The Power of Vaccines: ‘getting to zero’ for HIV and TB was an event hosted by the TB/HIV and Prevention Working Groups of the UK Consortium on AIDS and International Development. The meeting was sponsored by Pamela Nash MP and held on Friday, 18th May 2012, in Portcullis House, Westminster. Read more at http://storify.com/PamojaUK/the-power-of-vaccines http://www.pamoja.uk.com

1. Effective HIV vaccines are possible: update on
the science for non-scientists
Robin Shattock
Infectious Diseases, Medicine, St Mary’s, Imperial College, London, UK

2. •The total number living with HIV
continues to rise
•HIV prevalence (33 million) constant at
0.8% of global population since 2001
•6.6 million are now on antiretroviral
treatment (ART)
•9 million are waiting to receive it
•For every person starting ART two
people are newly infected
“Successful provision of •20 million more people predicted to
universal treatment acquire HIV by 2031
access may be critically •increasing potential treatment costs up
dependent on reducing to $35 billion a year2.
the number of new
infections” 1. UNAIDS, AIDS at 30: Nations at the Crossroads (2011)
2. R. Hecht et al., Lancet 376, 1254 (2010).

3. Challenges in developing a vaccine against HIV?
•Classic vaccines mimic natural immunity against re-
infection : no one has recovered from HIV-1 infection.
•Most vaccines protect against disease, not against
infection; HIV infection may remain latent for long
periods before causing disease (provirus).
•Protection against HIV infection may require sterilizing
immunity (preventing entry); no current vaccine is know
to do this.
•Many vaccines use attenuated pathogens, this approach
would not be appropriate for HIV due to inherent safety
concerns.
•HIV has multiple mechanisms of immune evasion
including: massive diversity, high mutation rate, viral
latency (hiding) and antigen masking (cloaking)

4. Vaccine research in perspective
Duration between discovery of microbiologic cause of selected infectious diseases and development of a vaccine
Virus or bacteria Year cause Year vaccine Years elapsed
discovered licensed
Typhoid 1884 1989 105
Haemophilus Influenzae 1889 1981 92
Malaria 1893 None –
Pertussis 1906 1995 89
Polio 1908 1955 47
Measles 1953 1995 42
Hepatitis B 1965 1981 16
Rotavirus 1973 1998 25
HPV 1974 2007 33
HIV 1983 None –
Source: AIDS Vaccine Handbook, AVAC, 2005

5. What’s in the prevention tool box?
1 2
4 3
Coates et al., Lancet 2008

6. The HIV prevention revolution
VACCINES
•AIDS vaccine shows first efficacy
in clinical trials
•Replicating viral vector effective in
controlling SIV in animal studies
•Multiple new antibodies and
targets on HIV discovered
MICROBICIDES
•Microbicide gel (CAPRISA 004)
reduces HIV infections in women
TREATMENT AS PREVENTION
•Initiating ART earlier reduces HIV
transmission among discordant couples
PRE-EXPOSURE PROPHYLAXIS
•Oral drugs reduces HIV infections
among MSM and transgendered
women

7. New biomedical intervention strategies
Study Effect size (CI)
Prime-boost HIV
31% (1, 51)
Vaccine (Thai RV144)
1% tenofovir gel 39% (6, 60)
(Caprisa 004, Karim et al.)
TDF/FTC oral-PrEP in MSM 44% (15, 63)
(iPrEx, Grant et al 2010)
Medical male circumcision 57% (42, 68)
(MMC) (Orange Farm, Rakai, Kisumu)
TDF/FTC oral-PrEP in 63% (22, 83)*
heterosexuals (TDF2, CDC)
TDF oral-PrEP in serodiscordant 62% (34, 78)*
Partner (Partners PrEP)
TDF/FTC oral-PrEP in serodiscordant 73% (49, 85)*
Partner (Partners PrEP)
Immediate ART for positive 96% (82, 99)*
Partners (HPTN052)
0% 10 20 30 40 50 60 70 80 90 100% Efficacy
*Provisional

8. The Thai trial (RV144): light in the tunnel?
• 125 infections from17,115 participants
• 74 out of 8,198 volunteers who received placebo
• 51 out of 8,917 volunteers who received prime boost
vaccine
• Protective efficacy a little over 31% p=0.039

9. RV 144 Vaccination and Follow-
up Schedule
HIV test,
risk assessment and counseling
0.5 1 2 3 (time in years)
6-month vaccination
schedule 3 years of follow-up (every 6 mo.)
ALVAC®-HIV (vCP1521) priming at weeks 0, 4, 12, 24
AIDSVAX® B/E gp120 (alum adjuvant) boosting at weeks 12, 24

10. 1.0 .96
Placebo
0.9 .84
0.8
Pr obability of HIV- 1 Infection ( %)
0.7 .64 .68
Vaccine
0.6 .58
Vaccine infections: 51
0.5 Placebo infections: 74
.41 p = 0.04
.38
0.4 Efficacy: 31.2%
95% CI (OBF): 1.1, 51.2
0.3
0.2 .15
RV144 Acquisition
0.1 Placebo
Vaccine Endpoint: Modified
0.0 Intent-to-Treat (mITT)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
YEARS
month 6 12 18 24 30
Events 16 42 67 82 95
Efficacy 54% 60% 44% 36% 36%

11. Lessons from RV144
– Protection from infection is possible
• Highest protection in first 6-12 months (61%)
• Antibody titers appear to wanes in line with protection
• Follow up studies planned to determine if boosting can
prolong protection
• Ongoing work to improve both the priming (ALVAC) and
boosting (AIDSVAX) components
• Planned studies to assess similar approach in Sub-Saharan
Africa

12. Unprecedented progress in the discovery of
neutralizing antibodies
• Up to 25% of infected subjects
found to have broadly
neutralizing antibodies a year
or more after infection
• 1% (elite controllers) have
potent activity against a
majority of strains
• Induction of responses to such
regions could provide potent
protection
*
Humans can make protective antibody responses – providing
unique tools for development of new vaccine candidates

13. >50% of macaques
immunized with a
replicating CMV
vector manifested
early complete
control of infection

14. Sustained funding to harnessing the
product development cycle
10,000s, 1000s 100s 10s 1-2
Product Development Partnerships (PDPs)
Multinational
National laboratories and Biotech / Small Medium pharmaceutical and
academic institutions Enterprises (SMEs) biotechnology
HIV Vaccine
Basic Applied Product Early product Advanced Large-scale Delivery
research research design development development Efficacy trials &
Access
Clinical Trials Partnerships

15. NUMBER OF VACCINE TRIAL VOLUNTEERS: THEN AND NOW www.avac.org
1997 2012 TOTAL VOLUNTEERS 1997 TO 2012
1,350
6,590
69,042
250 VOLUNTEERS
Total volunteers for 2012 is only inclusive of biomedical preventive HIV vaccine trials. The total number of volunteers including observational and therapeutic HIV vaccine trials is
more than 23,000. The total number of volunteers from 1997 – 2012 was assessed using information available on www.clinicaltrials.gov and is an approximate number.

17. VACCINE CLINICAL TRIALS: TRIAL PARTICIPANTS IN 2012 www.avac.org
Sweden
TOTAL TRIAL PARTICIPANTS 6,590 Switzerland 24
105
United Kingdom
124
France
105
China
Italy 48
50
United States Brazil
3,690 25 Kenya Thailand
157 782
Uganda
103
Tanzania
Peru
170
174
Mozambique
Rwanda
120
109
Zambia
46
South Africa
486
When participants by country were not specified by trial sponsors, funders, and/or implementers, total trial participants are divided evenly among countries. Not all trials in 2012 are
included, only those for which both estimated or actual participants and countries were available.

18. Pathway to reversing the epidemic
Seeing prevention research/funding as a continuum
Circumcision
Treatment for
prevention
Prophylaxis
(oral, topical, injectable)
Partially effective
vaccine
HIV incidence
highly effective
vaccine
Behavioral and structural interventions
Science. 2011;333:42-3