Hib, Pneumo, Hep A and B

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Hib, Pneumo, Hep A and B

• MedCh 401
• Lecture 4

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Haemophilus influenzae b

• Gram negative coccobacillus
• Respiratory pathogen, primarily of children
• Encapsulated and unencapsulated strains
• Unencapsulated strains from respiratory tracts of
  adults

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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

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H. influenzae capsule

• Composed of polyribosylribitol phosphate (PRP), a
  repeating polymer of ribosyl and ribitol
  phosphate
• Polysaccharide
• Six serotypes, a - f

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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)

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Hib vaccine efficacy

• Incidence of invasive Hib disease in children lt5
  years of age has dropped from gt20/ 100,000 in
  1990 to near zero in 2004

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Composition of Hib vaccines
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ActHIB

• Lyphilized vaccine
• Reconstituted with
• Saline
• DTP (sanofi Pasteur)
• DTaP (Tripedia sanofi Pasteur)

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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

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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)

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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

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Streptococcus pneumoniae

• Gram coccus
• Increasingly resistant to antimicrobial agents
• Commonly occurs as carrier state
• Both capsulated and non-capsulated
• 90 serotypes

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Pneumococcal Vaccines
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Comparative efficacy

• Prevnar - 100
• Pneumovax - 57

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Capsular serotypes

• Differ in prevalence

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Pneumococcal Vaccines

• Serotypes 4, 6B, 9V, 14, 18C, 19F and 23F
  (Prevnar) have been responsible for 80 of
  invasive pneumococcal disease in children lt6
• Pneumovax-23 - additional 16 serotypes gains
  protection against 10

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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

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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

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HepA Transmission

• Fecal-oral transmission
• 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

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HepA vaccine efficacy

• gt95 seropositive after one dose
• 100 seropositive after two doses

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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

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Hepatitis A Vaccines
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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)
• lt20 for general U.S. population

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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

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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

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Hepatitis B Vaccine

• Recombinant
• Old vaccine was pooled human plasma

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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

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Hepatitis B Vaccines