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

Robert Koch’s “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

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

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

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….

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

The BCG Atlas

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

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?

>50 candidate TB vaccines in pre-clinical development….

         Since Entered Phase 1 ID93 MTBVAC  Clinical Trials In South Africa

14 candidate TB vaccines in clinical development Prime Boost Boost Birth 6,10,14 weeks Adolescence Adulthood [BCG] VPM-1002 MTBVAC HOW DO WE MAKE THESE VACCINES? BCG - protection Heterologous prime boost 12 Our site, ths SA TB vaccine initiative 4, 3 more Newer vaccines – focused also on latent infection IC31 is a 2-component adjuvant comprised of an oligodeoxynucleotide ODN1a and a polypeptide KLK. The first component, ODN1a contains alternating sequences of the unusual bases inosine and cytidine: oligo-d(IC)13. This motif is similar to CpG motifs that act as T-cell adjuvants (Kochenderfer, 2006). The second component KLK is a synthetic cationic antimicrobial peptide composed of lysine (K) and leucine (L) in the sequence KLKLLLLLKLK. KLK is thought to enhance peptide specific immune responses by increasing uptake of the complexed antigen into antigen presenting cells. The negatively charged ODN1a and the positively charged KLK complex electrostatically. When IC31 is combined with H4, the adjuvant further complexes with the antigen to form H56:IC31 (AERAS-456). Monophosphoryl Lipid A (MPL, RIBI ImmunoChem), an adjuvant derived from lipopolysaccharide. The QS21 adjuvant is a nontoxic saponin derived from the soapbark tree Quillaja saponaria6. MPL is ASO TLR4 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)

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

The first infant TB vaccine efficacy trial since BCG…. SAFETY/HARM/INFECTION 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.

MVA85A did not offer additional protection against TB disease….

New TB vaccines induce T cells with distinct functional patterns MVA85A A402 M72 H1 HyVac4 H56 Dominant CD4 T cell subset IFN-γ+IL-2+TNF+ No dominance IFN-γ+IL-2+TNF+; IFN-γ alone IL-2+TNF+ IFN-γ+IL-2+TNF+; Th17 Co-expressed with Th1 None IL-17 alone Very few CD8 T cells Potent IFN-γ+TNF+ Some Remarkable Correlates of protection One such study Viral vectored Subunit + Th1 adjuvants Whole blood ICS assay Hawkridge et al., 2008; Scriba et al., JID 2011; Abel et al., AJRCCM 2010; Day et al., AJRCCM 2013

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

Classical Th1 cytokine responses after vaccination do not associate with risk of TB disease From 5,724 enrolled infants: TB cases (n=29) TB cases Community controls (n=55) Household controls (n=55) Here comes the big shocker!! RESPONSE MEASURED AS PRIMARY ENDPOINT IN MOST TRIALS 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.

The spread of MTB lineages Out-of-and-back-to- Africa 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….

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?

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

Interrupt of TB transmission Prevent TB among young adults

Adult TB vaccination Prime and boost strategy 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) Adult TB vaccination Prime and boost strategy BCG at birth New Vaccine TB Disease Protection against PTB disease Exposure & Infection Exposure & Infection Post-exposure Strategy (MTB and NTM)

QFT+ adolescents have 3-fold higher TB disease incidence than QFT- >60% of adolescents are TB infected before they leave High School 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 Worcester, Western Cape (SATVI) Hassan Mahomed, many others. TST+ if >5mm. Evaluate new TB vaccines for prevention of infection (and disease) in adolescents

Trials to Test Prevention of MTB Infection in Adolescents 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) Healthy, BCG-vaccinated, HIV uninfected adolescents Vaccine / Placebo QFT - QFT - 6 monthly follow-up QFT+ Endpoint QFT+ Conversion (0.35 IU/mL)

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

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) BCG vaccinated, HIV uninfected adults Smear and culture + pulmonary TB DIAGNOSIS SERIAL SPUTUM CURE SAFETY SERIAL SPUTUM RECURRENT TB TB TREATMENT FOLLOW-UP VACCINE / PLACEBO Risk of recurrent TB within 12 months almost 5% *Cape Town, South Africa *Standard-of-care treatment *Optimal adherence *Clinical trial conditions *Culture confirmed RELAPSE vs REINFECTION

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

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