BACKGROUND: The Bacille Calmette-Guérin (BCG) tuberculosis (TB) vaccine provides incomplete protection, necessitating development of an effective vaccine against TB disease. The Mtb72F/AS02 candidate vaccine was previously shown to be clinically well tolerated and immunogenic in Purified Protein Derivative (PPD)-negative adults. To improve the stability of Mtb72F, a point mutation was introduced into a putative serine protease site to give the final M72 construct. AS01 is an Adjuvant System that can potentially improve both humoral and cellular immune responses compared to the AS02 Adjuvant System or unadjuvanted vaccine. This study evaluated the safety and immunogenicity in Mtb-naïve adults of vaccines containing 40 μg of the M72 antigen with AS02 or AS01 and compared the results withMtb72F/AS02 vaccine (40 μg dose), M72 in saline (40 μg dose) and AS01 alone. METHODS: In this Phase I/II observer-blind controlled trial, 110 participants were randomized (4:4:1:1:1) to receive M72/AS01, M72/AS02, Mtb72F/AS02, M72/saline or AS01, following a 0, 1-month schedule. Subjects receiving the adjuvanted M72 vaccines were followed up until 3 years post vaccination. Evaluation of the immune response and safety/reactogenicity was performed. RESULTS: For all vaccines, solicited adverse events (AEs) were predominantly mild to moderate and transient. No vaccine-related serious AEs occurred and no subject withdrew due to an AE. Immune responses induced by Mtb72F and M72 antigens combined with AS02 were similar. M72/AS01 and M72/AS02 induced robust polyfunctional M72-specific CD4(+) T cell and antibody responses persisting at 3 years, with the highest CD4(+) T cell responses found with M72/AS01. CONCLUSION: This first clinical study with M72/AS01 and M72/AS02 showed that both vaccines were clinically well tolerated and induced high magnitude and persistent cell-mediated and humoral immune responses. The Mtb72F/AS02 and M72/AS02 vaccines were comparably immunogenic with significantly higher immune responses compared to the M72/saline control. Of the formulations tested, M72/AS01 demonstrated significantly higher vaccine specific Th1 CD4(+) T cell responses supporting its further clinical evaluation.
RCT Entities:
BACKGROUND: The Bacille Calmette-Guérin (BCG) tuberculosis (TB) vaccine provides incomplete protection, necessitating development of an effective vaccine against TB disease. The Mtb72F/AS02 candidate vaccine was previously shown to be clinically well tolerated and immunogenic in Purified Protein Derivative (PPD)-negative adults. To improve the stability of Mtb72F, a point mutation was introduced into a putative serine protease site to give the final M72 construct. AS01 is an Adjuvant System that can potentially improve both humoral and cellular immune responses compared to the AS02 Adjuvant System or unadjuvanted vaccine. This study evaluated the safety and immunogenicity in Mtb-naïve adults of vaccines containing 40 μg of the M72 antigen with AS02 or AS01 and compared the results with Mtb72F/AS02 vaccine (40 μg dose), M72 in saline (40 μg dose) and AS01 alone. METHODS: In this Phase I/II observer-blind controlled trial, 110 participants were randomized (4:4:1:1:1) to receive M72/AS01, M72/AS02, Mtb72F/AS02, M72/saline or AS01, following a 0, 1-month schedule. Subjects receiving the adjuvanted M72 vaccines were followed up until 3 years post vaccination. Evaluation of the immune response and safety/reactogenicity was performed. RESULTS: For all vaccines, solicited adverse events (AEs) were predominantly mild to moderate and transient. No vaccine-related serious AEs occurred and no subject withdrew due to an AE. Immune responses induced by Mtb72F and M72 antigens combined with AS02 were similar. M72/AS01 and M72/AS02 induced robust polyfunctional M72-specific CD4(+) T cell and antibody responses persisting at 3 years, with the highest CD4(+) T cell responses found with M72/AS01. CONCLUSION: This first clinical study with M72/AS01 and M72/AS02 showed that both vaccines were clinically well tolerated and induced high magnitude and persistent cell-mediated and humoral immune responses. The Mtb72F/AS02 and M72/AS02 vaccines were comparably immunogenic with significantly higher immune responses compared to the M72/saline control. Of the formulations tested, M72/AS01 demonstrated significantly higher vaccine specific Th1 CD4(+) T cell responses supporting its further clinical evaluation.
Authors: Chelsea Carpenter; John Sidney; Ravi Kolla; Kaustuv Nayak; Helena Tomiyama; Claudia Tomiyama; Oscar A Padilla; Virginie Rozot; Syed F Ahamed; Carlos Ponte; Valeria Rolla; Paulo R Antas; Anmol Chandele; John Kenneth; Seetha Laxmi; Edward Makgotlho; Valentina Vanini; Giuseppe Ippolito; Alexandra S Kazanova; Alexander V Panteleev; Willem Hanekom; Harriet Mayanja-Kizza; David Lewinsohn; Mayuko Saito; M Juliana McElrath; W Henry Boom; Delia Goletti; Robert Gilman; Irina V Lyadova; Thomas J Scriba; Esper G Kallas; Kaja Murali-Krishna; Alessandro Sette; Cecilia S Lindestam Arlehamn Journal: Tuberculosis (Edinb) Date: 2015-08-01 Impact factor: 3.131
Authors: Shabaana A Khader; Maziar Divangahi; Willem Hanekom; Philip C Hill; Markus Maeurer; Karen W Makar; Katrin D Mayer-Barber; Musa M Mhlanga; Elisa Nemes; Larry S Schlesinger; Reinout van Crevel; Raman (Krishna) Vankayalapati; Ramnik J Xavier; Mihai G Netea Journal: J Clin Invest Date: 2019-09-03 Impact factor: 14.808
Authors: M R Neeland; W Shi; C Collignon; E N T Meeusen; A M Didierlaurent; M J de Veer Journal: Clin Exp Immunol Date: 2018-01-23 Impact factor: 4.330
Authors: Mark T Orr; Christopher B Fox; Susan L Baldwin; Sandra J Sivananthan; Elyse Lucas; Susan Lin; Tony Phan; James J Moon; Thomas S Vedvick; Steven G Reed; Rhea N Coler Journal: J Control Release Date: 2013-08-09 Impact factor: 9.776