Hib, Pneumo, Hep A and B MedCh 401 Lecture 4 19May06 KL Vadheim Lecture 4

Haemophilus influenzae b Gram negative coccobacillus Respiratory pathogen, primarily of children Encapsulated and unencapsulated strains Unencapsulated strains from respiratory tracts of adults 19May06 KL Vadheim Lecture 4

Hib Transmission Person-to-person Respiratory droplets, contact with respiratory secretions Humans are only host May be carried in respiratory tract for long periods and transmitted to many people before causing disease 19May06 KL Vadheim Lecture 4

H. influenzae capsule Composed of polyribosylribitol phosphate (PRP), a repeating polymer of ribosyl and ribitol phosphate Polysaccharide Six serotypes, a - f 19May06 KL Vadheim Lecture 4

Type b capsule Antibody to serotype b conferred type-specific protection Type b strains account for 95% of all strains causing invasive disease ( bacteremia and meningitis) 19May06 KL Vadheim Lecture 4

Hib vaccine efficacy Incidence of invasive Hib disease in children <5 years of age has dropped from >20/ 100,000 in 1990 to near zero in 2004 19May06 KL Vadheim Lecture 4

Composition of Hib vaccines 19May06 KL Vadheim Lecture 4

ActHIB Lyphilized vaccine Reconstituted with: Saline DTP (sanofi Pasteur) DTaP (Tripedia; sanofi Pasteur) 19May06 KL Vadheim Lecture 4

Hib Conjugates C. diphtheriae CRM197 - nontoxic variant of diphtheria toxin Tetanus toxin - toxoided with formalin Outer Membrane Protein Comples from B11 strain of N. meningiditis serogroup B 19May06 KL Vadheim Lecture 4

Manufacturing processes H. influenzae grown in fermenters PRP purified from cells Conjugates grown in fermenters, proteins purified, tetanus toxin toxoided Conjugation reactions: ActHIB PRP covalently bound to tetanus toxoid HibTITET PRP coupled to CRM197 by reductive amination PedVaxHIB PRP covalently bound to N. meningitidis outer membrane protein complex (OMPC) 19May06 KL Vadheim Lecture 4

Pneumococcal Disease Leading cause of morbidity and mortality for all ages, worldwide U.S. annual incidence: 15-30 cases/100k case fatality rate 15-20% Major cause of : invasive infections: bacteremia, meningitis pneumonia, upper respiratory disease, acute otitis media, sinusitis 19May06 KL Vadheim Lecture 4

Streptococcus pneumoniae Gram + coccus Increasingly resistant to antimicrobial agents Commonly occurs as carrier state Both capsulated and non-capsulated ~90 serotypes 19May06 KL Vadheim Lecture 4

Pneumococcal Vaccines 19May06 KL Vadheim Lecture 4

Comparative efficacy Prevnar - 100% Pneumovax - ~57% 19May06 KL Vadheim Lecture 4

Capsular serotypes Differ in prevalence 19May06 KL Vadheim Lecture 4

Pneumococcal Vaccines Serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (Prevnar) have been responsible for ~80% of invasive pneumococcal disease in children <6 Pneumovax-23 - additional 16 serotypes gains protection against ~10% 19May06 KL Vadheim Lecture 4

Manufacturing Pneumococcal vaccine Pneumovax 23 - capsular polysaccharides purified from 23 types of S. pneumoniae Prevnar - capsular polysaccharides from 6 S. pneumoniae serotypes are purified, then conjugated to diphtheria CRM197 protein 19May06 KL Vadheim Lecture 4

Hepatitis A Systemic viral infection with liver pathology Symptoms indistinguishable from most other viral hepatitis infections Incubation period is ~15 - 50 days Disease may range from asymptomatic, to hepatitis, to fatal infection 19May06 KL Vadheim Lecture 4

HepA Transmission Fecal-oral transmission Replicates in the liver Person-to-person Infected food or water Replicates in the liver Humans are the only natural host No chronic infection or carrier state Virus shed in feces ~3 weeks, starting 1-2 weeks before symptoms 19May06 KL Vadheim Lecture 4

HepA vaccine efficacy >95% seropositive after one dose 100% seropositive after two doses 19May06 KL Vadheim Lecture 4

Hepatitis A Manufacturing Attentuated virus is propagated in MRC-5 cells Cells are harvested by centrifugation Cells are lysed to form a viral suspension Virus is inactivated with formalin Adsorbed onto aluminum adjuvant 19May06 KL Vadheim Lecture 4

Hepatitis A Vaccines 19May06 KL Vadheim Lecture 4

Hepatitis B Systemic infection with liver pathology Symptoms indistinguishable from Hepatitis A or other viral hepatitis infections Can cause primary hepatocellular carcinoma Lifetime risk of infection: 100% for high-risk groups (e.g., IV drug users) <20% for general U.S. population 19May06 KL Vadheim Lecture 4

Hepatitis B Carriers 200-300 million worldwide 1-1.25 million in U.S. 90% of neonates and 6-10% of infected adults will become carriers Carriers can infect others 19May06 KL Vadheim Lecture 4

Hepatitis B Transmission No host outside humans (no other reservoir of infection) Bloodborne transmission parenteral mucosal perinatal Communicable 1-2 months before and after onset of symptoms 19May06 KL Vadheim Lecture 4

Hepatitis B Vaccine Recombinant Old vaccine was pooled human plasma 19May06 KL Vadheim Lecture 4

Hep B Vaccine Manufacturing Cloned, purified Hepatitis B Surface Antigen (HBsAg) Genetically engineered into Saccharomyces cerevisiae (yeast) cells Yeast grown in fermenters HBsAg release by yeast cell disruption Purified Formalin-treated (Recombivax only) Adsorbed to aluminum adjuvants 19May06 KL Vadheim Lecture 4

Hepatitis B Vaccines 19May06 KL Vadheim Lecture 4