**5. On-going research targeting paediatric TB**

#### **5.1. New vaccine pipelines**

identified risk groups require special attention as part of the individual risk assessment

The optimal duration of MDR-TB treatment in children is not known. World Health Or‐ ganization guidelines recommend treatment until 18 months after the first negative cul‐ ture (24 months in XDR-TB). As children often have paucibacillary disease, documenting a culture conversion is usually difficult. Thus, the same duration as in adults would ap‐ ply. The duration of the intensive phase of treatment (when an injectable drug is given) should be at least 6 months. Surgical resection should be considered when the patient has localized lesions and has persistently positive smear or culture results inspite of ag‐

Approaches for prevention of TB include prevention of infection (through immunization) or of progression from latent infection to disease (chemoprophylaxis). Bacille Calmette-Guérin (BCG) vaccine, a live attenuated vaccine derived from Mycobacterium bovis that was developed in the 1920s, is administered to children at birth in many countries. WHO guidelines recommend administration of BCG soon after birth to all infants in countries with a high TB prevalence. Current WHO guidelines advise that all children below 5 years of age, who are in close contact with a sputum smear-positive index patient, should be actively traced, screened for TB, and provided preventive chemotherapy after

Although this is good policy, implementation is fraught with challenges, including difficulty in diagnosing latent TB in a highly BCG-vaccinated population, ruling out incipient active disease, and the lack of procedures for documentation and follow-up of contact screening and chemoprophylaxis in national programs. Because the majority of transmission in children below 3 years of age occurs in the household and they are also the group at highest risk of progression to disease after primary infection, this activity should be given higher priority in national infection-control programs. Moreover, active tracing and screening of household contacts at high risk would allow children with disease to receive a diagnosis earlier, thus

Furthermore, additional protection by revaccination with BCG has not been demonstrated (Rodrigues et al., 2005). To date, the efficacy of the BCG vaccination has not been determined in HIV infected individuals in whom the immune responses to BCG may be reduced, (Hesseli et al., 2007) although this is the subject of ongoing trials. Due to the risk of disseminated BCG disease which may rarely complicate use of this live vaccine in immunocompromised indi‐ viduals, BCG vaccination is no longer recommended in children known to be HIV-infected (Hesseling et al., 2007). In practice, this has had little impact in HIV-endemic countries, where the HIV-status of the baby is rarely established at birth, the usual time of BCG vaccination.

A large trial in southern India that included over 350,000 participants aged above 1 year concluded that BCG vaccine did not offer protection against the development of adult pulmonary TB (WHO, 2006). However, BCG vaccine has been shown to be protective against

(WHO, 2007; Salgado and Solovic et al., 2010).

412 Tuberculosis - Current Issues in Diagnosis and Management

gressive chemotherapy (Shah, 2012).

*4.5.9. BCG vaccination and HIV infection*

reducing complications.

active TB has been excluded (Marais et al., 2004).

The global commitment of the WHO and the Stop TB (WHO, 2005) campaign has spurred on the efforts of the international research community to develop a more effective anti-TB vaccine by the year 2015. In view of the proven efficacy of existing BCG vaccine in preventing disse‐ minated TB in children and reducing child mortality (Roth et al., 2006) two conceptually different strategies have been pursued: firstly, the development of 'priming vaccines', which, it is hoped, will replace BCG by providing better and longer protection; secondly, the design of 'booster vaccines' to boost pre-existing BCG-derived immunity. Novel vaccines currently under development all use a "booster-strategy" after priming with BCG in infancy (Doherty et al, 2007). As the current candidates are progressing through phase I and II trials, including studies in HIV-infected individuals and age-de-escalation, it is most likely that more than one vaccine will progress into phase III.

The most advanced vaccine candidate is MVA- 85A, currently in phase II under a prime-boost strategy with BCG. Four products are in phase I (72f, Hybrid 1, Aeras 402, rBCG-UreC-Hly), each stemming from PPPs. Many of the candidates are results from the EU FP6 projects, i.e. TBVAC and Muvapred, where valuable progress has been achieved. Several other candidates are still in the pre-clinical phase. For example, mutation of virulence genes produced a TB strain potentially conferring greater protection with fewer side effects than BCG. In addition, an improved, recombinant BCG vaccine with a higher efficacy and a better safety profile moving into phase I clinical trials is a possible prospect.

childhood tuberculosis especially in the endemic areas; 2) improving the understanding of the disease interactions with the immune system and re-evaluating the role of BCG and the new vaccine candidates in protecting children and adults against TB; 3) defining the diagnostic contribution of novel T-cell–based assays in endemic and non-endemic areas especially with regard to diagnosis of paediatric tuberculosis; 4) identifying new ways of diagnosing child‐ hood tuberculosis in HIV negative and in TB/HIV co-infection in children, particularly in resource-limited settings; 5) carrying out operational research aimed at improving the access of children in endemic areas to preventive therapy and treatment, using the existing DOTS/ DOTS Plus frameworks; 6) evaluating the efficacy of new short-course intermittent preventive chemotherapy regimens especially those aimed at childhood TB; 7) exploring shorter durations of treatment in immune-competent children with smear-negative disease; 8) defining the optimal treatment regimen and treatment duration in children with TB/HIV co-infection; 9) monitoring the impact of MDR and XDR tuberculosis on children and evaluating regimens for effective MDR/XDR disease prevention and treatment; 10) developing and evaluating new drugs that may shorten the treatment duration and/or assist with the treatment of MDR/XDR disease and emphasizing case finding and reporting as some of the strategies to combat the

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In the field of diagnosis, there is an urgent need to replace sputum microscopy the current gold standard test, with more sensitive tests that are applicable at point of care. Despite the fact that the technique can only pick up 60% of cases, it has been in use for over a hundred years. Furthermore, sputum culture is not suitable for extrapulmonary TB and for paediatric TB since children can not produce sputum. On the other hand, the newer immunological based tests such as IGRAs are not well suited for use in TB/HIV co-infection and in high burden TB areas, where they cannot be accurately used to distinguish active from latent TB. Since the majority of the infected people never actually develop the disease, there is need to have a diagnostic tool which is able to distinguish latent from active disease and help to identify healthy individuals from diseased ones. Improved diagnostics are critical to TB care and control.

The need for serious investment in the critical areas especially in new TB diagnostic tools, drug susceptibility testing, and development of new biomarkers to enable health providers detect TB disease activity and to determine follow up treatment outcomes cannot be over emphasised. The fact that a number of new diagnostic tools are in the pipeline, including culture-based tests to identify M. tuberculosis and those used to determine drug resistance based on molecular assays and immune response is good news. However, there is still need to ensure that the new tests can be availed world-wide and be used at the point-of-care even in resource-poor settings, where there may be limited technical expertise and the necessary equipment. [http://ec.euro‐

There are three major reasons that can be used to justify the need for new TB biomarkers : 1) a diagnostic test which is able to differentiate between healthy individuals with a latent TB

escalation of XDR-TB [http://ec.europa.eu/research/research-eu].

**6.3. Newer biomarkers for TB disease activity, cure and relapse**

**6.2. Need for more specific diagnostic tests**

pa.eu/research/research-eu]

New research is directed at the development of a multistage TB vaccine containing latency antigens, an attractive concept, which is actively being pursued (Andersen, 2007). Such a vaccine could be used as a booster vaccine with the goal of preventing new infections in those uninfected with MTB and to prevent reactivation in those with LTBI. Unfortunately, the lack of reliable correlates of protective immunity currently remains a major obstacle to predict vaccine efficacy in all TB vaccine trials for both adults and children.
