HIVAIDS in Southern Africa: Progress with Vaccines and Other Interventions

1
HIV/AIDS in Southern Africa Progress with
Vaccines and Other Interventions

• M. Essex
• Given Professor of Infectious Diseases,
• Harvard University
• Chair, Botswana-Harvard Partnership (BHP)
• Chair, Department of Immunology and Infectious
  Diseases, Harvard School of Public Health (HSPH)
• Chair, HSPH AIDS Initiative (HAI)

2
UNAIDS Adults Children Living with HIV, end
2005
(thousands)
40.3 million total
30,000
(67)
25,800
25,000
64
20,000
15,000
10,000
7,400
5,000
1,800
1,600
870
1,200
510
300
720
74
0
North Africa Middle East
Eastern Europe Central Asia
Latin America
North America
Caribbean
Sub-Saharan Africa
South South- East Asia
Western Europe
East Asia
Oceania
3
UNAIDS Adults Children Newly Infected in 2005
(thousands)
4.9 million total
3,500
(67)
3,200
3,000
65
2,500
2,000
1,500
990
1,000
200
140
500
270
67
30
43
22
8
0
North Africa Middle East
Eastern Europe Central Asia
Latin America
North America
Caribbean
Sub-Saharan Africa
South South- East Asia
Western Europe
East Asia
Oceania
4
UNAIDS Adults Children Deaths due to AIDS in
2005
(thousands)
3.1 million total
2,500
2,400
(67)
77
2,000
1,500
1,000
480
500
66
62
41
24
58
18
12
0.7
0
North Africa Middle East
Eastern Europe Central Asia
Latin America
North America
Caribbean
Sub-Saharan Africa
South South- East Asia
Western Europe
East Asia
Oceania
5
Adult HIV Prevalence in the World
All Other Developing Countries Outside
Sub-Saharan Africa
N. America and Western Europe
Southern Africa
Sub-Saharan Africa
6
HIV in Sub-Saharan Africa

• 80 of the worlds HIV-positive women are in
  sub-Saharan Africa.
• 90 of the worlds HIV-positive infants are in
  sub-Saharan Africa.
• Rates of infant infections in southern Africa are
  300-fold higher than in Europe or Asia.
• With no intervention, up to 1 in 7 infants
  infected in some countries within SADC region.

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Africa Regional Trends HIV
Data from UNAIDS
8
HIV

• Characterized by extremely great ability to
  change through genetic mutations and
  recombination to form chimeric progeny viruses.
• Results in moving target for vaccine immunity
  and drug resistance.

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HIV (continued)

• Characterized by unique ability to hide in
  chromosomal DNA, which results in long and
  unpredictable time periods before clinical AIDS
  disease occurs.

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HIV (continued)

• Transmission occurs through contact with
  reproductive tract fluids (during sex or birth),
  blood (transfusions or in utero while pregnant),
  or breastfeeding.
• Both free virus and infected cells can cause
  transmission.

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AB CDEFGHI J K ?
Type 2
HIV
Group M
Type 1
Group O
Group N
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Sub-Saharan Africa HIV-1 Subtypes in Millions
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Distribution of HIV-1 Subtypes in Africa
North 0.2
Horn 4.5
C
A/G
Western 5.0
A
Eastern 8.0
Central 6.0
C
Southern 20.0
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Can we make a vaccine for HIV-1C of Southern
Africa?

• Evaluate virus variation in region and select
  common denominator as either natural or
  designed virus immunogen.
• Determine scope and breadth of immune response
  genetics for population to receive vaccine.
• Identify immunodominant pieces of virus.

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Can we make a vaccine for HIV-1C of Southern
Africa?

• Formulate vaccine candidates and produce
  experimental vaccines.
• Conduct trials for safety and immunogenicity.
• Conduct trials for efficacy/protection.

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73 HIV-1C Near Full-Length Genome Sequences
India
South Africa
MPars Tree
ETH, IS, BR
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HIV-1 Diversity
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Emergence of HIV-1C in Dar es Salaam, Tanzania
HIV-1 Subtypes
YEAR
A D C Recombinants
1988 7(28) 17(68) 1(5)
- 1998 22(22) 19(19) 22(22)
36(36)
From Zwarf et al AIDS 7467, 1993 and Siwk et al
ARHR 121753, 1994. Includes 31 HIV-1C
recombinants.
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Recombinants in Tanzania
HIV-1 subtype
Envelope
p24
p7
V5
C3
V4
C4
C5
V3
C2
gag
env
D
D
TZB0063
D
D
TZB0069
D
D
TZB0070
D
D
TZB0071
D
D
TZB0109
D
D
TZB0110
D
D
TZB0112
D
D
TZB0111
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HIV Vaccines
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Frequency of HLA Haplotypes

• 10 most common HLA A/B haplotypes in Caucasians

Novitsky et al. Hum Imm 62146 (2001).
23
Normalized Cumulative HIV-1C-Specific CTL
Responses
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Lessons Learned

• Research and development for an HIV vaccine must
  be encouraged through governmental/international
  non-profit institutions. Must not count on
  corporate sector.

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Lessons Learned (continued)

• Design guidelines used for other conventional
  vaccines of little value to make a safe and
  efficacious HIV vaccine. Live attenuated vaccine
  designs (such as polio, measles, mumps, yellow
  fever) cannot be used due to safety concerns.

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Lessons Learned (continued)

• Animal models have contributed very little to
  development of HIV vaccines. Trials must be done
  in people.

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Lessons Learned (continued)

• Efficacy trials should be done in populations
  with the highest incidence. Vaccine designs
  should be formulated for such populations, and
  infrastructure and expertise must be developed
  and expanded in such locations.

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Lessons Learned (continued)

• Low efficacy vaccine (e.g. 30-60 efficacy) of
  low priority for developed countries, but would
  still be valuable product in high incidence
  populations.

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Ongoing Trials of HIV Vaccines as of August 2005
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Examples of Vaccine Designs Planned for Trials in
Southern Africa
31
Immunodominant Regions in HIV-1C
dominant
subdominant
tat
vif
nef
gag
rev
5LTR
vpu
pol
env
vpr
3LTR
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Epimmune Vaccine EP HIV-1090
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The recombinant anthrax protein-based HIV-1
vaccine candidate (LFn)
HIV-1 p24 Immunogen
Detoxified Anthrax Fragment
Chimeric Protein
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Kaplan-Meier Curve of Overall Survival for AIDS
Patients Treated with HAARTin Botswana
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Conclusions

• HIV shows greater mutational diversity than other
  viruses, making design of a vaccine more
  difficult than for other viral infections, such
  as polio, measles, yellow fever.
• Highest global rates for HIV are for HIV-1C in
  Southern Africa therefore greatest opportunities
  for designing and testing vaccines are also in
  Southern Africa.

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Conclusions (continued)

• Designing HIV-1C vaccines specifically for the
  region should assure greatest possible
  effectiveness and access for SADC countries.
• International cooperation and development of
  regional expertise on HIV vaccine design and
  testing is essential for progress.

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Conclusions (continued)

• Development of an effective vaccine may take
  substantial time conducting multiple trials with
  modern designs should accelerate progress.
• Until a vaccine is available, prevention of
  infection through behavior modification and
  treatment of individuals with clinical AIDS using
  anti-retroviral drugs are extremely important.

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Acknowledgements

• Ministry of Health and Vaccine Committee,
  Government of Botswana
• Botswana-Harvard Partnership Senior Staff T.
  Villafana, PhD, MPH J. Makhema, MD I. Thior, MD

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