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

2. 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

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

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

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….

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

7. The BCG Atlas

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

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?

11. >50 candidate TB vaccines in pre-clinical development….

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

13. 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)

14. 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

15. 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.

16. MVA85A did not offer additional protection against TB disease….

17. 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

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

19. 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.

20. 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….

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?

22. 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

23. Interrupt of TB transmission Prevent TB among young adults

24. 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)

25. 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

26. 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)

27. 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

28. 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

29. 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

30. EuropeAID