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
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Demonstrate proven tools for immediate impact • Daily oral TDF/FTC as PrEP • 1% tenofovir gel
Develop long-term solutions to end the epidemic • AIDS vaccines • 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
GOAL: A sustained d e c l i n e i n H I V infections (now at 2.5 million/year)
• Define and initiate the “core package” of PrEP demonstration projects
• Safeguard HIV Prevention Research Funding
• End confusion about “combination prevention”
• Narrow gaps in treatment cascade • Prepare for new non-surgical male
circumcision devices
• Testing • Treatment • Voluntary Medical Male Circumcision • Female and male condoms • Prevention of pediatric infection
Deliver proven tools for immediate impact
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
(1) Humoral immunity § Antibodies § Y-shaped proteins that
look for HIV to stop it from infecting cells
Preventive HIV vaccines are meant to illicit two arms of the immune system – humoral and cellular
Immune responses
www.avac.org/researchliteracy
(2) Cellular immunity § White blood cells or
CTL § White blood cells that
look for HIV-infected cells and kill them
Preventive HIV vaccines are meant to illicit two arms of the immune system – humoral and cellular
Preventing vs. controlling HIV infection
Courtesy of HIV Vaccine Trials Network
HIV PREVENT ESTABLISHED INFECTION?
*****
Vaccine Administered
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 have no chance of causing HIV infection
Developing an AIDS vaccine is difDicult
§ 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
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
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 efDicacy trial results
www.avac.org/presenta<ons
YEAR COMPLETED
PRODUCT/ CLADE/ TRIAL NAME
COUNTRIES NUMBER OF PARTICIPANTS
RESULT
2003 AIDSVAX B/B VAX003
Canada, Netherlands, Puerto Rico, US
5,417 No effect
2003 AIDSVAX B/E VAX004
Thailand 2,546 No effect
2007 MRK-‐Ad5 B Step
Australia, Brazil, Canada, Dominican Republic, HaiV, Jamaica, Peru, Puerto Rico, US
3,000 ImmunizaVons halted early for fuVlity; subsequent data analysis found potenVal for increased risk of HIV infecVon among Ad5-‐seroposiVve, uncircumcised men.
2007 MRK-‐Ad5 B Phambili
South Africa 801 ImmunizaVons 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/C HVTN 505
US 2,500 ImmunizaVons halted early for fuVlity; vaccine regimen did not prevent HIV infecVon nor reduce viral load among vaccine recipients who became infected with HIV; follow-‐up conVnues.
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
Research Studies: • RV144i immune correlates studies
• RV305 protein boost in volunteer‐subset from RV144
• RV306 expanded immunogenicity of RV144 regimen
• RV328 AIDSVAX B/E study
Partners/Funders: US Army, Thai government, NIH, Sanofi Pasteur, BMGF
RESEARCH TRIAL
Population: Heterosexual, high-risk
Products: DNA + NYVAC (Sanofi Pasteur) + protein/adjuvant (such as MF59) vs. NYVAC (Sanofi Pasteur) +protein/adjuvant
Partners/Funders: NIH, HVTN, Sanofi Pasteur, Novartis, BMGF
LICENSURE TRIAL: Thailand
Popula5on: MSM, high-‐risk
Products: ALVAC (Sanofi Pasteur) + gp120/adjuvant (such as MF59)
Partners/Funders: US Army, Thai government, NIH, Sanofi Pasteur, BMGF, NovarVs
LICENSURE TRIAL: South Africa Population: Heterosexual, high-risk
Products: ALVAC (Sanofi Pasteur) + gp120/MF59 (Novartis)
Partners/Funders: NIH, HVTN, Sanofi Pasteur, Novartis, BMGF
Source: This schematic comes from the Pox-Protein Public Private Partnership (P5), a collaboration spanning four continents established in 2010 to build on the results of RV144. P5 partners 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
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 II HVTN 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 I 2010
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 I 2010
IAVI B004, Phase I
HVTN 092, Phase I
TAMOVAC01-MZ, Phase I
GV-TH-01, Phase I 2010
IPCAVD004/IAVIB003, Phase I 2010
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
April 2013 Update of Vaccine Pipeline Candidates 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.
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
HIV-infected individual
Broadly neutralizing antibodies
Reverse Engineering Vaccines Passive ImmunizaVon Trials A 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
?
Neutralizing Antibodies: Research pathways in 2013 and beyond
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
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