1. A Clinical Trial to Demonstrate the Safety and Efficacy of H56:IC31 for the Prevention of Tuberculosis Infection
TBVI Annual meeting, Les Diablerets 2018
Ann Ginsberg
Use this as a blank template for internal or shorter presentations – includes some basic stock slides and blank templates.

2. Key Challenges in TB Vaccine Development
Complicated pathogen and disease
No known correlate of protection
Not yet known if animal models are predictive of human TB/protection
Multiple vaccine candidates in clinical development
Licensure trials long and expensive
Severely underfunded

3. Novel Trial Designs to De-risk Clinical Candidates Earlier
Phase II: Proof of Biological Activity (‘PoC’)
PHASE III
Prevention of Infection
Prevention of Recurrence
PHASE I
PHASE IIa
PHASE IIb
+/or
Aim of novel trial designs is to facilitate more robust decision-making at earlier stage of development. Based on working in high risk populations, i.e. those at higher risk of infection and/or disease than the general population
Conduct Pre-POC and POC trials in high-risk populations
QFT+TST+ adults – eg, Vaccae ph 3, M72 Ph2b
Adolescents at high risk of infection – H4/BCG revacc Ph 2, DAR-901 Ph2b, H56 Ph 2
Recently cured TB patients – eg, VPM1002 POR, H56 POR
Household contacts
Healthcare workers
Use Phase 2 trials to establish “plausible biological effect”
Prevention of (established) Infection (POI)
8X risk
Prevention of Recurrence (POR)
4-5X risk
Reduces risk of later, larger and more costly Phase 2b prevention of disease trials, in the absence of an immune correlate of protection

4. *or acquired immune response without T cell priming or memory
Figure 1 The spectrum of TB — from Mycobacterium
tuberculosis infection to active (pulmonary) TB disease
Figure 1. The spectrum of tuberculosis – from M. tuberculosis infection to active (pulmonary) TB disease.
Although tuberculosis (TB) disease can be viewed as a dynamic continuum from M. tuberculosis infection to active infectious disease, patients are categorized as having either latent TB infection (LTBI) or active TB disease for simplicity in clinical and public health settings. Individuals can advance or reverse positions, depending on changes in the host immunity and comorbities. Exposure to M. tuberculosis can result in the elimination of the pathogen, either because of innate immune response or acquired T-cell immunity. Individuals who have eliminated the infection via innate immune responses, or with acquired immune response but without retaining immune memory, can have negative tuberculin skin test (TST) or interferon-gamma release assay (IGRA) results. Some individuals will eliminate the pathogen, but retain a strong memory T-cell response and will be positive on TST or IGRA. These individuals will not benefit from LTBI treatment. If the pathogen is not eliminated, bacteria persist in a quiescent or latent state that can be detected as positive TST or IGRA results; these tests elicit T cell responses to M. tuberculosis antigens. Patients with subclinical TB might not report symptoms, but will be culture-positive (but generally smear-negative because of the low bacillary load). Patients with active disease experience symptoms such as cough, fever and weight loss, and the diagnosis can be usually confirmed with smear, culture and molecular tests. Patients with active disease might sometimes be negative on TST or IGRA because of anergy induced by the disease itself or immune-suppression caused by comorbid conditions such as HIV or malnutrition.
*or acquired immune response without T cell priming or memory
Pai, M. et al. (2016) Tuberculosis
Nat. Rev. Dis. Primers doi: /nrdp

5. Prevention of sustained Infection (PoI) Trials
Looking for evidence of biologic impact to up/down select vaccine candidates for advanced development.
POI as a licensable indication questionable
Might prevention of infection only occur in the 90% of persons infected with Mtb who will never develop TB disease?
H4:IC31/BCG revaccination POI study completed. Results imminent.
Lessons learned about endpoints, trial design, etc. to be applied to H56 POI protocol

6. Prevention of Infection as a Proof of Concept Study
Reduce sample size by:
Study population: IGRA (-) adolescents/adults at high risk of infection
~8x the risk of TB disease in the same population
Reducing statistical power of the study
As this is POC, consider power less than 90%. A reasonably powered study would have power >70%.
Increased risk that you will fail to find a significant result, even if one does exist (i.e., false negative result)
Increasing alpha: Type 1 error rate of 10% (1-sided)
Increases chance of having a statistically significant result when one does not exist (i.e., false positive result)
Less likely to ‘miss’ a true signal

7. H56:IC31 POI Study Objectives
Evaluate safety, immunogenicity, and prevention of Mtb infection, (measured by IGRA conversion) of H56:IC31 in remotely BCG vaccinated adolescents
Develop supportive data for advancing H56:IC31 into a Prevention of Disease trial

8. H56:IC31 POI study design
D M M M M24

9. Key Challenges in TB Vaccine Development
Complicated pathogen and disease
No known correlate of protection
Not yet known if animal models are predictive of human TB/protection
Licensure trials long and expensive
Severely underfunded

10. H56:IC31 Statistical Considerations
Designed to distinguish an ESAT-6 free IGRA conversion rate reduction of 50% for H56:IC31 compared to placebo with power of 80% and a type 1 error rate of 10% (1-sided).
Assume primary Mtb infection (as estimated by ESAT-6 free IGRA conversion) endpoint rate = 4% per year
Events occurring in the first 84 days excluded
Total sample size = 1400 participants; expected to provide 56 primary ESAT-6 free IGRA conversion endpoints after two years of follow-up.

11. Timeline First subject first visit – Q3 2018
Last subject last visit – Q3 2021
Data available – Q3 2021

12. POI Trial Co-funders

13. POI Partners

15. Figure 3 Mycobacterium tuberculosis infection
Figure 3. M. tuberculosis infection. a | Infection begins when M. tuberculosis enters the lungs via inhalation (step 1), reaches the alveolar space and encounters the resident alveolar macrophages (step 2). If this first line of defence fails to eliminate the bacteria, M. tuberculosis invades the lung interstitial tissue, either by the bacteria directly infecting the alveolar epithelium (step 3) or the infected alveolar macrophages migrating to the parenchyma (step 4). Subsequently, either dendritic cells or inflammatory monocytes transport M. tuberculosis to pulmonary lymph nodes for T cells priming. This leads to recruitment of immune cells including T and B lymphocytes to the lung parenchyma, to form a granuloma (step 5). b | The bacteria replicate within the growing granuloma. If the bacterial load becomes too great, the granuloma will fail to contain the infection 75 and bacteria will disseminate to the local lymph nodes, and eventually to other organs, including the brain. At this phase, the bacteria can enter the blood stream or re-enter the respiratory tract to be released — the infected host is now infectious and symptomatic and is said to have active disease.
Pai, M. et al. (2016) Tuberculosis
Nat. Rev. Dis. Primers doi: /nrdp