Therapeutic TB vaccines Shortening Treatment for …...3 The case for a therapeutic TB vaccine: Social, economic and human burden of TB treatment Drug-susceptible (DS-) TB 6 month

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Therapeutic TB vaccinesShortening Treatment for (DS- and) DR-TB?

Mark Hatherill

South African Tuberculosis Vaccine Initiative (SATVI)University of Cape Town, South Africa

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1. The need for a therapeutic TB vaccine

2. ‘Pure Therapeutic’ vaccine vs ‘Prevention of Recurrence (POR) Therapeutic’ TB vaccine strategies

3. Therapeutic vaccine strategies for DS- vs DR-TB

4. Feasibility of a therapeutic TB vaccine strategy

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The case for a therapeutic TB vaccine: Social, economic and human burden of TB treatment

Drug-susceptible (DS-) TB 6 month regimen @ US$ 40 per person(2 months isoniazid, rifampicin, ethambutol and pyrazinamide intensive phase, followed by 4 months isoniazid, rifampicin continuation phase)

Drug-resistant (DR-) TBRifampicin-resistant TB (RR-TB) – treated similar MDR-TB Multidrug-resistant TB (MDR-TB) - resistant to at least isoniazid and rifampicin Extensively drug-resistant TB (XDR-TB) - also resistant to a fluoroquinolone and any injectable (amikacin/kanamycin/capreomycin).

Previously 18-20 month regimen @ US$ 2,000–5,000 per personWHO 2016 guidance for shortened regimen (4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E / 5 Mfx-Cfz-Z-E) for pulmonary MDR/RR-TB that is not resistant to second-line drugs 9-12 month regimen @ US$ 1,000 per person

Km=Kanamycin; Mfx=Moxifloxacin; Pto=Prothionamide; Cfz=Clofazimine; Z=Pyrazinamide; Hhigh-dose= high-dose Isoniazid; E=Ethambutol

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WHO 2016 ReportAverage TB treatment success rates

83% DS-TB

52% for MDR/RR-TB (28% for XDR-TB)

The case for a therapeutic TB vaccine

Modest success of DS- and DR-TB treatment worldwide

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What defines therapeutic success for a TB vaccine?

Non-relapsing microbiological cure

(with reversal of host pathology)

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Could a Therapeutic TB vaccine…

Improve rate of microbiological cure?Reduce time to microbiological cure?

Reduce rate of relapse?

…...for both DS- and DR-TB?

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TB TREATMENT PHASE POST TB TREATMENT PHASE

DIAGNOSIS CURE

Pure Therapeutic TB vaccineImprove rate of cureReduce time to cure

POR Therapeutic TB vaccineDecrease rate of recurrence (POR)

Timing….

End of Treatment (EOT) microbiological cure vs EOT Treatment Failure

TB disease-free survival vs TB Recurrence (Relapse/Reinfection)

Endpoints of both strategies are microbiological

Both strategies would allow treatment shortening (DS and DR TB)

Might be same or different vaccines

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Friedrich Lancet Resp Med 2013

DS-TBMonth 2 of treatment

85% Xpert positive 30% at EOT40% MGIT culture positive <5% at EOT

When should a therapeutic TB vaccine be given to improve rate of microbiological cure and/or reduce time to cure?

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TB TREATMENT POST TB TREATMENT

DIAGNOSIS CURE

When should a pure therapeutic vaccine be given?

Options:At diagnosis / treatment startAt end of intensive treatment phaseAt conversion to negative sputum smearSome combination of the above

Two primary considerations:Safety – risk reactogenicity, theoretical consideration of Koch phenomenonMaximal safety risk early in treatment phase?

vsFor immune response to contribute to increasing rate of cure, maximal potential for impact early in treatment phase?

How early is too early?How late is too late?

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Observed PET–CT imaging consistent with active disease plus M.tb mRNA in sputum of HIV uninfected PTB patients after completion of standard 6-month treatment

34% patients at EOT had new or more intense PET-CT lesions

In M6 sputum, at least one MTB mRNA target was detected in 39% of patients22 (37%) from the cured outcome group

Is it feasible to expect a therapeutic TB vaccine to achieve greater/more rapid reduction in M.tbbacterial load during Rx?

Catalysis data suggest apparently curative TB therapy does not achieve sterilizing cure…

Pure Therapeutic TB vaccine

Month 1

Gerhard Walzl, Dan Zak, Tom

Scriba, others

Month 66

ge

ne

sc

ore

TB

diagnosis

7 28 168 Controls

Days on treatment

A 6-gene transcriptomic signature of TB risk tracks TB treatment response

SUN Immunology Research Group

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Baseline bacterial load (Xpert Ct) andtime to culture conversion (HR 1.06, p = 0.0023) likelihood of treatment failure (AUC = 72.8%)

The 3 top predictors of poor long-term outcome, by rank:

Pyrazinamide AUC ≤ 363 mg·h/L Rifampin AUC ≤ 13 mg·h/LIsoniazid AUC ≤ 52 mg·h/L

Risk factors for poor treatment outcomePharmacokinetics TB drugs, baseline bacterial load, baseline CXR cavitation, persistence cultured M.tb at 2 months

Benatar et al, Lancet 2002

Independent predictors of TB treatment relapsePositive sputum culture at 2 months (HR 2.8)Cavitation on baseline CXR (HR 3.0)

2-month culture conversion relapse

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Human evidence to support a therapeutic TB vaccination strategy - mixed

Inactivated M. vaccae safe and well-tolerated in HIV co-infected adults with pulmonary TBNo benefit of single dose regimen

Multiple dose inactivated M. vaccae given to newly diagnosed TB patients associated with improved clinical outcomes and early reduction in sputum bacillary load

Meta-analysis of 25 studies including 2,281 Chinese patients with MDR-TB showed multiple dose inactivated M vaccaeassociated with faster sputum smear conversion and resolution of radiological lesions

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Heat killed M vaccae

54 efficacy trials (RCT or CCT)

48 China

6 elsewhere

Improved time to sputum smear

negative conversion HR 1.07

In elderly TB patients HR 1.22

No significant effect on time to culture

conversion

Potential for live mycobacterial vaccines as therapeutic vaccines?

Evidence from prophylactic BCG trials in humans:BCG efficacy maximal in MTB uninfected infants/children (RR for TB 0.26) compared to MTB infected/uninfected adults (RR for TB 0.88)

Masking by pre-existing immunity?Limited BCG replication?

Implication that therapeutic indication for TB patients would present a high bar for live mycobacterial vaccines

Meta-analysis, Mangtani CID 2014

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Therapeutic TB vaccine for DS- and DR-TB?

No evidence that enzymatic mechanisms underlying drug-resistance (catalase, reductase, polymerase, transferase, gyrase, and ribosomal proteins) would affect immune response against current TB vaccine antigens

Schrager Trans R Soc Trop Med Hyg 2016

Aim to lower risk of relapse, and shorten duration of treatment

in both DR- and DS-TB

Likely that non-relapsing microbiological cure more difficult to achieve in setting of sub-optimal drug therapy (DR-TB)

Greater potential impact in DR-TB?

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Participants with newly diagnosed smear positive DS- and MDR-TB

Bedaquiline, Pretomanid, Pyrazinamide and Moxifloxacin containing regimens

B(200mg daily) - Pa - Z

Rifafour

B(200mg daily) - Pa - Z - M

B(registered dosing) - Pa - Z

Z=pyrazinamide (1500mg daily), M = moxifloxacin 400mg daily, Pa = PA-824 200mg daily , J(registered dosing) =

bedaquilline 400mg for 14 days then 200mg three times a week, J(200mg daily) = bedaquiline 200mg daily

60 per DS groupUp to 60 MDR

DS

Randomize 8 Weeks

MDR

Survival Follow-up Visits at 6, 12, 18 and 24 Months

What the future holds….? NC-005

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Overnight Spot Overnight Spot

B(loading)PaZ 67% 84%* 89% 88%*

B(200mg)PaZ 75%* 79% 84% 92%*

BPaZM (MDR) Z-sensitive

96%* 89%* 100%* 97%*

HRZE control 51% 63% 86% 79%

Liquid Culture

Solid Culture

NC-005% Patients Culture Negative at 2 Months

*Statistically significant vs HRZE

Need demonstration of safety, longer follow-up for non-relapsing cure, bigger trials

Future DS- and MDR-TB regimen <<6 months?

Major advances in therapeutics would limit potential for additional impact by a therapeutic TB vaccine

Patients with XDR TB who failed/intolerant to MDR TB treatment

What the future holds….? Nix-TB Trial

Pretomanid 200 mg

Bedaquiline 200 mg tiw after 2 week load

Linezolid 1200 mg qd**

6 months of treatment

Additional 3 months if sputum culture positive at 4 months

Follow up for relapse-free cure over 24 months

**Just amended from 600 mg bid strategy

33 participants had stable culture negative conversion by 4 months3 participants died with positive culture7 participants ongoing (last post-baseline culture positive)

XDR-TB regimen <6 months?

Francesca Conradie PI

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TB TREATMENT POST TB TREATMENT

DIAGNOSIS CURE

How frequent is recurrent TB disease?

When does recurrent TB disease occur?

When should a POR Therapeutic TB vaccine be given to reduce TB recurrence?

POR Therapeutic Vaccine Strategy

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91% of all relapse TB occurs within 12 months of end of Rx

Systematic review 15 clinical trialsAverage relapse TB rate 8%

Standard-of-Care Control Arm with DOTOFLOTUB 2.4% failure, 7.1% relapseREMOX 1% failure, 2% relapseRIFAQUIN 1% failure, 3,2% relapse

Standard-of-care Rx DS-TBRate of recurrent TB (SA) estimated 5% Approximately 5 x community incidence

Recurrent TB = 10.4% over 2 years (Hesseling IJTLD 2010)

South African goldminers 5.9% (Charalambous IJTLD 2008)

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TB TREATMENT POST TB TREATMENT

DIAGNOSIS CURE

When should a POR Therapeutic TB vaccine be given to reduce TB recurrence?

How early is too early?How late is too late?

Options:EOT after microbiological cureDuring treatment courseSome combination of the above

?

Convergence of POR strategy with pure therapeutic TB vaccine strategy

Administer after/during treatment - if safeClinical trials

DS-TB after cureXDR-TB during treatment?

Benatar et al, Lancet 2002Independent predictors of relapse

Positive sputum culture at 2 months (HR 2.8)Cavitation on baseline chest x-ray (HR 3.0)

A PHASE 2a, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CLINICAL TRIAL TO EVALUATE THE SAFETY AND IMMUNOGENICITY OF THE ID93 + GLA-SE VACCINE IN HIV UNINFECTED ADULT TB PATIENTS AFTER TREATMENT COMPLETION

Recently completed

60 HIV uninfected TB patients in South Africa

Enrolled at EOT if microbiological cure @ M4 and M5

<75% TB patients complete 180 doses within 6 months

Screening data (SATVI)

Xpert+ 43% @ M4; 39% @ M5; 18% @ M6

MGIT culture+ 2% @ M4; 0 @ M5; 4% @ M6

1 case of recurrent TB

No safety or site reactivity concerns at any dose group

Interim immunogenicity data on 1st cohort promising

CD4 T cell response ≈ QFT+ individuals

Antibody responses higher than QFT+ individuals

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A Phase I Study of Safety & Immunogenicity of AERAS-456 in HIV-Negative Adults Treated for Drug-susceptible Pulmonary TB

• 22 participants (16 H56:IC31:6 placebo)

• 5 µg H56: 500nmol IC31 vs placebo

• 2 doses administered 2 months apart

• No safety issues noted

• No TB recurrences

• Immunogenicity data

– H56 CD4 T cell responses were observed in the active treatment group

– Responses measured by the IFN-γ ELISpot and IgG antibody ELISA assays were generally consistent with the ICS assay results

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Van Zyl-Smit, AJRCCM 2017

Phase II randomized, placebo-controlled, double-blinded dose-escalation study in HIV-negative South African adults (n=72) with active pulmonary tuberculosis

(on Rx for 1- 4 months; or treated at least 12 months prior and considered cured)

No adverse changes in acute or Koch phenomenon-like reactions; lung function; or CXR abnormalities that were related to vaccine

Injection site reactions mild or moderate

AERAS-402 induced robust CD8+ and moderate CD4+ T cell responses, mainly to Ag85B

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Safety and Immunogenicity of Adenovirus 35 TB Vaccine Candidate in Adults with Active or Previous TB: a Randomized Trial

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TB TREATMENT POST TB TREATMENT

DIAGNOSIS CURE

POR Therapeutic TB vaccine strategy could test proof-of-concept efficacy of prophylactic vaccines against relapse and reinfection

Experimental Medicine designOperational efficiency5 x community TB incidence

Enrol @ start 6 month standard of care RxRandomize and vaccinate @ EOT cure

Follow 12 months for recurrent TBComparison baseline M.tb isolate with recurrent strain(reactivation vs reinfection)

*Not powered to differentiate

If assume 4% rate recurrent TB80% power to detect 60% VE POR

900 participants*

Take Home Messages

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Major need for a therapeutic TB vaccine

Convergence ofDS- and DR-TB therapeuticsPure Therapeutic and POR strategies

Some evidence to support either approachGreater potential for impact with POR strategy?

Both strategies might allow treatment shortening DS- and DR-TBGreater potential for impact in DR-TB?

281921 Model T Ford

In 4 years, our only licensed TB vaccine,

BCG, will be 100 years old…

EuropeAID

Acknowledgements