Center for Biomolecular Chemistry Vicente Verez Bencomo*, Violeta Fernandez Santana, Maria del Carmen Rodriguez Montero and Yury Valdes Balbin Vicente Verez Bencomo*, Violeta Fernandez Santana, Maria del Carmen Rodriguez Montero and Yury Valdes Balbin Vicente Verez Bencomo*, Violeta Fernandez Santana, Maria del Carmen Rodriguez Montero and Yury Valdes Balbin Vicente Verez Bencomo*, Violeta Fernandez Santana, Maria del Carmen Rodriguez Montero and Yury Valdes Balbin Vicente Verez Bencomo*, Violeta Fernandez Santana, Maria del Carmen Rodriguez Montero and Yury Valdes Balbin From synthetic oligosaccharides to human vaccines: The language of translational research Vicente Verez Bencomo Center for Biomolecular Chemistry Habana, Cuba

1980 ties

The rol of carbohydrate in recognition process Capsular polysaccharides (CPS) of bacteria are very important in pathogenesis Antibodies against the CPS are protective Advance in carbohydrate chemistry and biochemistry Analytical methods Modification of natural glycoconjugates Synthesis of oligosaccharides

Leprosy diagnostic Haemophilus influenzae type b glycoconjugate vaccine Pneumococcal conjugate vaccine Very Small Size Particles as a potent adjuvant in cancer treatment

Incubation time before clinical Symptoms: several years Mycobacterium leprae Incubation time before clinical Symptoms: several years

a phenolic glycolipid recognised by antibodies from infected persons 1983 P. Brenan isolated from Mycobacterium leprae a phenolic glycolipid recognised by antibodies from infected persons

J. Mariño-Albernas, V.Verez-Bencomo, Carbohydr.Res.,1988, 183, 175-82.

Institute of Tropical Medicine Pedro Kouri Center for Immunoessays MINSAP Antibodies in the serum of subclinical Infected patients CIE-UMELISA UMELISA-HANSEN Detection of seropositive chemotherapy Leprosy was reduced in Cuba and declared non-endemic J. Mariño-Albernas, V.Verez-Bencomo, Carbohydr.Res.,1988, 183, 175-82.

Haemophilus influenzae type b Major children pathogen: meningitis, pneumonia, sepsis

P.W.Andersson et al, J. Immunology 1989, 142, 2464-8 HibTITER Hib Wyeth Vaccines PedvaxHIB Hib Merck ActHIB Hib Sanofi Pasteur ProHIBIT Hib Connaught Laboratories P.W.Andersson et al, J. Immunology 1989, 142, 2464-8 S. Pillai et al, Infection Immunity 1991, 59, 4371-6 C.C.A.M.Peters et al, Infection Immunity 1992, 60, 1826-33

Classical approach (90-ties) Van Boom, Just, Norberg, Verez-Bencomo

Verez Bencomo et al Carbohydrate Vaccines, ACS Symposium series 989,61-74

V. Fernandez-Santana et al, Glycoconjugate J. 1998, 15, 549-553

N type participants doses dates Clinical Trials N type participants doses dates Phase I 40 adults 1 Aug/01 Sept/01 Phase I 133 children 1 Feb/02 Mar/02 3 Phase I 40 adults 1 Mar/02 Apr/02 4 Phase I 114 infants 3 Apr/04 Sept/02 5 Phase II 1041 children 1 May/02 Jun/02 6 Phase II 1098 infants 3 Aug/02 Apr/03 7 Booster 75 infants 1 Jul/03 Aug/03 8 Booster 250 infants 1 Mar/04 May/04 IPK, CIGB, CPH Camaguey, CIGB Camaguey

Verez Bencomo et al, Science 2004, 521-524 Since January 2004 Number of Hib-meningitis confirmed cases 2003 8 2004 6 2005 2 2006 4 2007 2 Pentavalent DPT-Hb + Hib Licenced in 2006 WHO prequalification 2009 Verez Bencomo et al, Science 2004, 521-524

The main driven force was the social need Center for Genetic Engineering and Biotechnology Institute for Tropical Medicine “Pedro Kouri” The main driven force was the social need Finlay Institute Center for Bioproduction (BioCen) Provincial Hygiene Center of Camaguey

Secondary driven force Epidemiology Social needs Price market Revenues Social Impact Provide more health Secondary driven force Market Deep contradiction “blockbuster” Strategy Increase the revenues Main driven force

Las 15 vacunas mas vendidas del 2012 MM USD Prevnar 13 3,718 Zostavax 651 Gardasil 1,900 Rotateq 648 PentAct-Hib 1,522 Synflorix 587 Infanrix 1,183 Pneumovax 580 Fluzone 1,152 Rotarix 549 Hepatitis franchise 986 Adacel 469 Varivax 846 Prevnar-7 399 Menactra 735 6,921

Heptavalent Conjugate vaccine Composition PS 1 conjugate to TT 2 mg PS 5 conjugate to TT 2 mg PS 6B conjugate to TT 4 mg PS 14 conjugate to TT 2 mg PS 18C conjugate to TT 2 mg PS 19F conjugate to TT 2 mg PS 23F conjugate to TT 2 mg TT 24 mg Aluminum phosphate 125 mg Sodium chloride thiomersal One dose 0,5 mL

Evaluación realizada en el laboratorio de referencia de la OMS en Londres (OPS)

¡La vacuna cubana protege al mismo nivel!

The Center for Molecular Immunology dedicated to cancer immunotherapy have develop in the nineties a VSSP technology

Neisseria meningitidis Outer Membrane Protein Very Small Size Particle GM3 ganglioside + Neisseria meningitidis Outer Membrane Protein complex DETERGENT DETERGENT Self-organized nanoparticle VSSP Very Small Size Particle Size 10-40 nM Zeta (mV) -(45-60) Estevez F, et al Vaccine. 1999 , 20;, 190-7

Several tumor-associated carbohydrate antigens are well known Can we revisited some of them more efficiently with VSSP technology?

CQB-601 GM2/VSSP CQB-602 LeY/VSSP CQB-603 GD2/VSSP Proof of concept Synthesis of the ganglioside VSSP preparation Preliminary physico-chem. and biol. evaluation Anti-Ganglioside analytical tools. Tumor models The new VSSP inherit the previous immunostimulating properties Display a new antitumor specific properties