1. Immune Strategies for HIV Prevention
Good morning. Thank you for the introduction and the opportunity to present to you today an outline of the various immune strategies for HIV prevention that are in development. Despite the tremendous growth of HIV prevention and treatment programmes, immune strategies will be required to guarantee a sustained end to the pandemic.
Dr L Stranix-Chibanda
UZ-UCSF Annual Research Day
17 April 2015

2. Outline Active immunisation Passive immunisation
Recent history of HIV vaccine development – RV144 trial
The P5 initiative and Uhambo
Passive immunisation
Monoclonal antibodies against HIV
Immunoprophylaxis by gene transfer
Today, I will take you through three approaches.
Active immunisation, beginning with a brief history of HIV vaccine development and an outline of Uhambo and the P5 initiative,
Passive immunisation, focusing on an introduction to monoclonal antibodies against HIV
Then an overview of immunoprophylaxis by gene transfer.

3. Active Immunisation
Administer an antigen and wait for the immune system to respond
Requires immune system capable of responding
Takes some time for response to develop
If successful, results in long term protection
Generally results in both antibody and T cell responses
An active immunisation approach is to administer an antigen and wait for the immune system to respond.
This requires an immune system capable of responding; it takes some time for the response to develop; if successful, it results in long term protection; and generally results in both antibody and T cell responses.
The vaccines administered to children through the Zimbabwe Expanded Programme of Immunisation utilise an active immunisation approach.
Until recently, all vaccines developed against HIV produced very disappointing results.

4. RV144 – study design
Thailand,>16,000 healthy, heterosexual, HIV negative adults
Intervention , 3-year follow-up concluded 2009
Tested 2 HIV vaccines
Prime: ALVAC HIV (vCP1521) pox 
Boost: AIDSVAX B/E (gp120)protein
The recent momentum in HIV vaccine development began with the RVI44 trial in Thailand that enrolled over 16,000 healthy heterosexual HIV negative adults.
The intervention, which involved 4 injections over 6 months, took place between 2004 and 2006, and the 3-year follow-up was concluded in 2009.
RV144 tested a pox-protein vaccine regimen consisting of two HIV vaccines – a prime using a canarypox vector with synthetic HIV nucleic acid insert at months 0,1,3 and 6, then a boost at months 3 and 6 with a synthetic gp120 protein from the HIV envelope for subtypes B and E.

5. RV144 – proof of concept/2009
The RV144 trial proved the concept that a vaccine could be used to PREVENT new HIV infections. And this was a terrific surprise! The vaccine efficacy was 60% at 6-12 months – meaning that vaccine recipients were protected from catching HIV 60% of the time. But this effect waned to 31% at 3 years. These results, however, brought new hope to the vaccine world when they were released in 2009, sparking a quest to discover the science behind this modest success when all previous vaccine regimens had failed.

6. P5 & Uhambo – a journey of hope
Identify a product submitted for regulatory approval and eventual public health introduction.
Building on the success of the RV144 trial, a global consortium of scientists formed the pox-protein public-private partnership – or P5 – with the mandate to identify a safe and effective HIV vaccine product that can be submitted for regulatory approval and eventual public health introduction. In Southern Africa, the programme has been termed Uhambo – a journey of hope.
HVTN 097 began in 2013 and is designed to evaluate the RV144 vaccine regimen in South African adults and initial results released in 2014 suggest that it was both safe and had similar immunogenicity to that observed in Thailand – meaning the vaccine caused the immune system to respond in the same way observed in the Thai vaccine recipients.
HVTN 100 is currently enrolling in South Africa, and is a phase 1 trial to evaluate a novel vaccine designed specifically for the subtype C HIV circulating in the region but based on the RV144 vaccine regimen.
If HVTN 100 is successful, it will proceed to a Phase 3 randomised controlled trial to assess efficacy and safety of this vaccine and then to apply for licensure.
Graphic: AVAC Report 2014/5

7. P5 & Uhambo – a journey of hope
Correlates of protection – AB & T-cell
The second track will identify correlates of protection – which regimens produce the best antibody and T-cell responses. The rationale behind this track is to optimize the vaccine regimen – to produce a higher level of protection against new HIV infections that lasts for a longer period of time than the modest response recorded in Thailand. This track involves a set of harmonised phase 1 trials of different prime-boost regimens that will take place across the region, including in Zimbabwe. These trial regimens all use the pox-protein vaccine designed for Southern Africa, but evaluate the effect of different dosing schedules, adjuvants and timing of the protein boost. The regimens that produce the best immune responses will be selected for phase 2b trials, leading to a phase 3 trial of up to 3 regimens hopefully within 3 years.
Graphic: AVAC Report 2014/5

8. Passive Immunisation Administer pre-formed antibodies
Does not require intact immune system
Immediate levels of antibodies detectable
Only lasts as long as the antibodies last
And then we have passive immunisation which administers pre-formed antibodies; does not require an intact immune system; immediate levels of antibodies are detectable; but only lasts as long as the antibodies last.

9. Passive immunisation is used to prevent a variety of infections
Polyclonal
Rabies Immune Globulin (RIG)
Hepatitis B Immune Globulin (HBIG)
Varicella Zoster Immune Globulin (VZIG)
Tetanus Immune Globulin
Monoclonal
Respiratory Syncitial Virus (Paluvizimab)
Anthrax
Passive immunisation is used to prevent a variety of infections. Polyclonal antibodies are used for rabies, hepatitis B, zoster and tetanus. And monoclonal antibodies are used for RSV infection and anthrax.

10. Monoclonal AB against HIV
Developed a few in 1990’s
Explosion in AB development >2008
next-generation sequencing
advances in in vitro B cell clonal amplification
high-throughput neutralisation assays
Identification of monoclonal antibodies from HIV-infected patients with broad and potent neutralisation potential
Now, to focus on monoclonal antibodies against HIV.
Scientists developed a few in the 1990’s but there has been an explosion in antibody development since 2008 due to advancements in laboratory assays, including next-generation sequencing, advances in in vitro B cell clonal amplification and high-throughput neutralisation assays.
This has lead to the identification of monoclonal antibodies from HIV infected patients with broad and potent neutralisation potential – that means these antibodies can effectively attack the particular strain of virus in that person’s body AND ALSO attack different strains of HIV. If a person has high levels of broadly neutralising antibodies against HIV, they are able to more effectively suppress the virus. These antibodies are more often found in people who have lived with the virus for some years.

11. Sites of Vulnerability for HIV Neutralisation
V1V2
PG9/16, CH01-04, PGT
V3/glycan
2G12, PGT , PGT ,
CD4 binding site
B12, VRC01-03, PG04, HJ16 CH30-34, NIH45-46, 12A12, VRC07, 3BNC17
membrane proximal domain
2F5, 4E10, CAP206-CH12, 10E8
This graphic illustrates a piece of the HIV envelope and its protein spike that it uses to bind onto a cell so it can enter and infect the cell. Scientists have described different regions on the spike that serve different functions. These are all different antibodies that have now been identified and can be manufactured in a laboratory. I will draw your attention to this one here, VRC01 which attaches to the CD4 binding site and blocks the virus from entering CD4 cells – or neutralises the virus.
Haynes et al. (2012) Nat.Biot. 5:
Kwong and Mascola et al. (2012) Immunity. 37:

12. Possible Roles for Monoclonals
Strong pre-clinical evidence that potent monoclonal antibodies (like VRC01) could be important for prevention and treatment of HIV.
Prevention of vertical transmission
Augment therapy in treated children and adults
Early treatment of infected infants
Strategy for cure
There is strong pre-clinical evidence that potent monoclonal antibodies like VRC01 could be important for prevention and treatment of HIV. Possible roles are in the prevention of vertical transmission – We know that 60-80% of untreated HIV-infected mothers WILL NOT TRANSMIT the virus to their infants, which suggests that the maternal viral load is not the only factor involved in determining transmission risk. We know that infants with HIV usually are infected with a single strain of virus, which the mother’s antibodies failed to neutralise. Pre-clinical evidence suggests that giving mothers or infants monoclonal antibodies could increase the protection against transmission to the infant.
Monoclonal antibodies could also be given to augment therapy in treated children and adults – to help suppress the viral load;
for early treatment of infected infants – they could suppress the viral load before viral reservoirs have been established;
and as a possible strategy for the cure of HIV infection.
Barin, Jourdain, Brunet et al. JID 2006

13. Antibody therapy Advantages Disadvantages
Single or intermittent injection, does not require daily meds, adherence
Could prevent disease or modify disease in those already infected
If it works, it provides critical data to inform the entire vaccine field
Disadvantages
Requires monthly injection
Currently expensive
The advantages of antibody therapy is that it involves a single or intermittent injection, instead of requiring daily medication and good adherence.
It could prevent the disease entirely, or modify the disease in those already infected.
If it works, it provides critical data to inform the vaccine field.
The disadvantages are that it requires a monthly injection and is currently expensive.

14. bnAB clinical trials VRC/NIH
Phase 1 trial US, S Africa, Zim
Single dose of SC VRC01 to high-risk newborns at birth (0-72hr)
In addition to the standard-of-care HIV prevention regimens
Verify safety
Determine PK profile of 20mg/kg dose
Proceed to 40mg/kg dose, if safe
VRC601/602 in adults, ?pregnancy
Vaccine Research Center and the NIH plan a series of clinical trials involving broadly neutralising antibodies to evaluate their safety and efficacy.
For example, a phase 1 trial planned for the US, S Africa and Zimbabwe will administer a single dose of subcutaneous VRC01 to high-risk newborns at birth in addition to std-of-care HIV prevention regimens in an attempt to boost prevention efforts. The trial will verify safety of the product in this age group and determine the PK profile of a 20mg/kg dose. The trial will proceed to determine the PK profile of a 40mg/kg dose if the lower dose is shown to be safe. And ultimately proceed to an efficacy trial in high risk newborns, if successful.
Additional trials are planned in adults – both for prevention and treatment of HIV – and there is interest in evaluating the impact on viral suppression and HIV transmission risk of delivering VRC01 to HIV-infected pregnant women.

15. Antibody summary
Potent and broadly neutralizing monoclonal antibodies provide a new opportunity for HIV prevention (also treatment / cure)
If effective, antibody production can be scaled up and altered to increase duration of effect (> 1 month)
In summary, potent and broadly neutralising monoclonal antibodies provide a new opportunity for HIV prevention, and perhaps treatment and cure.
If effective, production can be scaled up and altered to increase the duration of effect.

16. Immunoprophylaxis by gene transfer (IGT)
A form of gene therapy to modify the DNA of patients to enable them to produce antibodies that deactivate HIV
Pre-clinical studies in monkeys/mice
identify the genes that produce powerful antibodies against disease
create artificial versions of these genes
insert them into viruses  inject muscle
transfer the genetically engineered DNA to the muscle cells  alter programming
Another approach to immunisation is gene transfer.
This is a form of gene therapy to modify the DNA of patients to enable them to produce antibodies that deactivate HIV.
Pre-clinical studies have successfully been completed in monkeys and mice to identify the genes that produce powerful antibodies against disease; create artificial versions of these genes; insert them into virus vectors and inject this into muscle tissue. The virus then transfers the genetically engineered DNA to the muscle cells, alter their programming so they begin to produce antibodies.

17. In conclusion,
Various immune approaches are being explored against HIV infection
Advancements in laboratory techniques mean that the knowledge base is expanding rapidly
None are yet ready for clinical use
Immune strategies are required to guarantee a sustained end to the AIDS pandemic

18. Acknowledgements UZ College of Health Sciences
UZ-UCSF Collaborative Research Programme
HIV Vaccine Trials Network
IMPAACT Network
Dr C Cunningham and VRC
I would like to acknowledge the support of those appearing here. Thank you.