AVAC Global Advocacy for HIV Prevention AIDS Vaccines: The basics May 2014.

AVACGlobal Advocacy for HIV Prevention

AIDS Vaccines: The basics

May 2014

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 a 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 most 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

YEARCOMPLETED

PRODUCT/ CLADE/ TRIAL NAME

COUNTRIES NUMBER OF PARTICIPANTS

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.

2011 2012 2013 2014 2015 2016

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

Preventive HIV Vaccine Clinical Trials: A Research Timeline April 2013 *

RV 305, Phase II

HVTN 505, Phase IIb

2009

TaMoVac II, Phase II

ANRS 149 LIGHT, Phase II

NCAIDS X111012202, Phase IIHVTN 076, Phase Ib

HVTN 085, Phase Ib

IAVI S001, Phase I

HVTN 094, Phase II

EuroNeut-41, Phase I

HVTN 087, Phase II

SSC-0710, Phase I2010

ISS P-002, Phase I

VACCINE STRATEGY

Poxvirus (canarypox)

Poxvirus (MVA)

Poxvirus (NYVAC)

Protein (gp120)

Protein (gp140)

DNA (alternative delivery)

DNA (conventional delivery)

Adenovirus (human)

Protein (other)

Replicating viral vaccine

Lipopeptide

Recombinant Vaccinia Virus Tiantan

Poly-ICLC (adjuvant)

Vesicular stomatitis virus

HIV-1

Sendai virus

MF59C.1 (adjuvant)

HVTN 073E/SAAVI102, Phase I

HVTN 086/SAAVI103, Phase I

RV262, Phase I2010

IAVI B004, Phase I

HVTN 092, Phase I

TAMOVAC01-MZ, Phase I

GV-TH-01, Phase I2010

IPCAVD004/IAVIB003, Phase I2010

HVTN 088, Phase I

HVTN 096, Phase I

HVTN 097, Phase I

HVTN 099, Phase I

HVTN 098, Phase I

* Trial end-dates are estimates; due to the nature of clinical trials the actual dates may change. For full trial details, see www.avac.org/pxrd

Strategy Phase I Phase Ib Phase II Phase IIb

Poxvirus

MVA (MHRP, EDCTP, SAAVI, GeoVax, HVTN, Oxford)

MVA (EDCTP, GeoVax)

NYVAC (HVTN)

Protein

AIDSVAX (HVTN) ALVAC AIDSVAX (MHRP)

gp140 (Novartis, HVTN, SAAVI)

gp120 (GSK)

gp41 (EC)

mAb (Rockefeller)

Tat Protein (Istituto Superiore di Sanita, Novartis)

VICHERPOL (Russian Federation)

DNA

DNA plasmid (HVTN, GeoVax, Oxford)

PENNVAX (MHRP)

HIV-MAG (HVTN, IAVI) HIVIS (EDCTP)

HIVIS (EDCTP) GTU-Multi (ANRS)

IL-12 pDNA (HVTN)

SAAVI DNA-C2 (SAAVI, HVTN)

Adenovirus

rAd5 (HVTN, Brigham)

rAd35 (HVTN, IAVI)

rAd26 (Brigham)

ChAdV63.HIVconsv (Oxford)

Lipopeptide HIV-LIPO-5 (ANRS)

Sendai virus Sendai SeV-G (IAVI)

Replicating viral vector rTV (NCAIDS/China)

HIV-1 HIV-1 delta (Istituto Superiore di Sanita)

Vesicular Stomatitis virus VSV Indiana HIV gag (HVTN)

Visit www.avac.org/pxrd for more information.

April 2013 Update of Vaccine Pipeline Candidates

Antibody research

• Advanced screening techniques have identified 100s of broadly neutralizing antibodies (bNAbs)

• Aim to induce bNAbs with a vaccine– Scientists understand shape and identified where they

bind with HIV– Binding of antibody with virus will block infection

• Some bNAbs being tested as passive vaccines• Some may be developed into active vaccine

candidates

HIV-infected individual

Broadly neutralizing antibodies

Reverse Engineering Vaccines Passive Immunization TrialsA protein from HIV surface (envelope) interacting with an antibody.

Molecular characterization of the interaction between HIV envelope and BNAbs

* Modified env

Development of immunogens to mimic the portion of HIV envelope that connects with BNAbs

*

Combination of several immunogens = vaccine

Development of clinical grade purified form of BNAbs

Phase I: Safety and pharmacokinetic evaluation

Phase II/III: Efficacy trials

?Source: Adapted from: Burton, “Antibodies, viruses and vaccines,” Nature Reviews Immunology (2002) 2: 706-713.

Neutralizing Antibodies: Research pathways

HVTN 505 and Adenovirus

• Phase IIb, in circumcised MSM across US

• DNA prime/rAd5 boost (T cell-based)

• Immunizations halted in April 2013 due to futility

• No statistically significant difference between infections in vaccine vs. placebo arm; based on review, trial would never be able to find a difference

• All participants received the best available prevention services, however a number still became infected

• Ad5 vector candidates will not move forward any further; more attention/scrutiny around other adenovirus vectors

More information about HVTN 505: www.hopetakesaction.org Get involved: www.bethegeneration.org; www.hvtn.org/about/sites/html; www.vaccineforall.org

The Thai prime boost trial: RV144

• First glimpse of evidence a vaccine has a protective effect

• 31.2 % (modest effect)

• Not for licensure

• Sept 2011 – announcement of two immune responses potentially linked to risk of infection

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

Future priorities

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

in South Africa and Thailand

– Advancement of candidates/strategies currently in smaller scale trials, depending on results

• Continued preclinical work to discover bNAbs, new vectors, and other strategies and advance them to candidates and clinical trials

What is needed now?

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

• Ensure diversity of approaches beyond P5 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