AIDS Vaccine R&D (post-AIDSVAX®)

R&D challenges Products in development Funding AIDS vaccine R&D Access and advocacy

Today, deaths to AIDS account for more than half of all deaths in 7 African countries AIDS deaths as a percentage of total deaths, 2001 Source: US Census Bureau 50%100%

Even in the US, HIV transmission is on the rebound where once it showed significant signs of slowing 32% of gay black men ages are HIV-infected

Even in the US, HIV transmission is on the rebound where once it showed significant signs of slowing 32% of gay black men ages are HIV-infected

To end this epidemic, treatment, behavioral intervention, and prevention technologies must all be pursued aggressively.

Why is developing an AIDS vaccine so difficult? Traditional vaccine approaches too risky (live attenuated, whole killed) Huge variability of HIV genetic structure (role of subtypes?) Ideal immune response still unknown Antibodies? Cellular immune responses? Others? No ideal animal model Significant clinical trial challenges

Non-Scientific Challenges Impact of partially effective vaccine unknown Difficulty in testing combinations of vaccines Ethical challenges in conducting trials Treatment for infected participants Prevention counseling Access Manufacturing challenges World still does not value vaccines Limited investment in AIDS vaccines by govt, companies

But an AIDS vaccine is increasingly likely New knowledge that high levels of antibodies can protect Evidence that cellular immune responses protect humans Exposed but uninfected sex workers Long term non-progressors Better ways to measure immune responses (Cellular, mucosal antibodies) Some vaccines now protect monkeys against SIV disease Phase III trials can be done - AIDSVAX

The AIDSVAX® Trials North America trial 5000 MSMs, 400 high risk women 2/3 vaccinated, 1/3 placebo clade B/B Seven doses: at 0, 1, 6, 12, 18, 24, 30 month Thai trial 2500 IDUs ½ vaccinated, ½ placebo clade B/E Seven doses: at 0, 1, 6, 12, 18, 24, 30 months

AIDSVAX: Not Effective in preventing HIV infection in this Phase III trial Placebo groupVaccine groupEfficacy (95% confidence) All volunteers 1679 volunteers 98 infections (5.8%) 3330 volunteers 191 infections (5.7%) 3.8% (-22.9%–24.7%) White, Hispanic (5.4%) (6.0%) -9.7% (-42.8%–15.7%) Black, Asian, other (9.9%) (3.7%) 66.8% (30.2%–84.2%)* Black (8.1%) (2.0%) 78.3% (29.0%–93.3%)** Asian 20 2 (10.0%) 53 2 (3.8%) 68.0% (-129.4%–95.5%) Other 40 6 (15.0%) 71 6 (8.5%) 46.2% (-67.8%–82.8%) * p <.01 ** p <.02 Source: VaxGen Inc.

Volunteers in AIDSVAX Trial Did Not Increase Their Risk Behavior Have HIV+ partner Unprotected anal sex Unprotected anal receptive sex Vaccine group Placebo group 50% 40% 30% 20% 10% 0 Men who have sex with men in group Month into trial Source: VaxGen Inc.

Some Key Challenges in AIDS Vaccine R&D Too many “Me Too” products Most products now in development not expected to prevent disease Difficulty in testing best combinations Clinical trial infrastructure Private sector investment still very limited Funding, funding, funding

Overview of Clinical Pipeline ALVAC+ gp120 Aventis/VaxGen (Phase III approved) DNA + AdenoMerck (Phase I-II) Adeno +ALVACMerck/Aventis (pre-clinical) DNA + Adeno(A,B,C)NIH VRC (Phase I soon) DNA + MVA, AAV IAVI Partners (Phase I-II) DNA + MVAEmory University, NIAID Tat-nef, env + adjuvantGlaxo-SmithKline (Phase I-II) VEEAlphaVax (Phase I soon) VSV + DNA, IL-12, IL-15Wyeth (Phase I soon) Gp140, DNA, SFVChiron (Phase I soon) LipopeptidesANRS (Phase I)

Therapeutic HIV Vaccines Now have vaccines that generate more potent cellular immune responses Hope is that vaccines with HAART can “teach” the immune system to control HIV without drugs Merck, Glaxo SmithKline now testing HIV vaccines as therapies in HIV-infected individuals

Vaccines are undervalued as a healthcare product Total worldwide revenues for all vaccines (pediatric, adult) $6.5 billion per year Total revenues for biggest selling single drugs Approximately $7 billion Total revenues for Viagra® Approximately $1.8 billion

Still not a priority: What the world spends on developing AIDS vaccines 1996: $ 175 million (the cost of producing ONE major Hollywood movie) 2001: $ 400 million (the cost of producing TWO major Hollywood movies)

IAVI AIDS Vaccine R&D Spending Project Analysis of public sector spending by area NIH - $329m 2002, IAVI - $31m 2002, ANRS – $10m Comprehensive analysis of private sector investment Huge differences in current estimates Development of generic cost assumptions Pre-clinical, Clinical, Phase III, Manufacturing, Staffing, Lab assays Estimate of total global investment/spending

AIDS Vaccine R&D: Future Funding Challenges Flat NIH Funding Competition among PPPs for global health R&D funding Weakening global economy Pressure on pharmaceutical companies (patent expiration, pricing) Uncertain biotech market Disappointing VaxGen results

Standard Vaccine Access Timeline Years after start of pre-clinical research years Vaccine licensed in 1 country years Vaccine licensed in most countries Country-by- country approvals Manufacturing scale-up Financing for developing countries Delivery systems 35+ years 2/3 deployment in developing countries

Access Challenges: Setting Priorities Demand Estimates Manufacturing Regulatory Financing Delivery

AIDS Vaccine Advocacy Coalition AVAC Annual Report: How Do You Fight a Disease of Mass Destruction and Other Questions on the Road to an AIDS Vaccine? Background reports on AIDSVAX results Legislative collaboration with IAVI, microbicide groups, MVI

June 1981…CDC reports 5 young men……

Since then... 79,000,000 infections 10 new HIV infections a minute95% of new infections in developing countries