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Update on TB Vaccines Mark Hatherill South African TB Vaccine Initiative (SATVI) University of Cape Town 1

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Robert Kochs Therapeutic TB vaccine 1890: Purified Tuberculin Protein 1891: First negative reports of clinical trials Total 1769 patients More patients died during therapy than were cured Fewer that 20% of all patients improved substantially 50% showed no improvement at all

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3 1921: Bacille Calmette-Guerin (BCG) Albert Calmette (physician) and Camille Guerin (vet), Pasteur Institute, Lille, France Attenuated cow TB strain (M. bovis)

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Does BCG work? Trials and observational studies 0 - 81% protection Vaccine efficacy varies by latitude, age group, type of disease, among other things.. 4

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5 Does BCG work in children? Clinical trials in infants: 74% protection against TB disease (all forms) But the last infant trial was published half a century ago.

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6 BCG protects against severe disease in children 64% efficacy against TBM 78% efficacy against disseminated TB disease

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The BCG Atlas 7

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Does BCG work in adults? 8 Little evidence to suggests that BCG protects against PTB in adults who are the source of transmission

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10 We need a new TB vaccine strategy Safe + effective .in infants, children, and adults .and in HIV infected people What do we mean by protection against TB? -Primary infection? -Pauci-bacillary childhood disease? -Disseminated TBM / miliary disease / death? -Adult-type cavitatory pulmonary TB?

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>50 candidate TB vaccines in pre-clinical development.

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Since Entered Phase 1 ID93 MTBVAC Clinical Trials In South Africa

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14 candidate TB vaccines in clinical development [BCG] VPM-1002 MTBVAC MVA-Ag85A (MVA85A) Ad35-Ag85A, 85B, TB10.4 (Aeras-402) Mtb32,39 in ASO1E (M72) Ag85B,TB10.4 in IC31 (H4) ESAT-6,Ag85B in IC31 (H1) ESAT-6,Ag85B,Rv2660c in IC31 (H56) Rv2608, Rv3619, Rv3620, Rv1813 in GLA-SE (ID93 ) Birth 6,10,14 weeks Adolescence Adulthood PrimeBoost

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Infant TB vaccination Prime and boost strategy 14 BCG at birth Childhood TB Disease Exposure & Infection New vaccine Adult TB Disease Long-lasting protection against all forms of TB disease Pre-exposure Strategy

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The first infant TB vaccine efficacy trial since BCG. CBS News: Tuberculosis vaccine MVA85A fails to protect babies in new study SABC News: Key tuberculosis vaccine fails, more waiting in the wings Deutsche Welle: There is good news. And there is bad news.

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16 MVA85A did not offer additional protection against TB disease.

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MVA85A A402M72H1HyVac4H56 Dominant CD4 T cell subset IFN- +IL- 2+TNF+ No dominance IFN- +IL- 2+TNF+; IFN- alone IL-2+TNF+ IFN- IL- 2+TNF+; IL-2+TNF+ Th17 Co- expressed with Th1 NoneIL-17 aloneVery few CD8 T cells NonePotent IFN- +TNF+ SomeNone Whole blood ICS assay Hawkridge et al., 2008; Scriba et al., JID 2011; Abel et al., AJRCCM 2010; Day et al., AJRCCM 2013 New TB vaccines induce T cells with distinct functional patterns Viral vectored Subunit + Th1 adjuvants

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Verreck, et al. PlosOne 2009;4:e5264. Vordermeier, et al. Infect. Immun. 2009;77:3364. Preclinical development Animal models of MVA85A

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Classical Th1 cytokine responses after vaccination do not associate with risk of TB disease Many other T cell markers also investigated: none differed between cases and controls Ben Kagina, many others! *BCG given at birth. Infants followed for 2 years to assess protection; Whole blood incubation with BCG at 10 weeks of age for 12 hours. From 5,724 enrolled infants: TB cases (n=29) TB cases Community controls (n=55) Household controls (n=55)

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20 Homo sapiens and Mycobacterium tuberculosis have co-evolved Expect variation in MTB genes encoding antigens attempt to evade host immune system Since MTB interacts with humans through antigen-specific CD4+ or CD8+ T-cells Expect T cell epitopes to be the most diverse genes in the MTB genome. The spread of MTB lineages Out-of-and-back-to- Africa

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21 T cell epitopes are highly conserved in the MTB genome Suggests human T cell recognition offers some evolutionary benefit to the pathogen Human T cell response Establishment of latency Subsequent cavitation Transmission to later generations of susceptible hosts Could vaccine-induced immunity against highly conserved T cell epitopes perversely increase TB transmission long-term?

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Newborn TB vaccination BCG replacement strategy The Holy Grail 22 New vaccine at birth Childhood TB Disease Exposure & Infection Adult TB Disease Long-lasting protection against all forms of TB disease Pre-exposure Strategy VPM-1002 MTBVAC

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Interrupt of TB transmission Prevent TB among young adults

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Adult TB vaccination Prime and boost strategy 24 BCG at birthNew VaccineTB Disease Exposure & Infection Protection against PTB disease Post-exposure Strategy (MTB and NTM) Mtb32,39 in ASO1E ( M72 ) Ag85B,TB10.4 in IC31 ( H4 ) ESAT-6,Ag85B in IC31 ( H1 ) ESAT-6,Ag85B,Rv2660c in IC31 ( H56 ) Rv2608, Rv3619, Rv3620, Rv1813 in GLA-SE ( ID93 )

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Worcester, Western Cape (SATVI) Hassan Mahomed, many others. TST+ if >5mm. Evaluate new TB vaccines for prevention of infection (and disease) in adolescents QFT+ adolescents have 3-fold higher TB disease incidence than QFT- (640 per 100,000 person years) Mahomed et al, PLOS ONE 2011 Recent QFT+ converters have 8-fold higher TB disease incidence than persistent QFT- adolescents (1,460 per 100,000 person years) Machingaidze et al, AJRCCM 2012 >60% of adolescents are TB infected before they leave High School

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Trials to Test Prevention of MTB Infection in Adolescents 26 QFT - 6 monthly follow-up QFT+ Healthy, BCG-vaccinated, HIV uninfected adolescents Endpoint QFT+ Conversion (0.35 IU/mL) Endpoint QFT+ Conversion (0.35 IU/mL) Vaccine / Placebo QFT - Mtb32,39 in ASO1E ( M72 ) Ag85B,TB10.4 in IC31 ( H4 ) ESAT-6,Ag85B in IC31 ( H1 ) ESAT-6,Ag85B,Rv2660c in IC31 ( H56 ) Rv2608, Rv3619, Rv3620, Rv1813 in GLA-SE ( ID93 )

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Thinking Out-of-the-Box To understand mechanisms of vaccine-induced protection and demonstrate efficacy proof-of-concept.. Identify a target population with very high risk of incident TB Perform small, efficient Phase II trials Green Light vaccine candidates with an efficacy signal to expand into large Phase III trials 27

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28 TB TREATMENT FOLLOW-UP DIAGNOSIS CURE VACCINE / PLACEBO RECURRENT TB SERIAL SPUTUM SAFETY RELAPSE vs REINFECTION BCG vaccinated, HIV uninfected adults Smear and culture + pulmonary TB Trials to Test Prevention of Recurrent TB Disease Mtb32,39 in ASO1E ( M72 ) Ag85B,TB10.4 in IC31 ( H4 ) ESAT-6,Ag85B in IC31 ( H1 ) ESAT-6,Ag85B,Rv2660c in IC31 ( H56 ) Rv2608, Rv3619, Rv3620, Rv1813 in GLA-SE ( ID93 ) Risk of recurrent TB within 12 months almost 5% *Cape Town, South Africa *Standard-of-care treatment *Optimal adherence *Clinical trial conditions *Culture confirmed

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Take Home Messages Many new TB vaccine candidates in pre-clinical development Include live recombinant and subunit vaccines, targeted at prime and/or boost strategies Prevention of TB in adults critical to interrupt transmission Animal models problematic in guiding up-selection for clinical development Proof-of-concept trials in humans may detect efficacy signal to green light expansion to large Phase III trials 29

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