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

2. 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

3. 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

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

5. 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

6. 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

7. Composition of Hib vaccines
19May06
KL Vadheim Lecture 4

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

9. 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

10. 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

11. 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

12. 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

13. Pneumococcal Vaccines
19May06
KL Vadheim Lecture 4

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

15. Capsular serotypes
Differ in prevalence
19May06
KL Vadheim Lecture 4

16. 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

17. 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

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

19. 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

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

21. 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

22. Hepatitis A Vaccines
19May06
KL Vadheim Lecture 4

23. 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

24. 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

25. 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

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

27. 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

28. Hepatitis B Vaccines
19May06
KL Vadheim Lecture 4