This is the idea of using an antibody made in the lab and giving it to people directly, i.e. using an intravenous (IV) infusion, to prevent HIV infections.

14. Who is Doing the AMP Studies?
The study is being conducted by the HIV Vaccine Trials Network and the HIV Prevention Trials Network, in partnership with their combined clinical trial sites.

15. AMP Study Research Sites (As of July, 2016)

16. AMP in sub-Saharan Africa
7 Countries
HARARE
CHITUNGWIZA
LILONGWE
BLANTYRE
BLANTYRE
LILONGWE
GAUTENG
KZN
W CAPE
MAPUTO
KISUMU
15 Sites
MBEYA
GABERONE

17. Why Study VRC01? Promising antibody for HIV prevention
Broadly neutralizing & potent in lab studies
Good results in early Phase I studies
May supplement other prevention approaches
Move the HIV vaccine search forward
Teach us the amount of antibody a vaccine may need to elicit to prevent HIV
Help us find a safe, effective HIV vaccine more efficiently
PREVENTION
HIV VACCINE

18. The AMP Study: Objectives & Endpoints
Safety & Tolerability of VRC01 infusion
Reactogenicity, AEs, SAEs, discontinuation rates
Efficacy to prevent HIV infection
HIV infection by week 80 in those HIV-negative at enrollment
Develop a marker(s) of VRC01 that correlates with the level and antigenic specificity of efficacy
Serum VRC01 concentration
Serum mAb effector functions
Breakthrough HIV infection sequences
VRC01 neutralization sensitivity of, & effector functions against, HIV strains from infected trial participants
PRIMARY
SECONDARY
9/20/2018

19. The Main AMP Study Questions
Is the VRC01 antibody safe to give to people?
Are people able to “tolerate” the antibody without becoming too uncomfortable?
Does the antibody lower people’s chances of getting infected with HIV?
If the antibody does lower people’s chances of getting infected with HIV, how much of it is needed to provide protection from HIV?

20. Study Schema for The AMP Studies
HVTN 704/HPTN 085
HVTN 703/HPTN 081
REGIMEN
MSM & TG in the Americas
Women in
sub-Saharan Africa
TOTAL
VRC mg/kg
900
500
1300
10 infusions total -
given every 8 weeks
Study duration:
~22 months
VRC mg/kg
Control
Total
2700
1500
4200

21. Rationale for 2 Cohorts
As these are test-of-concept trials we selected the two populations in which novel biomedical interventions are needed
MSM + TG
Heterosexual women in sub-Saharan Africa
We suspect that route of acquisition and genital tract immunology and anatomy may influence the distribution of VRC01 and potential efficacy

22. HVTN 704/HPTN 085: Select Eligibility Criteria
Men & transgender people who have sex with men, years of age
HIV uninfected
Risk behavior related criteria:
Male or TG who has had condomless anal intercourse with ≥ 1 male or TG partner(s) or any anal intercourse with ≥ 2 male or TG partners in the past 6 months
All volunteers in a mutually monogamous relationship with an HIV(-) partner for > 1 year are excluded.
Volunteers with clinically significant medical conditions are excluded
9/20/2018

23. HVTN 703/HPTN 081: Select Eligibility Criteria
Heterosexual Women, years of age
HIV uninfected
Risk behavior related criteria:
Female who has had vaginal or anal
intercourse with a male partner in the
past 6 months
All volunteers in a mutually monogamous relationship with an HIV(-) partner for > 1 year are excluded.
Volunteers with clinically significant medical conditions are excluded

24. STUDY DURATION: about 22 months
AMP Study Procedures
IV: receive an IV over a minute period every 8 weeks (10 times total)
Blood draw: get a blood draw at the clinic every 4 weeks (includes an HIV test)
STI testing: get STI testing (urine and rectal swabs) Q 6 months
Questionnaires: complete questionnaires about sexual behavior & general health every 4-8 weeks
STUDY DURATION: about 22 months

25. AMP Monitoring Monitoring for harm, non-efficacy, high efficacy
Monitoring for futility to assess prevention efficacy
Safety assessment/slow down once enrollment reaches n=450 participants/n=300 participants

26. Study Progress, as of 18 July 2016
Americas
SSA
Protocol opened March 31, 2016 (N=2700)
First participant enrolled April 6, 2016
Sites activated – 19/24
Number currently enrolled (received VRC01/control): 249
Number randomized (not yet received VRC01/control: 15
Protocol opened May 9, 2016 (N=1500)
First participant enrolled: May 17, 2016
Sites activated – 5/15
Number currently enrolled (received VRC01/control): 29
Number randomized (not yet received VRC01/control: 9

27. What happens with success?
We define the level of plasma mAb needed to protect against infection
Translate that into:
Single dose administration of mAbs to achieve this level
Incentive to develop next generation mAb (more potent, longer half life)
Options for genetic immunization to provide medium to long- term protective antibody levels
Knowledge that neutralizing mAb can protect will guide vaccine field

28. What happens with success?
How could bnAbs be used for HIV prevention in the future?
Cover a period of risk for newborns (during & right after birth, during breastfeeding)
Cover the “tail” of a long-acting PrEP injection, when protection may not be as strong
Cover the ramp-up period of an HIV vaccine regimen that is given over several months
Combine with other mAbs in a prevention “cocktail”

29. Acknowledgements
Some of this slide set was adapted from versions created by Dr. J Mascola, Dr. S Edupuganti, Dr S Karuna, Dr L Corey, Dr M Cohen, Dr F Laher

30. Finding Info About the AMP Studies
HVTN 703/HPTN 081 (Africa):
HVTN 704/HPTN 085 (US):
Websites for Brazil & Peru in development
Stop by our booth in the Global Village for more information!

31. AMP Protocol Team Chairs: Larry Corey & Mike Cohen
co-Chairs: Sri Edupuganti & Nyaradzo Mgodi
Protocol Team Leader & Core Medical Monitor: Shelly Karuna
DAIDS Medical Officers: Marga Gomez & David Burns
Statisticians: Allan DeCamp, Deborah Donnell, Peter Gilbert, Michal Juraska, Nidhi Kochar
Laboratory Representatives: John Hural, Sue Eshleman, On Ho, David Montefiori, Vanessa Cummings, Estelle Piwowar-Manning
VRC Representatives: Julie Ledgerwood, Barney Graham, John Mascola
Investigator Representatives: Ken Mayer, LaRon Nelson, Manuel Villaran, Sinead Delany-Moretlwe
Social & Behavioral Scientist: Michele Andrasik
DAIDS Protocol Pharmacist: Scharla Estep
Regional Medical Liaison: Simba Takuva
Clinical Safety Specialist: Maija Anderson
Protocol Development Manager: Carter Bentley
FHI360/HPTN LOC Director: Niru Sista
Senior Research Clinician: Phil Andrew
Clinical Research Manager: Liz Greene
Clinical Trials Manager: Carissa Karg
SDMC Representatives: Lynda Emel, Gina Escamilla, Evangelyn Nkwopara
Regulatory Affairs Representative: Meg Brandon
Communications Representatives: Jim Maynard & Eric Miller
Community Engagement Representatives: Gail Broder, Jonathan Lucas, Jontraye Davis
Clinic Coordinators: Deb Dunbar, Lilian Saavedra, Elaine Sebastian
CAB Representatives: Likhapha Faku, Mark Hubbard, Jim Wick
Community Educators/Recruiters: DaShawn Usher & Luciana Kamel
Technical Editor: Erik Schwab