TB was declared a global emergency by the World Health Organization (WHO). In 2017, the number of new cases of disease was reported to be 10 million. According to the Global TB Report of 2018, about 1.5 million people die from the disease each year. Thus, TB continues to be the leading cause of death by infectious disease worldwide. 

HIV infection, malnutrition, tobacco use, and diabetes are risk factors for TB. In children, TB most commonly occurs in those aged < 5 years. BCG vaccine is the only vaccine in use for prevention of TB disease, and is thought to also prevent TB infection, although this has not been confirmed. BCG is effective against severe disease including TB meningitis among others. However protection has not been consistent particularly for pulmonary TB in all age groups hence the development of additional vaccines that provide greater protection for all ages and populations. 

This is a proposed phase III study of a single dose vaccine administration with two groups of newborn infants receiving either VPM1002 or BCG SII (1:1 allocation). The study will enroll babies across sites in South Africa, Uganda, Tanzania, Kenya and Gabon, recruiting 6940 neonates. In Kenya, there are two sites; KEMRI CRDR Nairobi and KEMRI-CRDR Siaya, which will enrol approximately 1160 infants. There will be competitive enrolment across sites and its possible more than 1160 will be enrolled at the two Kenyan sites out of the sample size of 6940 infants in the global study. 8 SSA V2.1 13 Jan 2020 

Healthy male or female newborn infants will be randomly selected to receive either the standard vaccine, BCG, or the investigational vaccine, VPM1002 Approximately 10% of infants enrolled with be HIV-exposed, and assignment to VP1002 and BCG will be in a 1:1 ratio. A single dose of VPM1002 or BCG SII 0.05 ml will be administered, within 14 days of birth. The objective is to assess how well VPM1002 works in preventing Mtb infection, and how this will impact the TB disease frequency in this vulnerable group. Participants will be followed up for at least 12 months and a maximum of 36 months. There will be two sub-groups, which will enroll 300 (Immunogenicity cohort) and 500 (reactogenicity cohort) babies into either one of the groups, across the sites. 

There will be minimal risks to those taking part in the study. The risk of blood draws include minor bruising or bleeding at the puncture site, or some mild light headenedness. The study vaccine (VPM1002) has been tested in animals and humans. The human studies showed that a single vaccination of the study vaccine (VPM1002) was safe and did not cause many side effects. Some of the discomforts caused included pain and swelling at the injection area, weakness, fever and allergic reactions, all of which are easily manageable. 

There is no direct financial benefits to the participants or their guardians. Participants will however be direct beneficiaries of this intervention should efficacy be demonstrated. Participants will also directly benefit from frequent follow up in the study. In future, people at risk for developing TB may benefit from the information that is learned in this study. 

The study is expected to start in the Q2 or Q3 2020,therefore recruitment is expected to complete by Q2 or Q32022 and follow up will be complete approximately 12-36 months thereafter. Across all sites, recruitment is expected to be complete within 24 months of initiating the first site.

According to the Global TB report 2018, Tuberculosis (TB) is the leading cause of death globally, resulting in more deaths than HIV and malaria. Modeling studies estimate a significantly higher burden of disease in children than has been notified in the past in 22 high burden countries. (Peter J. Dodd, 2014). Children under five years are particularly affected. TB is also a top ten cause of death in children worldwide (Peter J. Dodd, 2017). A large proportion of deaths are due to untreated disease, this follows, as making a diagnosis of TB in young children is challenging. 

BCG is the only licensed vaccine against TB. It’s protective against leprosy and severe forms of disease however it’s efficacy against pulmonary TB is partial and inconsistent. A meta-analysis suggests it could also protect against infection. 

Vaccines are the most cost-effective tool in infectious disease control. Therefore a newer more efficacious TB vaccine is needed. In this study, a recombinant urease C-deficient listeriolysin expressing BCG vaccine strain (VPM1002) will be tested in a 1:1 ratio against conventional BCG (Serum Institute of India) for prevention of TB infection. Safety, immunogenicity and reactogenicity will also be compared. Infants will be followed up for 12-36 months. 

The results of this pivotal phase III trial could significantly impact the epidemic, by preventing new infections in infants who once infected tend to progress to disease faster. (Ben Marais, 2004), and thereafter suffer greater morbidity and mortality due to diagnostic difficulties. 

The study will be conducted in Kenya, Uganda, Gabon and South Africa, recruiting 6940 neonates. In Kenya, there are two sites; KEMRI CRDR Nairobi and KEMRI-CRDR Siaya, which will together enrol at least 1200 infants.