SAFETY AND EFFICACY OF MVA85A, A NEW TUBERCULOSIS VACCINE, IN INFANTS PREVIOUSLY VACCINATED WITH BCG: A RANDOMISED, PLACEBO-CONTROLLED PHASE 2B TRIAL Michele D Tameris*, Mark Hatherill*, Bernard S Landry, Thomas J Scriba, Margaret Ann Snowden, Stephen Lockhart, Jacqueline E Shea, J Bruce McClain, Gregory D Hussey, Willem A Hanekom, Hassan Mahomed†, Helen McShane†, and the MVA85A 020 Trial Study Team Lancet 2013; 381: 1021– 호흡기내과 R2 박재훈

INTRODUCTION MVA85A recombinant strain of modified Vaccinia Ankara virus expressing antigen 85A heterologous boost for BCG  improved BCG- induced protection against mycobacterial challenge induced antigen-specific Th1, Th17 cells  important in protection against Tb Assess safety, efficacy, immunogenicity of MVA85A in infants who were previously vaccinated with BCG

METHODS - STUDY DESIGN AND PARTICIPANTS Parallel-group, randomised, placebo-controlled, double-blind trial at the South African Tuberculosis Vaccine Initiative (SATVI) site in Cape Town, South Africa Incidence of Tb in South Africa(2011) 1%(3% in <24months) Healthy 4-6months infants who had received BCG within 7 days of birth pneumococcal vaccine HIV negative QuantiFERON-TB Gold negative no exposure to a patient with known Tb

METHODS Randomisation and masking one intradermal dose of MVA85A Candida skin test antigen as placebo Specific cohorts for specialised analyses study group 1 : at screening, on day 7, 28 after vaccination study group 2 : assessed immunogenicity in 3 subsequent cohorts of up to 60 participants with an ELISA study group 3 : ICS assay for PBMCs counts study group 4 : whole blood ICS assay study group 5 : remaining infants

METHODS Adverse events for 7, 28 days after vaccination incidence of solicited and unsolicited local (injection site) systemic adverse events At every 3 months cough, failure to thrive, weight loss, QFT or tuberculin skin test conversion, household Tb contact Chest radiography, tuberculin skin test, QFT, HIVELISA, 2 consecutive early morning gastric lavage samples, and 2 induced sputum

METHODS 3 Disease endpoint End point 1 (panel 1) Endpoint 2 (included all infants who met endpoint 1 criteria) marginally less stringent criteria End point 3 all participants placed on treatment for tuberculosis by a health professional The endpoint of infection with M tuberculosis conversion to a positive QFT test during follow-up M tuberculosis infection QFT during screening, 1 year after vaccination, and at the close-out visit

METHODS - STATISTICAL ANALYSES Efficacy outcome analysis based on the per- protocol population primary efficacy outcome - endpoint 1 assumed a cumulative Tb incidence of 3% after 18 months’ follow-up in the placebo group with an estimated 7 ・ 5% loss to follow-up  1392 participants Vaccine efficacy, months to initial Tb diagnosis after vaccination (no adjustment for multiplicity) secondary efficacy outcome - infection with M tuberculosis exploratory efficacy outcome - endpoints 2, 3

RESULTS

126(5%) 62(2%) 11(<1%) ~ (F/U end at ) 24.6 months

Local adverse event 628(45%) < 1251(89%) Sytemic adverse event 1059(76%) 1120(80%) Serious adverse event 258(15%) 257(18%) 24.6 months

136

DISCUSSION

MVA85A & CD4-positive T cells well tolerated and immunogenic with safety no significant efficacy against tuberculosis or M tuberculosis infection Infants group is not responsible for most transmission of M tuberculosis  MVA85A protect adults & have high efficacy against severe forms of Tb without preventing infection or mild forms

DISCUSSION BCG-specific Th1, 17 response not to correlate with risk of Tb in infants Ag85A-specific T cells were very low, undetectable In adults & adolescents Significantly higher Ag85A-specific responses Low frequencies of BCG-induced cells in infants restrict the immunogenicity, efficacy of MVA85A in this age group

DISCUSSION/CONCLUSION High incidence of respiratory and gastrointestinal serious adverse events burden of childhood morbidity in this community No disseminated Tb, deaths from Tb M tuberculosis infection  suitable endpoint MVA85A well tolerated, modestly immunogenic no significant protection against Tb infection