1. Passive and Active Immunization
Nono Mkhize, PhD
National Institute for Communicable Diseases, a division of the
National Health Laboratory Service (NHLS) of South Africa,
University of the Witwatersrand, Johannesburg, South Africa
UZ-UCSF 5 May 2017

2. Both concepts rely on HIV-specific antibodies
We are at a pivotal point in the HIV epidemic with 2 efficacy trials are running concurrently southern Africa
Both concepts rely on HIV-specific antibodies

3. 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
Pre-formed broadly neutralizing antibody VRC01 is infused to provide protection against HIV infection. This is being tested in the HVTN 703 (AMP trial)

4. The Immune System learns, responds faster and better upon challenge
Passive (maternal)
Natural
Active (infection)
Adaptive immunity
Passive
(Antibody transfer)
Artificial
Active
(Immunization)
Everyone is born with innate (or natural) immunity, a type of general protection. Innate immunity also includes the external barriers of the body, like the skin and mucousmembranes (like those that line the nose, throat, and gastrointestinal tract), which are the first line of defense in preventing diseases from entering the body. If this outer defensive wall is broken (as through a cut), the skin attempts to heal the break quickly and special immune cells on the skin attack invading germs.
The second kind of protection is adaptive (or active) immunity, which develops throughout our lives. Adaptive immunity involves the lymphocytes such as B cells and T cells and develops as people are exposed to diseases or immunized against diseases through vaccination
Immunity
Innate Immunity
Early, inflammation, nonspecific (or somewhat specific

5. Active Immunization
Uses the adaptive immune response to mount a response and block subsequent infection
Contact with pathogen or antigen develops immunity- antibodies produced
Effect lasts for a long time, may be life long

6. Types of vaccines Live bacterial or viral vaccines
Vaccinia, yellow fever, measles, oral poliovirus
• Killed bacterial or viral vaccines
Hepatitis A, injectable polio, injectable typhoid
• Subunit vaccines
Hepatitis B, influenza, pertussis, diphtheria

7. HIV active immunization
Many vaccine approaches have been tried
Killed HIV vaccines?
Safety concerns
Subunit vaccines
HIV Env proteins alone aren’t protective (AIDSVAX)
Vectored vaccines
Deliver HIV proteins to stimulate adaptive immune response

8. Clinical HIV-1 Vaccine Efficacy Trials(Barouch & Michael, 2013)
Study/
location
Vaccine/s
Risk Group/HIV incidence
Result
1. Vax003
Thailand
AIDSVAX B/E gp120 in alum
IDUs
3.4%
No VE
1. Vax004
US/Europe
AIDSVAX B/B gp120 in alum
MSM/high risk women
2.6%
2. HVTN 502
Americas
STEP
MRKAd5 HIV-1 gag/pol/nef 3%
Halted for futility; early transient increased infection in vaccinees
2. HVTN 503
RSA
Phambili
Heterosexual men & women
3.7%
No VE; late increased HIV infection in unblinded male vaccinees
3. RV144
ALVAC-HIV vCP1521, AIDSVAX B/E rgp120 in alum
Heterosexual men and women with variable risk
0.28%
31.2% 42/12;
60% 12/12
4. HVTN 505
DNA(gag/pol/nef/env)
rAD5gag/pol/env (A,B,C)
Circumcised MSM Ad5 neg
1.8%
Halted at interim analysis for futility

9. Thai Trial (RV144) Primary Results
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.9
0.8
0.7
0.6
0.4
0.3
0.2
0.1
Years
Probability of HIV Infection (%)
Placebo
Vaccine
Modified Intention-to-Treat Analysis*
125 HIV infections in subjects

10. 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.
The first step was to address the durability of responses. The vaccination schema for HVTN 097 and RV144 included only 2 protein boosts and even though there are high responses at peak, by 6 months they decay to low levels. For the subsequent phase 1 trials an additional boost at 12 months was evaluated.

11. The Strategy for the ALVAC/Protein Phase 3 Program
Construction of Bivalent Subtype C gp120/MF59
Booster at
12 months
Construction of ALVAC-HIV-C
(vCP2438)
Optimize regimen by increasing potency and durability

12. HVTN Strategy for the Phase 3 Program
Designed to evaluate RV144 vaccine regimen in RSA and compare immunogenicity to that in Thailand
HVTN 100
A standard phase 1 trial of the clade C products to decide whether to proceed to phase 3
HVTN 702
A Classic phase 3 assessing efficacy and safety aimed at licensure
Additional boost
Subtype change
Go/no-go met

13. Peak CD4+ T Cell Response Rates and Magnitudes are Higher in Prevalence in 097 vs. RV144
50.3% % % %
88/ / / /78
Response rate:
RV144
HVTN 097
RV144
HVTN 097
92TH023-ENV
LAI-GAG
Gray G HIVR4P, 2014

14. V1V2 IgG responses between HVTN097 and HVTN100

15. Active Immunization Passive Immunization
Pre-formed broadly neutralizing antibody VRC01 is infused to provide protection against HIV infection. This is being tested in the HVTN 703 (AMP trial)
HVTN 702
May 2016

16. Summary: HIV active immunization vaccines
Vaccines are immunogenic; CD4 T cells, non-neutralizing and neutralizing but these are short-lived, even after an additional boost
Different vaccines are needed to induce Tier 2 neutralizing antibodies (which we believe would be protective)

17. 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
Pre-formed broadly neutralizing antibody VRC01 is infused to provide protection against HIV infection. This is being tested in the HVTN 703 (AMP trial)

18. Passive Immunization
Antibody produced by others can be transfused to provide immunity. No contact with antigen
Human antibodies can be transfused
IVIG, gamma globulin
Immunity develops immediately but is short-lived. No memory

19. Passive immunization and HIV
Passive immunization studies will provide proof-of-concept for bNAb-mediated protection
A new concept in HIV field
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

20. (Unmutated common ancestor )
Understanding how broadly neutralizing antibodies develop in HIV infection
Breadth
Years of Infection
B cell
we have been fortunate to be part of CAPRISA that has allowed us to follow participants from HIV negative up to the initiation of ART an deven during ART and our data confirm that bNAbs develop in a small number of individuals- about 20% only. You get an initiating virus that stimulates the original B cells to produce antibodies called UCAs. After rounds of differentiation, due to escaping virus, antibodies become more broad- have the ability to neutralize mutliple HIV strains.
Infecting virus
UCA
(Unmutated common ancestor )
Penny Moore

21. VRC01 Blocks Attachment to CD4

22. Phase I Study of VRC01 (Safety and PK)
28 healthy adults
Dose escalation (5, 20, 40 mg/kg)
2 infusions (iv and sc-5mg/kg only)
Safe and well tolerated
No ADA (anti-VRC01 or anti-allotype antibodies)
Anti-viral activity of VRC01 in serum matched experimental values
Potentially protective VRC01 levels for up to 8 weeks after infusion

23. A phase 2b study to evaluate the efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection

24. Why CAP256-VRC26.25LS is a candidate for passive immunization?
Good (82%) anti-C breadth vs VRC01 (78%) & PGT121 (70%). 63% coverage across all subtypes
Among the most potent mAbs currently available
LS version has suitable pk in monkeys
No identified cross-reactivity (with human proteins)
Part of best current combination of MAbs
Future translation to a HIV vaccine: this antibody can acquire breadth within months, not years
Efficacious for prophylaxis in macaque model

25. Summary: Passive immunization
Currently only 2 mAbs tested in humans (VRC01 and 3BNC117) with many others in the pipeline (VRC07, PGT121/ , CAP256-VRC26.25 and PGDM1400). PG9 also in Phase I trial as VIP
Broader and more potent antibodies are being engineered
Possibilities to extend half-life of antibodies

26. Vaccine-Induced SeroPositivity (VISP)
Lessons learnt from vaccine trials:
Vaccine induced antibodies can be detected by commercial HIV tests whose HIV diagnosis depends on antibodies (not the virus itself)
Study participants who receive HIV vaccines will often test positive (seropositive) on these standard tests but it doesn’t mean they are HIV-infected.
Duration of these antibodies is unknown- could be years
Social implications
HVTN has developed a testing algorithm to distinguish true infections from VISP
HVTN resource

27. HVTN HIV testing algorithm
VISP can be distinguished from true HIV infection using specific laboratory tests, but these are not usually used as first-line diagnostic tests in community testing centers
John Hural

28. Efforts to address VISP
Evaluation of seroreactivity is conducted on all vaccine recipients in HVTN studies at the last study visit
Launch of the HVTN VISP Testing Service – Africa (VTS-A) for study participants in Africa (April 2017)
Testing provided by HVTN/DAIDS to all participants during, and post-study to help mitigate social harms related to VISP
HVTN 910 (for DAIDS sites, only) seeks to gather data on durability and implications of VISP
HVTN resource

29. So why are we talking about VISP now?
HIV testing programs are increasing globally, with an emphasis on people knowing their HIV status.
Increasing numbers of clinical trials, participants, and more sophisticated vaccine products increase the chances for VISP to occur.
Study participants may need to be educated to “opt out” of testing at their doctor’s office or local testing centers.
HVTN resource

30. Collaborators and Funders
NICD
Lynn Morris
Penny Moore
Tandile Hermanus
Valerie Bekker
Jay Patel
Carol Crowther
Bronwen Lambson
Sharon Madzorera
Adriaan Basson
Charmaine van Eeden
HVTN/HPTN
Julie McElrath
John Hural
Erica Andersen-Nissen
Glenda Gray
Larry Corey
Mike Cohen
Gavin Churchyard
SCHARP
April Randhawa
Shannon Grant
Duke
David Montefiori
Georgia Tomaras
HVTN 073/E, HVTN 086, HVTN 097, HVTN 100, HVTN 702, HVTN 703 Protocol Teams and all HVTN vaccine trial participants

31. Issues related to VISP
Several outside factors may affect study participants who have VISP:
Personal issues – feelings of anxiety, stress, frustration
Social issues – stigma or discrimination if you are mistakenly thought to be HIV-infected
Medical issues – what do you need to talk about with your doctor? Do providers believe their patients when they decline testing because of being in a study?
Public Health policy – what is the HIV testing policy in your community? Can people opt out?
Research – what if someone wants to join another trial (of any kind) in the future? What are the implications for that research?
We must be able to communicate effectively about the range of problems that could result from VISP. The hassle of dealing with any of these issues is no small thing!
While this list is from the study participant’s point of view, there is also a concern that a participant who gets testing done elsewhere could unblind themselves, and potentially unblind the site staff as well (if staff need to assist with mitigating a social harm incident). If this were to happen in significant numbers, it could pose a problem for maintaining the integrity of the study and the data being collected.