TB038 is a clinical study to assess the non-specific effects of BCG vaccination and gain a better understanding of how the body's immune system reacts to BCG and in turn potentially prevents infection from other bacteria.

Since 1927, it has been observed that BCG-vaccinated neonates have lower all-cause mortality rates. This heterologous or non-specific effect within the first 6-12 months of life has been demonstrated in randomised and observational studies in low income countries with high childhood mortality rates. The most consistent effect is reduced neonatal mortality due to fewer cases of neonatal sepsis, respiratory infection and fever. The main limitation of these studies is the risk of confounding inherent in their cross sectional and observational designs. It is essential that we determine the cogency of this effect, as potential BCG replacement vaccines must be non-inferior to BCG in this regard.

There is a plausible rationale that BCG, a replicating mycobacterium, is capable of inducing non-specific innate immunity, which could induce protection against disease and death from non-mycobacterial infections early in life. For example, intravesical BCG is an effective treatment for bladder cancer, an effect presumed to be non-specific and innate. However, our understanding of the immunological mechanisms involved is incomplete. Data is needed from robust experiments to quantify any causal relationship between infant survival and BCG vaccination. Demonstrating an effect of recent BCG vaccination on the growth of common bacterial pathogens involved in neonatal sepsis, using whole blood in an in-vitro human model, would provide evidence to support a randomised controlled trial in infants in TB high burden countries and would impact on public health vaccination scheduling. In addition it would provide us with an in-vitro model by which to assess future BCG replacement vaccines.

Healthy BCG naïve adults in the UK have been selected for this study because of their low baseline level of anti-mycobacterial immunity and therefore reduced ability to suppress BCG growth. Whilst the target population for the heterologous effects of BCG vaccination is infants, the blood volume required in order to optimise the GIA would not be possible to collect from infants. Therefore by undertaking this work in healthy BCG naïve UK adults we can obtain the blood volumes required for this exploratory work in a population of individuals with a similar background mycobacterial exposure to infants in TB high burden, low income countries.

Volunteers in this study will receive BCG vaccination at the standard dose of 2-8x10^5 cfu. BCG SSI containing Mycobacterium bovis strain Danish 1331 is preferred as it is licensed in the UK for vaccination. However BCG SSI can frequently go into short supply globally with impact on UK supply. In the event of this occurring, BCG vaccine supplied by the Sii (Serum institute of India) will be used instead which contains Mycobacterium bovis BCG strain Moscow 361 I and is on the WHO list of prequalified vaccines. The same strain will be used for all volunteers.

Inclusion Criteria:

Volunteers must meet all of the following criteria to enter the study:

• Healthy adult aged 18-45 years
• BCG naïve
• Resident in or near Oxford (for CCTVM and John Warin Ward) or Birmingham (for NIHR WTCRF) for the duration of the study period
• No relevant findings in medical history or on physical examination
• Allow the Investigators to discuss the volunteer's medical history with their GP
• Use effective contraception for the duration of the study period (females only)
• Agreement to refrain from blood donation during the duration of the study and for a period of 3 months after their last visit
• Give written informed consent
• Allow the Investigator to register volunteer details with a confidential database to prevent concurrent entry into clinical trials or studies
• Able and willing (in the Investigator's opinion) to comply with all the study requirements

Exclusion Criteria:

Volunteers must meet none of the following criteria to enter the study:

• Laboratory evidence at screening of latent M. tb infection as indicated by a positive IGRA response
• Clinical, radiological, or laboratory evidence of current active TB disease
• Previous vaccination with BCG, or any candidate TB vaccine
• Within the last year had close household contact with an individual with smear positive pulmonary tuberculosis
• Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer (except BCC or CIS), cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse
• History of serious psychiatric condition
• Concurrent oral or systemic steroid medication or the concurrent use of other immunosuppressive agents
• Concurrent use of long term antibiotic therapy
• History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the BCG vaccine
• Any abnormality of screening blood or urine tests that is deemed to be clinically significant or that may compromise the safety of the volunteer in the study
• Positive HBsAg, HCV or HIV antibodies
• Female confirmed pregnant or intention to become pregnant during study period, or currently lactating
• Current involvement in another study or trial that involves regular blood tests or an investigational medicinal product
• Use of an investigational medicinal product or non-registered drug, live vaccine, or investigational medical device for four weeks prior to dosing with the study vaccine
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned challenge date
• Any other significant disease, disorder, or finding, which, in the opinion of the Investigator, may either put the volunteer at risk, or may influence the result of the study, or may affect the volunteer's ability to participate in the study