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