1. HIV vaccine research and development: current status, challenges and opportunities
Thumbi Ndung’u, BVM, PhD
HIV Pathogenesis Programme
Doris Duke Medical Research Institute
Nelson R. Mandela School of Medicine
University of KwaZulu-Natal

2. Turning to more serious part of the talk
Turning to more serious part of the talk. This graph from gapminder shows the relationship between poverty and HIV. On the bottom axis is income per person and on the left is the HIV prevalence for each country. You can see that the poorest countries bear the highest HIV burden and that these are almost exclusively in Africa colored blue. South Africa while it is wealthier has a high prevalence and also has the largest size bubble meaning it is the country with the most number of HIV infected people in the world. Populated countries such as India and China have much lower prevalence's and so much smaller bubbles. So it is clear that Africa nears the brunt of the HIV epidemic and in particular South Africa.

3. Clinical trial evidence for preventing sexual HIV transmission – July 2011
Study
Effect size (CI)
Treatment for prevention
(Africa, Asia, America’s)
96% (73; 99)
PrEP for discordant couples
(Partners PrEP)
73% (49; 85)
PrEP for heterosexuals
(Botswana TDF2)
63% (21; 48)
Medical male circumcision
(Orange Farm, Rakai, Kisumu)
54% (38; 66)
PrEP for MSMs
(America’s, Thailand, South Africa)
44% (15; 63)
STD treatment
(Mwanza)
42% (21; 58)
39% (6; 60)
Microbicide
(CAPRISA 004 tenofovir gel)
HIV Vaccine
(Thai RV144)
31% (1; 51)
0% %
Efficacy

4. Major Infectious Disease Cases in U. S
Major Infectious Disease Cases in U.S. before and after Vaccine Availability
Disease
Total Cases
Year
Cases in 1994
% Change
Diptheria
206,939
1921 2
-99.9%
Measles
894,134
1941
963
Mumps
152,209
1968
1537
Pertusis
265,269
1934
4617
Polio
12,269
1952 0*
100%
Rubella
57,686
1969
227
Tetanus
1,560
1923 51

5. Years to develop vaccine
Duration between discovery of microbiologic cause of selected infectious diseases and development of a vaccine
Disease
Years to develop vaccine
Typhoid
105
Haemophilus influenzae 92
Pertussis 89
Polio* 47
Measles 42
Hepatitis B 15
HIV
30…
In fact vaccine development takes a long time. This is a list of some vaccines and how long it took to develop a vaccine after the description of the diseases. In the case of polio it took 47 years and there were many hurdles along the way that could have derailed this process.
*In the 1930s, two experimental polio vaccines failed because they were determined to be unsafe, and polio vaccines were almost abandoned.
Source: Modified from H. Markel, NEJM, August 25, 2005

6. Vaccines in brief Effective disease prevention strategies
Used for decades around the world, most commonly in children
Very safe when manufactured and used properly
Very cost-effective compared to treatment
Eliminated smallpox worldwide, almost polio…
Read slide.

7. Steps to an HIV Vaccine Stage One: Ideas (Lab/Basic)
Stage Three: People (Clinical)
Stage Two: Animals (Pre-Clinical)
Stage Four: Delivery (Licensure)
Stage Four: Delivery (Licensure)
Vaccines are tested in people in a series of studies. This process takes years.
Vaccine Ideas
Best Vaccine Ideas
Experimental Vaccines
Test in tubes and other laboratory equipment.
Once an HIV vaccine is found to be safe and effective, it must be delivered around the world to people who need it.
Once an HIV vaccine is found to be safe and effective, it must be delivered around the world to people who need it.
Experimental vaccines are produced in small amounts and tested and improved in animals. The vaccines that seem safe and most effective in animals are then considered for testing in people.
Read slide - reading each box top to bottom.

8. stop the virus entering cells
How do vaccines work?
Immune Responses
Humoral Cellular
Vaccines work by building up immunity, Specifically they stimulate the production of antibodies called humoral immunity. These are proteins that circulate in our blood and find virus particles, bind them and prevent them from getting into cells. Cellular immunity constituted cytotoxic T cells or CTL that kill infected cells. Helper T cells are like the conductor of the orchestra and direct and help the immune system,.
Neutralizing
Antibodies
stop the virus entering cells
Cytotoxic T cells (CTL) destroy cells infected with HIV. Helper CD4 T cells stimulate immunity

9. Aims of a Prophylactic HIV Vaccine
Induces sterilizing immunity HIV is never detected in the body
(Ultimate goal, but may not be possible)
Induces immunity that allows transient
HIV replication
Induces immunity that holds the virus at low levels such that both progression to AIDS and transmission are prevented

10. Past HIV Vaccine Concepts
Although only three concepts have undergone clinical efficacy testing to date, each HIV vaccine efficacy trial has yielded unexpected outcomes that have transformed the HIV landscape.
2003
2007
2005
2009
2003: AIDSVAX STUDIES
VaxGen Env gp120
Humoral Immunity
Phase III studies in high- risk subjects in the US/Thailand
Elicited type-specific Abs but not broadly reactive NAbs
No efficacy
2007: STEP- PHAMBILI STUDIES
Merck Ad5- Gag/Pol/Nef
Cellular Immunity
Phase IIb study in high-risk subjects in North/South America and South Africa
Elicited cellular immunity by IFN-γ ELISPOT assays
No efficacy, possible increased HIV-1 acquisition
2009: RV144
Sanofi ALVAC prime,
AIDSVAX gp120 boost
Humoral and Cellular Immunity
Phase III study in low-risk subjects in Thailand
31% reduction in HIV-1 acquisition with no viral load effect
To date 3 vaccine concepts have been tested in large scale efficacy trials to see if the vaccine works or not and all have yielded unexpected outcomes, The first was testing a recombinant protein made from the envelope spike of the virus. This was shown to stimulate only weak antibodies and not the broadly neutralizing antibodies that we need. The second vaccine trial was designed to stimulate the cellular arm of the immune response and although it did this this vaccine also did not work - indeed it was worse than that in that there was a suggestion that it may have caused harm and increased infection rates. The 3rd trial - the results of which were release at the end of 2009 was designed to stimulate both arms of the immune response and in fact used a vaccine that was shown earlier not to be work. This vaccine was shown to have a modest effect but it is the first sign of a positive signal in any HIV vaccine trials.
Advancing HIV vaccine candidates to efficacy trials will accelerate progress in the field, bringing us closer to an effective global vaccine.
from Nelson Michael and Jerome Kim
June 2010

11. Why haven’t these vaccines worked?-Scientific Obstacles
The natural immune response to HIV infection does not control the virus
The natural immune response to HIV infection does not protect against superinfection
Enormous sequence variability. We do not know how to construct an immunogen to cover this sequence variability
We do not know what constitutes a protective immune response

12. Relative Genetic Diversity: HIV-1 and Influenza A
All HIV-1 subtypes, sub-subtypes, CRF
One HIV-1 subtype
Annual global Influenza A
HIV-infected patient
Adapted from Francine McCutchan and from Korber B, et al. Brit Med Bull 2001; 58:19-42.

13. What are Mosaic Antigens
What are Mosaic Antigens? Algorithm to Generate a k=4-Valent Mosaic Vaccine
Input: Single clade or M group
Iterations improve the populations, improve the cocktail
Ad35, Ad26 and other vectors
Fischer et al. Nat. Med. 2007; 13:

14. SIV challenge revealed an entirely new pattern of protection in animals given CMV vectors!
54% (13/24) of CMV vector-vaccinated RM, upon infection, manifested immediate virologic control, bringing plasma virus to undetectable levels, and 12 of these 13 maintained this stringent protection for >52 weeks. TEM biased, high immunogenecity, responses indefinitely maintained, no Ab responses

15. Evolution of a T cell HIV/AIDS Vaccine Paradigm:
Old Paradigm:
2006
Vaccine-elicited immunity controls infection below
threshold for transmission
2010
New Paradigm:
Vaccine-elicited immunity prevents or aborts infection, or provides early complete control.

16. Stanley Plotkin, Review in CVI, 2010 "Correlates of protection induced by vaccination"
After the administration of nearly all vaccines, prevention of infection correlates with the induction of specific antibodies
It is likely that vaccines of the future, such as those for HIV, will obey the same paradigm
Promising data on neutralizing antibodies in humans and in monkey models
A review that juts cam out couple weeks ago from Stanley Plotkin who is one of the father of modern vaccination stated that almost all vaccines work by stimualting antibodies and that HIV is likely to do the same.

17. New Minds: Making Breakthrough Discoveries
Nobel Laureates in Three Disciplines Stratified by Age at Time of Award-Winning Discovery
Dietrich, Arne, and Narayanan Srinivasan The optimum age to start a revolution. Journal of Creative Behavior. 41:

18. So, are we closer to developing a vaccine against HIV?
Most certainly YES...
First sign of protection in humans
Significant advances in basic sciences
BUT……
We probably need to expect more failures than successes
A vaccine is NOT around the corner
It will NOT be a magic bullet
We need to do more basic and clinical research
This effort needs public and government support

19. Acknowledgements Dan Barouch- Harvard Medical School
Loius Picker- Oregon
Lynn Morris- NICD
Many others whose ideas, data and slides I have liberally borrowed