AVACGlobal Advocacy for HIV Prevention

AIDS Vaccines: The basics

May 2015

Presentation Overview

• What is a vaccine?• How would an AIDS vaccine work?• Where are we in the search?• What is needed now?

What is a vaccine?

• A substance that teaches the immune system how to protect itself against a virus or bacteria

• No effective AIDS vaccine available today

• AIDS vaccines cannot cause HIV• No vaccine is 100% effective • Most vaccines licensed in the US

70%-95% effective

Why the interest in AIDS vaccines?

• Proven prevention options have slowed HIV’s spread – but thousands of people continue to get infected daily

• There is a need for a range of HIV prevention methods; there is no silver bullet

• Vaccines are one of the world’s most effective public health tools

• Cost-effective – single or several doses likely provide protection for years

How vaccines are crucial to ending AIDS

Types of AIDS vaccines

• Preventive vaccines–Designed for people who are not infected with

HIV– If effective, would reduce risk of infection–May also reduce viral load set point after

infection• Therapeutic vaccines–Designed for people who are living with HIV– If effective, would use the body’s immune system

to help control or clear HIV in the body

How do preventive vaccines work?

By teaching the body to recognize and fight a pathogen

• Vaccine carries something that ‘looks and feels’ like the pathogen, but is not really the pathogen

• Body reacts by creating antibodies or killer cells and a memory response

• Upon exposure to the ‘real’ pathogen, antibodies and killer cell are waiting to respond and attack

Note: This is a general definition, not specific to HIV vaccines

How might preventive HIV vaccine work?

A preventive vaccine would teach the body to recognize and fight HIV, should it be exposed

• Vaccine would carry a component that ‘looks and feels’ like HIV, but is not HIV and cannot cause HIV infection

• Component might be a synthetic fragment of HIV known to generate an immune response

• Body would react by creating antibodies and/or killer cells and a memory response

• Upon possible exposure to HIV, antibodies and killer cells would be waiting to prevent and/or control infection

Immune responses

(1) Humoral immunity• Primary action of humoral

arm is creating antibodies• Antibodies are Y-shaped

proteins developed in response to a pathogen to prevent infection

Preventive HIV vaccines are meant to elicit two arms of the immune system – humoral and cellular

Immune responses

(2) Cellular immunity• Cytotoxic T

lymphocytes and T-helper cells

• Cells recognize HIV-infected cells and kill them

Preventive HIV vaccines are meant to elicit two arms of the immune system – humoral and cellular

Preventing vs. controlling infection

Courtesy of HIV Vaccine Trials Network

HIVPREVENT ESTABLISHED INFECTION?

*****

VaccineAdministered

A. Lower Initial Peak of Viremia

A

B. Lower Set Point

B

C. Delay Progression

C

HAART

How have many vaccines been made?

• Live attenuated vaccines (examples: measles, mumps, and rubella)

• Whole killed virus vaccines (example: influenza and rabies)

How are AIDS vaccines made?

Recombinant vaccines• DNA vaccines• Vector vaccines• Subunit vaccines

Do not contain HIV – only synthetic copies of fragments of HIV that will create an immune response but do not cause HIV infection

Developing an AIDS vaccine is difficult

• Numerous modes of transmission

• HIV kills the very immune cells used in defending the body against HIV

• HIV makes many copies of itself and mutates, making itself unrecognizable to the immune system

• Mutation leads to different subtypes of the virus throughout the world

Vaccine research in history

Virus or bacteria Year cause discovered

Year vaccine licensed

Years elapsed

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 –

Duration between discovery of microbiologic cause of selected infectious diseases and development of a vaccine

Source: AIDS Vaccine Handbook, AVAC, 2005

AIDS vaccine efficacy trial results

www.avac.org/presentations

YEAR PRODUCT/ CLADE/ TRIAL NAME

LOCATION # RESULT

2003 AIDSVAX B/BVAX003

Canada, Netherlands, Puerto Rico, US

5,417 No effect

2003 AIDSVAX B/EVAX004

Thailand 2,546 No effect

2007 MRK-Ad5 BStep

Australia, Brazil, Canada, Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico, US

3,000 Immunizations halted early for futility; subsequent data analysis found potential for increased risk of HIV infection among Ad5-seropositive, uncircumcised men.

2007 MRK-Ad5 BPhambili

South Africa 801 Immunizations halted based on Step result.

2009 ALVAC-HIV (vCP1521) and AIDSVAX B/E Thai Prime-Boost/RV 144

Thailand 16,402 Modest effect (31.2%)

2013 DNA and Ad5 A/B/CHVTN 505

US 2,500 Immunizations halted early for futility; vaccine regimen did not prevent HIV infection nor reduce viral load among vaccine recipients who became infected with HIV; follow-up continues.

Pox-Protein strategies

• In 2009 clinical study in Thailand (‘RV144’) showed evidence a vaccine can reduce HIV risk– Pox-protein, prime-boost regimen using canary pox (ALVAC) and

manufactured HIV protein-GP120– Moderately effective – 31% protection; not licensable– Follow up research identified possible explanations for vaccine-

related protection and avenues for improvement• New clinical trials launched by P5 in southern Africa in January 2015– Modified regimen being tested for potential licensure; efficacy

trial planned to start in 2017– Other regimens being tested for proof-of-concept, improved

responsesMore information about Rv144 and the follow-up at: http://hivresearch.org/research.php?ServiceID=13

Pox-Protein Public-Private Partnership (P5)

Antibody research

• 100s broadly neutralizing antibodies (bNAbs) identified since 2009– Work against majority of HIV strains– Target limited number of sites on HIV surface

• Direct transfer of antibodies—passive immunization—being tested as prevention, treatment, part of cure– Early clinical trials show safety, tolerability, significant viral

reduction among HIV-positive participants– Larger-scale studies planned for safety, dosing, efficacy– Hope to increase potency of bNAbs and duration of

responses in humans

Future priorities

• Continued clinical research– P5 strategy – large-scale trials following RV 144 results in

South Africa and Thailand– Clinical trials of vaccine using “mosaic” (cross-clade)

immunogen by Janssen (division of J&J)– Advancement of candidates/strategies currently in smaller-

scale trials, depending on results• Further bNAb research—pre-clinical discovery and

advancement of current bNAbs in clinical trials• Continued identification of novel vectors, adjuvants and

other strategies for improved candidates

What is needed now?

• Monitor timelines of clinical trials, especially delays and the reasons for them

• Ensure diversity of approaches beyond pox-protein strategy, exploring novel directions for vaccine design

• More stakeholder involvement, e.g., on trial design, standard of prevention/care, decision-making on moving candidates through the clinical pipeline

Key resources• AVAC: www.avac.org/vaccines• Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID)

o At Duke: www.chavi-id-duke.org o At Scripps: www.cavi-id.org

• Collaboration for AIDS Vaccine Discovery: www.cavd.org • Global HIV Vaccine Enterprise: www.vaccineenterprise.org • HIV Px R&D Database (PxRD): www.data.avac.org • HIV Vaccines & Microbicides Resource Tracking Working Group: www.hivresourcetracking.org • HIV Vaccine Trials Network (HVTN): www.hvtn.org • International AIDS Vaccine Initiative (IAVI): www.iavi.org • Military HIV Research Program (MHRP): www.hivresearch.org • NIAID: www.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/default.aspx • NIH Vaccine Research Center (VRC): www.vrc.nih.gov • Pox-Protein Public-Private Partnership (P5): www.hivresearch.org/media/pnc/9/media.749.pdf