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TB vaccines: what is on the horizon? . Tom Evans, MD Chief Scientific Officer, Aeras IAC, Washington, D.C., July 27, 2012. Global Plan will not eliminate TB by 2050. Chris Dye, WHO; London 2009. Predicted Impact of a 60% Efficacious TB Vaccine. 39% 52% 37% 80% 92%.

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tb vaccines what is on the horizon

TB vaccines: what is on the horizon?

Tom Evans, MD

Chief Scientific Officer, Aeras

IAC, Washington, D.C., July 27, 2012

predicted impact of a 60 efficacious tb vaccine
Predicted Impact of a 60% Efficacious TB Vaccine

39%

52%

37%

80%

92%

Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME Proc Natl Acad Sci USA. 2009

key challenges
Key Challenges
  • Lack of validated animal models or clear correlates of protection of immunity

Active Disease

Latent

  • Large and expensive trials needed to prove efficacy

BCG

  • Diversity of BCG, populations, and environmental factors may require more than one vaccine

Pre-infection

Infants

Adolescents

Adults

HIV+ All Ages

Covered by existing vaccine

No coverage or impact from existing vaccine

slide5

Better TB Vaccines: Reasons to be Optimistic

  • Most people (80-90%) do not get disease when infected
  • Evidence of BCG vaccine efficacy in children
  • New TB vaccine candidates protect in animal models
  • There are clinical clues to guide immunologic hypotheses
      • Low CD4+ T cells are more susceptible to M.tb infection
      • Anti-TNF treatment is associated with reactivation
  • New TB vaccines boost cellular immune responses in multiple clinical studies
strategies for tb vaccine development
Strategies for TB Vaccine Development

Pre-infection: to prevent infection

Improved priming vaccines

Novel booster vaccines

Block Initial Infection

  • Post-infection: to prevent disease
    • Develop novel booster vaccines to extend and enhance immune protection

Prevent Latent

Infection

Prevent Early Disease

Prevent Reactivation

Disease

  • Immunotherapeutic: treatment
    • Shorten the course of chemotherapy for active TB
    • Improve efficacy of MDR/XDR/TDR-TB treatment
why conduct tb vaccine studies in hiv patients
Why conduct TB vaccine studies in HIV+ patients?
  • PROS
  • 1/3 of all deaths from HIV in Africa
  • Incidence ~ 2% annually despite ART and INH preventative Rx
  • Population with high mortality
  • Able to access through the medical system
  • Easier “downstream” population to vaccinate
  • CONS
  • Immune response may be modified, with possible negative results
  • Use of preventative INH as recommended by WHO is not uniformly followed
  • May be a greater rate of re-infection as opposed to reactivation
  • Continually changing treatment and prevention landscape for trials lasting 3-4 years
  • Possible issues of safety, especially with live vaccines
reality of tb vaccine trials in hiv samandari et al 2011 botswana
Reality of TB vaccine trials in HIV+Samandari et al., 2011, Botswana
  • The increased incidence is made almost entirely from those that are skin test +
  • There is a lag between INH preventative therapy and this increased incidence
  • If given preventative therapy, on ART and CD4>200, incidence is not highly differentiated from the general population

Should trials be first done in the general population, and only then bridged back to the HIV+ population?

slide9

Global Clinical TB Vaccine Pipeline – 2000

Phase I

Phase II

Phase IIb

Phase III

M. Vaccae

global clinical tb vaccine pipeline 2012
Global Clinical TB Vaccine Pipeline – 2012

Phase I

Phase II

Phase IIb

Phase III

MVA85A/AERAS-485OETC, Aeras

VPM 1002Max Planck, VPM, TBVI

Mw

DBY, India, M/s. Cadila

IN hu Ad5 Ag85A

McMaster CanSino

M72 + AS01GSK, Aeras

AERAS-402/Crucell Ad35Crucell, Aeras

Hybrid-I + IC31SSI, TBVI, EDCTP, Intercell

ID93 + GLA-SE IDRI, Aeras

M. Vaccae

Anhui Longcom, China

Mycobacterial – whole cell or extract

Hyvac 4/ AERAS-404 + IC31SSI, sanofi-pasteur, Aeras, Intercell

RUTIArchivel Farma, S.L

Clinical trials in HIV+ patients

Viral vector

H56 + IC31SSI, Aeras, Intercell

rBCG

Protein/adjuvant

m vaccae dardar study of tb prevention in newly diagnosed hiv in tanzania
M. vaccae:DarDar study of TB prevention in newly diagnosed HIV in Tanzania

von Reyn et al. AIDS, 2010

  • Study was the first to have a signal of possible TB vaccine efficacy
  • Phase III, RCT in Tanzania; Eligibility: CD4≥ 200, prior BCG
  • 5 doses of heat killed M. vaccaevs placebo (compliance 84%)
  • Median CD4~400/µl, VL~ 4.1 Log10
  • 31% INH x 6 mos for TST ≥ 5 mm; 28% ART during trial
  • Low loss to f/u (18%)
  • Safe, no adverse effect on CD4 or VL
mva85a
MVA85A
  • Oxford Emergent TB Consortium (OETC)/Wellcome Trust/Aeras
  • Modified Vaccinia Ankara (MVA) expressing M.tb antigen 85A
    • Attenuated poxvirus, replication deficient in mammalian cells
    • Administered to 120,000 vaccinees (smallpox eradication)
  • Protects animals in multiple models from M.tb challenge after BCG prime-MVA85A boost administered intradermally
  • 14 clinical trials completed or ongoing involving >2000 participants
  • Acceptable safety profile in all populations studied
    • Site of injection reactions in most subjects
  • Preferentially induces CD4+ (vs. CD8+) T cell responses
    • Appears more immunogenic in adults, two doses needed in HIV+
    • No effect of vaccination on CD4 count or viral load (Scriba et al. 2012)
inf g elispot responses in hiv scriba et al ajrccm 2012
INFg ELISPOT Responses in HIV+Scriba et al. AJRCCM, 2012
  • Less robust than HIV uninfected
  • Persist (and can be boosted)
  • Minimally affected by ART
  • Exhibited CD4+ T cell polyfunctionality in ICS assays
  • Phase 2b, randomized, double-blind, controlled trial (supported by EDCTP)
  • HIV-infected adults (South Africa, Senegal, N=1400) initiated
  • Both ART and non-ART enrolled, all PPD+ given INH for 6 mo prior to enrollment
  • Over 400 subjects enrolled
aeras 402 crucell human ad35
AERAS-402 / Crucell human Ad35

Human adenovirus 35 encoded 3 M.Tb antigens

Multiple Phase I/IIa trials completed and ongoing, including in:

Adults with/without latent TB infection; Adults with active TB; Infants

Dosing range: 1.5x108- 1x1011 viral particles administered IM

Acceptable safety profile; no SAEs related to AERAS-402

Immunogenic (CD8+ T cell responses preferentially)

Phase IIb proof-of-concept study in infants ongoing

  • Phase 2, HIV infected, BCG vaccinated; Aurum Institute, South Africa
  • First dose (3 x 1010 or placebo) administered to 26 patients and showed the vaccine to be immunogenic and safe with no change in VL or CD4 count
slide15

VPM1002 in HIV-exposed infants

  • BCG is not recommended by WHO for HIV-infected infants, although this recommendation is not followed in practice.
  • rBCG that expresses listeriolysin to induce endosomal perforation, apoptosis induction, and cross presentation to increase CD8+ responses
  • Safer than BCG in the SCID mouse model
  • Showed superior protection to BCG in some animal studies
  • Studied in healthy adults, TB infected adults, and infants
  • Presently in a trial in HIV uninfected infants in South Africa in preparation for a Proof of Concept trial in HIV exposed newborns
slide16

Decade of progress

  • $600 million invested since 2005
  • Robust pipeline of discovery and preclinical candidates
  • Rich pipeline of 15 new vaccine candidates entered clinical trials
  • Promising activities for development of new biomarkers emerged
  • Capacity for vaccine production and carrying out large-scale clinical trials established
  • Better understanding of safety and immunogenicity
slide17

Decade to come

  • First efficacy data from proof-of-concept trials that are underway
  • Better understanding of correlates of immunity, accelerating the testing of future vaccines
  • Start of multiple phase III studies
  • Possibility of TB vaccine licensure
slide18

Aeras gratefully acknowledges the volunteers in our clinical trials, hard work of many partners, and support of the following major donors:

Netherlands Ministry of Foreign Affairs

US Food and Drug Administration

thank you
Thank You!

For more information:

www.aeras.org

An ounce of prevention is worth a pound of cure.