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Inactivated whole cell NTM vaccine for the prevention of tuberculosis SRL 172 DAR-901 2016 TBVI Symposium Les Diablerets Switzerland Ford von Reyn MD Geisel School of Medicine at Dartmouth Investigational TB vaccines that have completed

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Inactivated whole cell NTM vaccine for the prevention of tuberculosis SRL 172 DAR-901

2016 TBVI Symposium Les Diablerets Switzerland Ford von Reyn MD Geisel School of Medicine at Dartmouth

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Investigational TB vaccines that have completed human efficacy trials

Vaccine Subjects Location Dates Ref SRL 172 (whole cell NTM) 2013 HIV-pos adults with prior BCG Tanzania Phase III 2001-2008 von Reyn et al AIDS 2010 MVA 85A (subunit) 2797 HIV-neg infants with prior BCG South Africa Phase IIb 2009-2013 Tameris et al Lancet 2013

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Inactivated whole cell NTM booster vaccine Target Product Profile

  • Booster vaccine for the prevention of TB and MDR-TB

– in adolescents & adults primed with childhood BCG

  • Safe, well-tolerated

– heat-inactivated, no adjuvant – safe in HIV and latent TB

  • Polyantigenic and broadly immunogenic

– cell wall, secreted and cytosolic Ags – theoretical advantage for both human and pathogen diversity – stimulates both cellular and humoral immunity

  • Effective both pre- and post-infection
  • Timing of administration

– Healthy persons: immunize all adolescents and adults primed with BCG – HIV infected persons: immunize at time of diagnosis of HIV

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SRL 172: an inactivated NTM vaccine

  • Heat-inactivated, whole-cell preparation derived from rough

variant of an environmental non-tuberculous mycobacterium

– originally designated M. vaccae (phenotypic methods) by J. Stanford &

  • G. Rook (now identified as M. obuense based on 16S RNA sequencing)

– originally targeted for therapy of TB

  • Animal studies

– immunogenic and effective in preventing TB (Skinner, Hernandez-Pando, Abou-Zeid)

  • GMP product manufactured by SR Pharma (agar-based method)

– 0.1 mL intradermal dose contained estimated 109 CFU – Demonstrated safe and well-tolerated in humans

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SRL 172 – Dartmouth Phase I, II and III Trials

(multiple dose)

Phase Site SRL172 (N) Control (N) 1 US HIV - 9 US HIV+ 23 12 US HIV+ 11 2 Zambia 22 22 Finland 19 20 3 Tanzania ~1000 ~1000

1995 2000 2005 2010

  • All studies investigator-initiated (funding: NIH, EGPAF, Sigrid Juselius Foundation)
  • Dartmouth group conducted an entirely independent development program (safety,

immunogenicity, and efficacy) – no direct support, involvement or reference to work by Stanford, Rook, SR Pharma, Silence Therapeutics, or Immodulon

  • All results presented in peer-reviewed publications

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Finland Phase II: Immunogenicity in HIV-positives

* P = 0.001 § p = 0.02 † p = 0.008

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Study population: HIV pos, BCG pos; 70% on ART CV = control (Hep B) MV = SRL 172

IFN-γ responses to SRL 172 sonicate

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DarDar SRL-172 Trial 2001-2008

(Dartmouth / Dar es Salaam, Tanzania)

  • “Prime-Boost” Hypothesis

– In persons who had childhood BCG (prime), SRL 172 inactivated whole cell NTM (boost) will reduce incident disseminated TB by 50% and definite TB by 50%

  • Study Population

– Residents of Tanzania – HIV-positive, CD4 >200 – BCG scar

  • Rationale

– High-risk group provides most expeditious, efficient population in which to demonstrate efficacy

  • Sponsor

– Division of AIDS (DAIDS), NIH

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DarDar SRL 172 Study

Placebo-controlled, randomized (1:1), double-blind

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2000 subjects randomize (1:1) SRL-172 (0, 2, 4, 6, 12 mo) Placebo

Safe and well tolerated Doses administered:

  • SRl-172: 4616 (84% completed 5 doses)
  • Placebo: 4603 (83% completed 5 doses)
  • Vaccine site reactions:
  • Induration: average 5-6
  • Desquamation: 37-58%
  • Local drainage: 22-49%
  • Sterile abscesses: 3 (0.06% of doses)

HIV viral load and CD4 after each dose in 150 subject safety substudy

  • No difference in SRL-172 vs placebo
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Median f/u = 3.3 years von Reyn et al. AIDS 2010; 24:675-85

DarDar SRL-172 Study – Outcome

At year 7, DSMB recommended the trial be stopped based on efficacy in preventing definite TB

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Median f/u = 3.3 years von Reyn et al. AIDS 2010; 24:675-85

DarDar SRL-172 Study – Outcome

At year 7, DSMB recommended the trial be stopped based on efficacy in preventing definite TB

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Median f/u = 3.3 years von Reyn et al. AIDS 2010; 24:675-85

DarDar SRL-172 Study – Outcome

At year 7, DSMB recommended the trial be stopped based on efficacy in preventing definite TB

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Lahey et al Vaccine 2010

Immunogenicity of SRL-172 in DarDar Trial

  • Significant IFN-γ and lymphocyte proliferative responses to

SRL-172 vaccine sonicate

  • Significant antibody responses to LAM

IFN-γ response to SRL-172 LPA response to SRL-172 Anti-LAM Ab response

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Risk of TB among placebo recipients in DarDar trial was lowest if they had polyantigenic IFN-γ responses at baseline = to 3 mycobacterial antigens (ESAT-6, Ag 85, MTB whole cell lysate)

  • Results are adjusted for age, baseline CD4 count, previous TB

treatment and a positive TST. Results were similar among TST-pos and TST-neg, and across HIV viral loads.

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Lahey et al PLoS ONE 2011

Number of antigen preparations eliciting positive IFN-Υ responses

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SRL-172 to DAR-901

  • Agar-grown SRL 172 (1994-2008)

– Limited size of production lots, not scalable – Identified as M. vaccae based on phenotypic methods

  • Broth-grown DAR-901 (2011- )

– Product development in collaboration with Aeras

  • Established MCB from seed lot used for SRL 172
  • GMP broth manufacturing process – high yield, scalable
  • SRL 172 and DAR-901 identity confirmed by sequencing

– 16sRNA indicates 99.6% homology with M. obuense (first isolated in Obu, Japan;Tsakamura J Gen Micro 1971)

  • Animal toxicology and immunogenicity completed

– Feb 2014: Phase I IND accepted by FDA – April 2014: multiple injection, dose-escalation study initiated

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DAR-901 booster - Phase I Dose Escalation

Dose Group HIV Status IGRA status DAR-901 dose DAR-901 x3 (N) Saline x2 BCG x1 (N) Saline x3 (N) Total

A1 Neg Neg 0.1 mg 10 3 3 16 A2 Neg Neg 0.3 mg 10 3 3 16 A3 Neg Neg 1 mg 10 3 3 16 A4 Neg Pos 1 mg 6 – – 6 B1+B2 Pos Neg+Pos 1 mg 5 – – 5 Total 41 9 9 59

Safe, well-tolerated, dose of 1 mg selected for further clinical trials Immune assays pending:

  • IFN-γ response to vaccine Ag and MTB
  • 13-color ICS assay and modified Ki-67/gamma delta TCR ICS assay

Support: Dartmouth, Aeras US Study among adults BCG primed at birth ID administration at 0, 2, 4 months; f/u to 10 months after last dose

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Median injection site reactions at 7 days (mm)

Cohort DAR-901 dose Injection 1 (N=30) Injection 2 (N=30) Injection 3 (N=28) Erythema Induration Erythema Induration Erythema Induration A1, 0.1 mg 5 6.5 6 4 7 3.5 A2, 0.3 mg 6 4 6 6.5 7.5 3 A3, 1 mg 10 4.5 8 6 8 5 Note:

  • Excludes subjects with 0 reactions for all 3 doses;
  • Excludes subjects with 0 reactions at dose 1 & dose 2, and large reactions at dose 3.
  • Measurement for erythema more reliable than for induration.
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DAR-901 Phase II prevention of infection trial in adolescents (DAR-PIA)

  • Hypothesis: DAR-901 will reduce new TB infection by 50%

– Defined as conversion of IGRA from negative to positive

  • Design: Placebo-controlled, randomized (1:1), blinded
  • Study population: Tanzania, 650 adolescents, age 13-15
  • Eligibility: BCG, positive; baseline IGRA, negative
  • Intervention: intradermal DAR-901 or placebo at 0, 2, 4 mo.
  • Duration: Feb 2016- Feb 2018
  • Follow-up: repeat IGRA at 2, 12, and 24 months

– Repeat IGRA in new positives to confirm “persistent Infection”

  • Funded by GHIT - Japan
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DAR-901 Summary

  • Inactivated whole cell NTM booster remains

the only investigational TB vaccine shown effective in preventing TB disease in humans

  • Extensive prior safety data
  • DAR-901

– High-yield, scalable, broth-based product – Phase I multiple dose escalation – complete – Phase II Prevention of Infection trial

  • Funded by GHIT
  • Starting in Tanzania, February 2016
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Acknowledgements

Dartmouth Richard Waddell Tim Lahey Sue Tvaroha Wendy Wieland-Alter Ruth Connor Leway Kailani Lisa Adams Todd Mackenzie Mark Carey Chip Cole Peter Wright Brenda Haynes Tanzania Lillian Mtei Kisali Pallangyo Muhammad Bakari Mecky Matee Isaac Maro Sajida Kimambo Johnson Lyimo Betty Mchaki Boston Robert D. Arbeit

  • C. Robert Horsburgh

Finland Jenni Vuola Juhani Eskola Matti Ristola Hanna Soini New York Barry Kreiswirth Aeras Tom Evans Eric Tsao Ann Ginsberg Veerabadran Dheenadhayalan Dominick Laddy Bernard Landry

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SRL-172: Phase II in HIV-positives with CD4>200

Study Design Assays Comment

Zambia1 5 doses (0, 2, 4 mo and 6, 12 mo) N: 22 SRL, 22 PLA BCG pos & BCG neg LPA to MV Responses greater in BCG pos Immunogenicity data limited to 5 doses Finland2 5 doses N: 19 SRL, 20 PLA BCG pos only LPA to MV LPA to MTB IFNg to MV Included 10 HIV-neg controls – had greater LPA responses

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  • 1. Waddell et al, Clin Infect Dis 2000; 30: S309-15
  • 2. Vuola et al, AIDS 2003; 17: 2351-2355
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Conclusions from Phase II trials

  • Zambia (BCG neg and BCG pos; all HIV pos)

– SRL 172 immunogenic in both BCG-positive and BCG-negative – Immunogenicity greater in BCG-positive

  • Finland (all BCG pos; HIV neg and HIV pos)

– SRL-172 immunogenic after 3 doses – Immunogenicity greater in HIV-negatives

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