Therapeutic TB vaccines Shortening Treatment for (DS- and) DR-TB? Mark Hatherill South African Tuberculosis Vaccine Initiative (SATVI) University of Cape Town, South Africa 1
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 2
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-) TB Rifampicin-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 person WHO 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 3
The case for a therapeutic TB vaccine Modest success of DS- and DR-TB treatment worldwide WHO 2016 Report Average TB treatment success rates 83% DS-TB 52% for MDR/RR-TB (28% for XDR-TB) 4
What defines therapeutic success for a TB vaccine? Non-relapsing microbiological cure (with reversal of host pathology) 5
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? 6
Pure Therapeutic TB vaccine Improve rate of cure Reduce time to cure POR Therapeutic TB vaccine Decrease rate of recurrence (POR) Endpoints of both strategies are microbiological Both strategies would allow treatment shortening (DS and DR TB) DIAGNOSIS CURE Might be same or different vaccines TB TREATMENT PHASE POST TB TREATMENT PHASE Timing. End of Treatment (EOT) microbiological cure vs EOT Treatment Failure TB disease-free survival vs TB Recurrence (Relapse/Reinfection) 7
When should a therapeutic TB vaccine be given to improve rate of microbiological cure and/or reduce time to cure? DS-TB Month 2 of treatment 85% Xpert positive 30% at EOT 40% MGIT culture positive <5% at EOT Friedrich Lancet Resp Med 2013 8
When should a pure therapeutic vaccine be given? DIAGNOSIS CURE Options: At diagnosis / treatment start At end of intensive treatment phase At conversion to negative sputum smear Some combination of the above TB TREATMENT How early is too early? How late is too late? POST TB TREATMENT Two primary considerations: Safety risk reactogenicity, theoretical consideration of Koch phenomenon Maximal safety risk early in treatment phase? vs For immune response to contribute to increasing rate of cure, maximal potential for impact early in treatment phase? 9
Pure Therapeutic TB vaccine Is it feasible to expect a therapeutic TB vaccine to achieve greater/more rapid reduction in M.tb bacterial load during Rx? Catalysis data suggest apparently curative TB therapy does not achieve sterilizing cure 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 patients 22 (37%) from the cured outcome group 10
6 gene score A 6-gene transcriptomic signature of TB risk tracks TB treatment response Month 1 Month 6 TB diagnosis 7 28 168 Controls Days on treatment Gerhard Walzl, Dan Zak, Tom Scriba, others SUN Immunology Research Group
Risk factors for poor treatment outcome Pharmacokinetics TB drugs, baseline bacterial load, baseline CXR cavitation, persistence cultured M.tb at 2 months Benatar et al, Lancet 2002 The 3 top predictors of poor long-term outcome, by rank: Pyrazinamide AUC 363 mg h/l Rifampin AUC 13 mg h/l Isoniazid AUC 52 mg h/l Independent predictors of TB treatment relapse Positive sputum culture at 2 months (HR 2.8) Cavitation on baseline CXR (HR 3.0) Baseline bacterial load (Xpert Ct) and time to culture conversion (HR 1.06, p = 0.0023) likelihood of treatment failure (AUC = 72.8%) 2-month culture conversion relapse 12
Human evidence to support a therapeutic TB vaccination strategy - mixed Inactivated M. vaccae safe and welltolerated in HIV co-infected adults with pulmonary TB No 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 vaccae associated with faster sputum smear conversion and resolution of radiological lesions 13
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 14
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 15
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? 16
What the future holds.? NC-005 Participants with newly diagnosed smear positive DS- and MDR-TB Bedaquiline, Pretomanid, Pyrazinamide and Moxifloxacin containing regimens B (registered dosing) - Pa - Z DS Randomize B (200mg daily) - Pa - Z Rifafour 8 Weeks Survival Follow-up Visits at 6, 12, 18 and 24 Months MDR B (200mg daily) - Pa - Z - M 60 per DS group Up to 60 MDR 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 17
Overnight Spot Overnight Spot B(loading)PaZ 67% 84%* 89% 88%* B(200mg)PaZ 75%* 79% 84% 92%* BPaZM (MDR) Z-sensitive NC-005 % Patients Culture Negative at 2 Months Liquid Culture Solid Culture 96%* 89%* 100%* 97%* HRZE control 51% 63% 86% 79% *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 18
What the future holds.? Nix-TB Trial Francesca Conradie PI Patients with XDR TB who failed/intolerant to MDR TB treatment **Just amended from 600 mg bid strategy Pretomanid 200 mg Bedaquiline 200 mg tiw after 2 week load Linezolid 1200 mg qd** Follow up for relapse-free cure over 24 months 6 months of treatment Additional 3 months if sputum culture positive at 4 months 33 participants had stable culture negative conversion by 4 months 3 participants died with positive culture 7 participants ongoing (last post-baseline culture positive) XDR-TB regimen <6 months?
POR Therapeutic Vaccine Strategy DIAGNOSIS CURE TB TREATMENT POST TB TREATMENT 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? 20
Standard-of-care Rx DS-TB Rate of recurrent TB (SA) estimated 5% Approximately 5 x community incidence Systematic review 15 clinical trials Average relapse TB rate 8% Recurrent TB = 10.4% over 2 years (Hesseling IJTLD 2010) South African goldminers 5.9% (Charalambous IJTLD 2008) Standard-of-Care Control Arm with DOT OFLOTUB 2.4% failure, 7.1% relapse REMOX 1% failure, 2% relapse RIFAQUIN 1% failure, 3,2% relapse 91% of all relapse TB occurs within 12 months of end of Rx 21
When should a POR Therapeutic TB vaccine be given to reduce TB recurrence?? Benatar et al, Lancet 2002 Independent predictors of relapse Positive sputum culture at 2 months (HR 2.8) Cavitation on baseline chest x-ray (HR 3.0) DIAGNOSIS CURE TB TREATMENT POST TB TREATMENT How early is too early? How late is too late? Options: EOT after microbiological cure During treatment course Some combination of the above Convergence of POR strategy with pure therapeutic TB vaccine strategy Administer after/during treatment - if safe Clinical trials DS-TB after cure XDR-TB during treatment? 22
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 1 st cohort promising CD4 T cell response QFT+ individuals Antibody responses higher than QFT+ individuals 23
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 24
Safety and Immunogenicity of Adenovirus 35 TB Vaccine Candidate in Adults with Active or Previous TB: a Randomized Trial Van Zyl-Smit, AJRCCM 2017 Phase II randomized, placebo-controlled, double-blinded dose-escalation study in HIVnegative 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 25
POR Therapeutic TB vaccine strategy could test proof-of-concept efficacy of prophylactic vaccines against relapse and reinfection Experimental Medicine design Operational efficiency 5 x community TB incidence If assume 4% rate recurrent TB 80% power to detect 60% VE POR 900 participants* DIAGNOSIS CURE TB TREATMENT POST TB TREATMENT Enrol @ start 6 month standard of care Rx Randomize and vaccinate @ EOT cure Follow 12 months for recurrent TB Comparison baseline M.tb isolate with recurrent strain (reactivation vs reinfection) *Not powered to differentiate 26
Take Home Messages Major need for a therapeutic TB vaccine Convergence of DS- and DR-TB therapeutics Pure Therapeutic and POR strategies Some evidence to support either approach Greater potential for impact with POR strategy? Both strategies might allow treatment shortening DS- and DR-TB Greater potential for impact in DR-TB? 27
EuropeAID Acknowledgements In 4 years, our only licensed TB vaccine, BCG, will be 100 years old 1921 Model T Ford 28