TB is the world’s 2 nd most deadly infectious disease, after AIDS
Although TB is curable, treatment is lengthy and costly– often spanning 6 months to a year – and is not easily accessible to all who need it .
22 high-burden countries: 80% of all new TB cases 0 500 1000 1500 2000 India China Indonesia Bangladesh Nigeria Pakistan Philippines South Africa Russian Federation Ethiopia DR Congo Viet Nam Kenya UR Tanzania Brazil Thailand Myanmar Zimbabwe Uganda Cambodia Afghanistan Mozambique Estimated new TB cases ('000s)
BCG is the most widely used vaccine in the world - and not highly effective
BCH may provide ~70% protection against severe TB in young children, so it will continue to be used until something better is available
BCG provides little protection against childhood pulmonary TB and it is questionable if any protection later in life when it is given to infants
Variable Efficacy of BCG vs. Pulmonary TB British School Children British School Children British School Children S. India (Madanapalle) USA (Georgia & Alabama) S. India (Chingleput) USA (Georgia Children) USA (Chicago Infants) Puerto Rico (Gen. Pop.) N. American Indians Brazil (Sao Paolo) Argentina (Buenos Aires) Brazil (Belo Horizonte) Cameroon (Yaounde) Canada (Manitoba Indians) Surinam (Rangoon) Sri Lanka (Colombo) Colombia (Cali) Argentina (Santa Fe) Togo (Lome) Thailand Indonesia (Jakarta) Vaccine Efficacy (%) -900 -500 -300 -100 0 20 40 60 70 80 90 Population
Mtb antigens delivered by RNA capsid system to boost rBCG Pre-clinical PhI Q2-07 Aeras AERAS X05 Recombinant Mtb antigens 85B and 10.4 combined with adjuvant IC31 to boost BCG Pre-clinical Phase I Q2 -07 SSI/Intercell Aeras HyVac 4 (AERAS 404) Replication deficient adenovirus35 which expresses antigens 85A, 85B, and 10.4 to boost rBCG Pre-clinical Phase I Q3-06) Crucell/Aeras AERAS 402 Fusion molecule comprised of a protein from the PPE family (Rv1196), combined with an inactive serine protease Rv0125 to boost BCG Phase I Aeras/GSK M72 Recombinant BCG which over expresses antigens 85A, 85B and 10.4, rvwith endosome escape Pre-Clinical Phase I Q2-07 Aeras AERAS 403 Recombinant BCG genetically modified to over express antigen 85B Phase I UCLA/Aeras rBCG30 Description Stage Source Vaccine Aeras’ TB Vaccine Candidates Under Development
rBCG better then BCG in Guinea pig Protection Guinea pigs Vaccinated with Sham, BCG or rBCG30 Challenged with Live aerosolized TB White arrows point to Granulomas seen at sacrifice
Humoral & Cellular Immunity CD 4 T cell CD 8 T cell TH1 TH2 TH1 TH2 IFN- γ IL-2 TNF- α IL-4 B - cell antibodies DTP, Hib, Pneumococcus, Measles, Polio, Hep B, Rotavirus, HPV, Malaria TB, Malaria, HIV Will CD4’s be Enough? Do we need a balance of CD4 & CD8? What cytokine profile to we need?
2011 2012 2013 2014 Phase III Infants Phase III Adolescents 2006 2007 2008 2009 2010 License, Launch & Distribute Timeline Aeras 403 prime Aeras 402 boost Phase I Is it safe in 20-40 subjects in each age group . . . Phase II Does it induce an immune response? Is it safe in 200-600 subjects: infants & adolescents ? . . . Does it induce an immune response & show some protection? (Confidence for Ph III) Is it safe in 6000-9000 infants & 10000-15000 Adol ? Does it protect against TB at a licensure standard ? Can you consistently manufacture it? Will it be used ?