AIDS Vaccines Cannot Cause HIV § No Vaccine Is 100% Effective § Most Vaccines Licensed in the US 70%-95% Effective Why the Interest in an AIDS Vaccine?

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 an AIDS vaccine?

§ 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

Deliver proven tools for immediate impact • End confusion about “combination • Testing prevention” • Treatment • Narrow gaps in treatment cascade • Voluntary Medical Male Circumcision GOAL: A sustained • Prepare for new non-surgical male • Female and male condoms circumcision devices • Prevention of pediatric infection decline in HIV infections (now at 2.5 million/year) Demonstrate proven tools for immediate impact

• Define and initiate the “core • Daily oral TDF/FTC as PrEP package” of PrEP • 1% tenofovir gel demonstration projects

Develop long-term solutions to end the epidemic COMBINE • AIDS vaccines • Safeguard HIV Prevention Research Funding • Cure • Multi-purpose prevention technologies • Next generation ARV-based prevention • Non-ARV-based microbicides • Rectal microbicides

Years to Impact Zero to 5 5 to 10 10 to End Types of AIDS vaccines

§ Preventive vaccines o Designed for people who are not infected with HIV o If effective, would reduce risk of infection or viral load set point after infection

§ Therapeutic vaccines o Designed for people who are living with HIV o 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 cells are waiting to respond and attack

Note: This is a general definition, not specific to HIV vaccines How might a preventive HIV vaccine work?

By teaching the body to recognize and fight HIV, should it be exposed § Vaccine carries something that ‘looks and feels’ like HIV, but is not HIV and cannot cause HIV infection o Use a synthetic fragment of HIV known to generate an immune response § Body reacts by creating antibodies and/or killer cells, and a memory response § Upon possible exposure to HIV, antibodies and killer cells are waiting to prevent and/or control infection Immune responses

Preventive HIV vaccines are meant to illicit two arms of the immune system – humoral and cellular (1) Humoral immunity § Antibodies § Y-shaped proteins that look for HIV to stop it from infecting cells Immune responses

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

(2) Cellular immunity § White blood cells or CTL § White blood cells that look for HIV-infected cells and kill them

www.avac.org/ researchliteracy Preventing vs. controlling HIV infection

HIV PREVENT ESTABLISHED INFECTION? ***** C

A B HAART

Vaccine A. Lower Initial Peak of Viremia Administered B. Lower Set Point

C. Delay Progression Courtesy of HIV Vaccine Trials Network 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 have no chance of causing HIV infection Developing an AIDS vaccine is dificult

§ 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 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 Ongoing vaccine trials – April 2013

• Over two dozen safety and immunogenicity studies • HVTN 505 – immunizations halted April 2013; follow up of participants ongoing • RV144 follow-up trials planned AIDS vaccine eficacy trial results

YEAR PRODUCT/ CLADE/ COUNTRIES NUMBER OF RESULT COMPLETED TRIAL NAME PARTICIPANTS

2003 AIDSVAX B/B Canada, 5,417 No effect VAX003 Netherlands, Puerto Rico, US 2003 AIDSVAX B/E Thailand 2,546 No effect VAX004 2007 MRK-Ad5 B Australia, 3,000 Immunizaons halted early for fulity; Step Brazil, Canada, subsequent data analysis found potenal for Dominican increased risk of HIV infecon among Ad5- Republic, Hai, seroposive, uncircumcised men. Jamaica, Peru, Puerto Rico, US 2007 MRK-Ad5 B South Africa 801 Immunizaons halted based on Step result. Phambili 2009 ALVAC-HIV (vCP1521) Thailand 16,402 Modest effect (31.2%) and AIDSVAX B/E Thai Prime-Boost/RV 144

2013 DNA and Ad5 A/B/C US 2,500 Immunizaons halted early for fulity; vaccine HVTN 505 regimen did not prevent HIV infecon nor reduce viral load among vaccine recipients who www.avac.org/presentaons became infected with HIV; follow-up connues. 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 ongoing Follow-on Trials Based on RV144: Strategy includes development and research tracks

RV144 FOLLOW-UP: Thailand LICENSURE TRIAL: Thailand

Research Studies: Populaon: MSM, high-risk • RV144i immune correlates studies Products: ALVAC (Sanoﬁ Pasteur) + gp120/adjuvant • RV305 protein boost in volunteer‐subset from RV144 (such as MF59) • RV306 expanded immunogenicity of RV144 regimen Partners/Funders: US Army, Thai government, NIH, • RV328 AIDSVAX B/E study Sanoﬁ Pasteur, BMGF, Novars

Partners/Funders: US Army, Thai government, NIH, Sanofi Pasteur, BMGF LICENSURE TRIAL: South Africa Population: Heterosexual, high-risk Products: ALVAC (Sanofi Pasteur) + gp120/MF59 (Novartis) Partners/Funders: NIH, HVTN, Sanofi Pasteur, Novartis, BMGF RESEARCH TRIAL

Population: Heterosexual, high-risk

Products: DNA + NYVAC (Sanofi Pasteur) + protein/adjuvant Source: This schematic comes from the Pox-Protein Public (such as MF59) vs. NYVAC (Sanofi Pasteur) +protein/adjuvant Private Partnership (P5), a collaboration spanning four continents established in 2010 to build on the results of RV144. P5 partners Partners/Funders: NIH, HVTN, Sanofi Pasteur, Novartis, BMGF include the US NIAID, the Bill & Melinda Gates Foundation, the HIV Vaccine Trials Network, the US Military HIV Research Program, Sanofi Pasteur and Novartis Vaccines and Diagnostics.

AVAC Report 2012: Achieving the End – One year and counting. www.avac.org/report2012 HVTN 505

• Phase IIb, in circumcised MSM across US • DNA prime/rAd5 boost (T cell-based) • Parts of vaccine regimen are similar to the vaccine used in Step and Phambili • Endpoints: – Prevention of HIV in individuals who receive the vaccine (HIV acquisition as an endpoint was added to the trial design in part based on RV144 results) – Reduction of viral load in individuals who receive the vaccine and go on to become infected with HIV

HVTN 505

• 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 • Scientists are working to understand why this vaccine candidate did not work • Will likely have an impact on Ad5 vector candidates moving forward; possibly on all adenovirus vectors

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

Preventive HIV Vaccine Clinical Trials: A Research Timeline April 2013 * 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 HVTN 505, Phase IIb

ANRS 149 LIGHT, Phase II 2009 RV 305, Phase II

TaMoVac II, Phase II VACCINE STRATEGY

NCAIDS X111012202, Phase II Poxvirus (canarypox) HVTN 076, Phase Ib Poxvirus (MVA) HVTN 085, Phase Ib Poxvirus (NYVAC) IAVI S001, Phase I IPCAVD004/IAVIB003, Phase I HIV-1 2010 HVTN 094, Phase II Recombinant Vaccinia Virus Tiantan GV-TH-01, Phase I 2010 Sendai virus TAMOVAC01-MZ, Phase I HVTN 099, Phase I DNA (alternative delivery) HVTN 092, Phase I DNA (conventional delivery) RV262, Phase I 2010 Lipopeptide HVTN 087, Phase II Protein (gp120) IAVI B004, Phase I Protein (gp140)

ISS P-002, Phase I Protein (other)

SSC-0710, Phase I Adenovirus (human) 2010 EuroNeut-41, Phase I Replicating viral vaccine

HVTN 088, Phase I Vesicular stomatitis virus

HVTN 073E/SAAVI102, Phase I Poly-ICLC (adjuvant)

HVTN 086/SAAVI103, Phase I MF59C.1 (adjuvant)

HVTN 098, Phase I

HVTN 097, Phase I

* Trial end-dates are estimates; due to the nature of HVTN 096, Phase I clinical trials the actual dates may change. For full trial details, see www.avac.org/pxrd April 2013 Update of Vaccine Pipeline Candidates

Strategy Phase I Phase Ib Phase II Phase IIb MVA (MHRP, EDCTP, SAAVI, GeoVax, MVA (EDCTP, GeoVax) HVTN, Oxford) Poxvirus NYVAC (HVTN)

AIDSVAX (HVTN) ALVAC AIDSVAX (MHRP)

gp140 (Novartis, HVTN, SAAVI)

gp120 (GSK)

Protein gp41 (EC)

mAb (Rockefeller)

Tat Protein (Istituto Superiore di Sanita, VICHERPOL (Russian Novartis) Federation)

DNA plasmid (HVTN, GeoVax, Oxford)

PENNVAX (MHRP)

HIV-MAG (HVTN, IAVI) HIVIS (EDCTP) DNA HIVIS (EDCTP) GTU-Multi (ANRS) IL-12 pDNA (HVTN)

SAAVI DNA-C2 (SAAVI, HVTN)

rAd5 (HVTN, Brigham)

rAd35 (HVTN, IAVI) Adenovirus 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. Antibody research

§ Advanced screening techniques have identified 100s of broadly neutralizing antibodies (bNAbs) § Aim to induce bNAbs with a vaccine o Scientists understand shape and identified where they bind with HIV o Binding of antibody with virus will block infection § Some bNAbs being tested as passive vaccines § Some may be developed into active vaccine candidates Neutralizing Antibodies: Research pathways in 2013 and beyond

HIV-infected individual

Broadly neutralizing antibodies

Reverse Engineering Vaccines Passive Immunizaon Trials

A protein from HIV surface Development of clinical grade purified form of BNAbs (envelope) interacting with an antibody.

Phase I: Safety and pharmacokinetic evaluation Molecular characterization of the interaction between HIV envelope and BNAbs

* Modified env Phase II/III: Efficacy trials Development of immunogens to mimic the portion of HIV envelope that connects with BNAbs

Combination of several immunogens = vaccine ?

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

§ Continued clinical research o P5 strategy – large scale trials following RV 144 results in South Africa and Thailand o Advancement of candidates/strategies currently in smaller scale trials, depending on results § Continued work to discover bNAbs and advance them to candidates and clinical trials What is needed now?

§ Vaccination to protect against infection, mitigate infection and prevent transmission to others § Focus investigation to better understand the RV144 trial result § Ensure diversity of approaches beyond RV144 and P5 strategy, exploring novel directions for vaccine design § More stakeholder involvement, e.g. on trial design, standard of prevention/care 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