Birth  BCG, Hep B, OPV

6 weeks DTP, Hep B, OPV, Hib

10 weeks DTP, OPV, Hib

14 weeks (booster) DTP, OPV, HepB, Hib

9 (or 12) months Measles, Rubella, 2 doses yllw fvr

women childbearing TT

• Bacteria
• Action of toxin: toxin catalyzes reaction (toxin brought into cell) inactivating elongation factor (EF2)
• Formalin inactivated w/ aluminum adjuvant
• w/vaccine can get D+ but be asymptomatic - immunization does not illuminate organism but removes effect of toxin
• Spike in adult cases - waning immunity
• Cyclical outbreaks

DTwP

Killed, whole cell pertussis

Diptheria + tetanus toxoid

Alum adjuvant

DTaP

PT-inactived, 2 surface proteins, 1 outer membrane protein

T+D

alum?

• Bacteria
• Associated w/ malnutrition
• Whole cell or acellular
• Highest # deaths in <6 yr olds
• Vaccine more effective for severe, long lasting cough
• Maternal antibodies inhibit
• Waning immunity - still immunize
• Immunize contacts
• EPI: DTP 6, 10, 14 weeks
• vs: DTAP 8, 16 weeks, 6 months + booster -> min age 6 weeks

1. No chronic infectious state
2. No significant non-human reservoir
3. Highly effective vaccines
4. Political will
5. New strategies improve effectiveness

• RNA virus
• Edmonston B live attenuated by serial passage. Now: serial passage, lyophilize. Combine w/MR -> MMR or MMRV
• 2 doses b/c of waning immunity
• Having measles confers lifelong immunity
• Eliminated in US - all cases imported
• EPI: 9 months
• US: 12-15 months, 2nd dose min 1 month later
• rec 4-6 years
• waning immunity so 2 doses
• Measles: Can cause blindness, VitA supplements help, Neurological breakdown later

• Virus
• In MMR, MMRV - so live attenuated, serial passage
• Mumps has waning immunity even after 2 doses
• Murabe caused meningitis, Jeryl Lyn used
• US: 12-15 months
• 4 weeks min later, recommended 4-6 yrs

• Virus, causes hearing loss, congenital Rubella: shed virus for longer, can be re-infected
• included in MMR, MMRV
• live attenuated, serial passage
• ADD MORE

• Virus
• Serial passage - 2 doses (some waning immunity)
• 12-15 months, 4-6 yrs, minimum 3 months b/t doses
• Congenital varicella - causes stillbirths, zoster "bands"
• Zoster: varicella persists in spinal cord -> outbreaks in older individuals
• Lowered risk if you have children in the home (booster)
• Vaccine: prevents zoster and prevents postherpetic neuralgia
• >60 years

• Bacterium
• BCG+ saline
• Live attenuated, intradermal
• Passaged in bile, bovine virus (xenotropic)
• Does not protect from primary infection; organism will take. Immunization helps eliminate it / completely encase organism so it never disseminates.
• Side effects - some disseminated disease, abscess, lymphadenitis
• Benefits outweigh risk (in HIV+ esp.).
• 1 dose at birth

• Seasonal, regional
• Result of antigenic drift (A&B)
• influenza A and B
• older ppl at more risk

• Rapid global spread
• Refers to global spread, not severity
• Influenza A only
• Antigenic shift (A only)
• Young ppl at risk

Minor changes in viral HA and NA from:

• spontaneous mutation
• selection for mutations based on herd immunity
• occurs frequently/continuous

Major changes in viral HA and NA from:

• Reassortment of viruses in nature (genetic recomb / exchange of gene segments)
• Direct animal to human transmission
• Occurs infrequently

Ways to increase influenza vaccine production and increase global supply!

1. Create cell culture based vaccine - easier to rapidly scale up
2. Adjuvants (use less vaccine component for each dose)
3. Increase manufacturing capacity - can become hub for region
4. Novel manufacturing approaches

• synthetic influenza?
• universal flu vaccine?

• A - moderate/severe, all ages
• B - milder, more in children, humans only
• C - rarely in humans

Three types: A, B, C

LAIV (live attenuated influenza vaccine): attenuated - cold adaptation + serial passage. Intranasal in eggs.

TIV (trivalent influenza vaccine): inactivated - just HA subunit

TIV for <2, >50, pregnant. LAIV for 2-49 yrs

Not on Epi

US: min age 6 months. 

Annual recommendation

TIV: waning immunity <1 year + antigenic drift, so vaccinate annually. Intramuscular

RNA virus: Types 1, 2, 3

3 doses

Immune after infection

IPV: Formalin inactivated. Salk. Alum adjuvant. Few vaccine induced cases. Higher serum immunity. Used exclusively in USA.

OPV: Attenuated oral polio - serial passage. Sabin. 

Transmitted to others b/c replicates in intestines

Higher intestinal immunity (can give at birth)

Type 2 replicates fastest in intestine so less in vaccine.

EPI: (Birth), 6, 10, 14 weeks OPV

US: IPV min 6 months, 6-18 months, >4 yrs (6 months+). If 4th before age 4, give 5th dose.

Attack Rate Unvacc - Attack rate Vacc

-----------------------------------------------------  x100

Attack Rate Unvacc

1. Funding - donor fatigue
2. Lagging surveillance
3. VAPP: vaccine associated paralytic polio. more likely to have received multiple injections.
4. CVDPV: circulating vaccine derived poliovirus, can mimic outbreak of wild-type OPV reverts. pockets of susceptible children.
5. IVDPV: immunodeficient VDPV. prolonged excretion of type 1 poliovirus
6. aVDPV: ambiguous VDPV. isolates from vaccine but 1% different

1. Interrupt and contain wild polio
2. Ensure global surveillance/notification
3. Establish mOPV stockpile and response mechanism
4. Implement IPV in biohazard settings
5. Synchronize cessation of IPV
6. Contain Sabin polioviruses

....this will never happen

1. Cost
2. Competition for intro of other vaccines. ex. MMR, Hib
3. Limited IPV production capacity currently
4. WHO wants Sabin type vaccines not wild - risk of wild type escape

Virus - 100s of types- 16, 18, 6, 11 in vaccines.

Bivalent:

16 and 18.

Recombinant in yeast or insect

Bivalent adjuvant: monophosphoryl Lipd A

cervical cancer

Quadrivalent:

• 16,18,6,11
• Recombinant in yeast. (C1) surface antigen self assembles to create virus-like particles.
• Alum adjuvant
• Recommended for men.
• Prevent cancer and genital warts.

• Persistent infection used as a marker (rather than cancer). Serologic testing not useful b/c of lag after infection
• 16-26 years of age. Bridging study: 9-15 yr olds.

1. Safe
2. Pure 
3. Potent
4. Manufactured consistently (according to current Good Manufacturing Practices)

Phase 1: Safety and Immunogenicity

Phase 2: Safety, Immunogenicity, dose ranging

Phase 3: Safety, immunogenicity, efficacy

Clinical trials for each:

Phase 1: Initial use, small sample size

Phase 2: randomized controlled. Determine dose, check immune interference with other current vaccines

Phase 3: Test efficacy

Phase 4: Observe on the market!

60-90 day incubation

Chronic carriers

Highest concentration in blood. 

Young adults: sex and drugs

Originally for high risk only, but not good enough coverage, so now it's for all.

Plasma derived: formalin, urea inactivated.

Intramuscular

Recombinant: DNA inserted in producer cells (yeast) to make antigen. Purified.

Contents: HBsAg, Alum, residual yeast, and HB serum antigen

EPI: not on schedule

US: Birth, 1-2 months, 4 months.

Doses: min 4 weeks, 12 weeks, no earlier than 24 weeks

Can give at birth: placenta good barrier to antibodies. Waning antibodies but not waning protection

• Process of chemically bonding polysaccharide to a protein "carrier" to create more effective antigen.
• Changes from T independent to T dependent.
• Improves immunogenicity, especially in younger kids
• Repeat doses expect to elicit booster response

Virus - food and waterborne

Incubation is 30 days

Immunity highest in developing countries, susceptibility highest in developed countries

Intramuscular

Whole virus, formalin inactive, 0, 6-12 months schedule

12-23 months old

Min age: 12 months

2 doses, 6 months apart

Bacteria

Capsule type b (Hib) virulent - composed of PRP responsible for virulence and immunity 

Polysaccharide vaccine: T cell independent, hyporesponsiveness w/ repeat dosing. Neg. efficacy

-> now, polysaccharide conjugate. T cell dependent. 

Herd effect, broader effect, memory

Impacts carriage

Better response, fewer adverse events, effective in infants

Intramuscular

Schedule: 8 weeks age. 8 weeks separation, 4 weeks min, 2-3 doses. 

Things that can be eliminated! :)

Things that can't be eliminated! :-(

Can: Measles, mumps, rubella, polio

Can't: Influenza (animal reservoir and constant mutation), tetanus (found everywhere), pertussis (vaccine not effective enough, chronic carrier state)

• Disease: severity, risk, and cost
• Vaccine: efficacy, cost, safety, practicality
• Other alternatives
• Public/provider acceptance

• FDA requires data to support a specific indication
• Advisory committees take into account a broader mandate than FDA.
• FDA can only weight info from manufacturer. ACIP may know something about another product.
• ACIP can take into account info on other vaccines.

In Africa: higher risk of infection. Malnutrition, VitA deficiency, HIV lead to decreased maternal antibodies sooner.

In US: largely eradicated so less risk, also better maternal antibodies.

• A - further research unlikely to change estimated effect on health outcomes
• B - lower
• C - lower
• D - Available data insufficient to provide estimate of effect on health outcomes

Crowding and high exposure to diseases like measles puts babies at higher risk. 

If you live in a household with other children, you're more likely to get it.

• Other: Public perception of need, cost of alternate strategies
• Vaccine: inexpensive, safety, efficacy
• Disease: cost, severity, risk

Can differ for different groups!

1. No consistent rules or #'s
2. Efficacious range 50-98%
3. Risk changes as incidence increases
4. What would happen if vaccination stopped?
5. Unrealistic expectation of zero risk
6. Vocal special interest groups

Cutter Incident

Tainted Salk vaccine - children exposed to live polio.

Led to CDC for epidemiologic investigation of vaccine safety. Establishment of vaccine safety division, Bio standards (FDA)

Lessons: scaling up creates problems, quality control every change in process, need for epi assessment of post-licensure safety

Immunoglobulin with Measles vaccines: Explain why we give it and why not give it at the same time as the vaccine.

(question 12 on exam 1)

Why we give it: lowers rate of adverse events, helps clear infection faster (increased rate of clearance). Give 5 months after measles.

Why not give it at the same time as vaccine? IG will interact with vaccine and lower the efficacy

Measles vaccine mimics natural infection (replicates) while DTP does not.

Measles - cellular and humoral

DTP - humoral only

1 dose of Measles = 90-95%, 2 doses = 99%

Virus, causes gastroenteritis. leading cause of severe gastroenteritis/diarrhea. Causes lots of hospitalization in US, lots of death in developing countries.

Not in EPI

Rhesus Rotashield: live attenuated with reassortant tech. higher risk of intussusception. Off the market.

Rotarix: oral live attenuated monovalent. 2 doses (2,4 months)

Rotateq: live attenuated bovine-human reassortant. Pentavalent (G1,2,3,4,P8). Oral. 3 doses: 2,4,6 months. Max age 14 weeks for 1st doese

Intussusception risk? Not in US, but Mexico maybe. Australia slight increase?

Can't start vaccination earlier than 6 weeks or after 14 weeks. No doses after 8 months.

Question 3 from Exam II.

Child in Nicaragua, unknown status.

a. 6 months old?

b. when to return?

c. What should child receive?

d. 15 months old?

e. Criteria for not giving?

a) BCG, DTwPHibHep, OPV, Influenza, PCV either way

b) 4-8 weeks, 8 optimal

c) DTwPHibHep, OPV, Influenza OK

d) BCG, DTwPHibHep, OPV, MMR, Influenza, PCV OK

e) too many injections. 9 OK according to CDC. Live vaccines as long as 4 weeks apart. If child has acute illness.

Question II from Exam I.

An emergency room doctor calls you for advice. What preventive regimen do you give a 22 year old construction worker in Baltimore who: punctured her foot on a nail laying on the ground today who: (Note: think about all the vaccines that contain tetanus toxoid). 

a) Does not know her vaccine history? 

b) Had received several doses of DTP as a child and a dose of Td vaccine 6 years ago? 

c) Is 3 months pregnant and has no vaccination records or recall of prior vaccination? 

d) Reports that she attended public school in Baltimore and her mother said she was fully immunized as a child. She received injections for tetanus prevention one year ago and two years ago following similar injuries. 

e) Had received several doses of DTP as a child and a dose of Td vaccine 6 years ago, but she has an immunocompromised 1 year old daughter living at home? 

a. Tdap and TIG

b. Tdap only

c. TD (maybe Tdap) and TIG

d. Nothing

e. Tdap only

Tetanus, influenza

Can't eradicate if: non-human reservoir, chronic infectious state, ineffective vaccines

TDaP: less pertussis + Diptheria, same amount of tetanus, alum adjuvant

DTaP: no thimerosal, inactivated pertussis, alum adjuvant

Split bacteria, take out immunogenic components parts of organism that cause immune response. Examples of subunit : acellular pertussis, inactivated influenza

2. polysaccharide. Doesn't activate specific response. T cell independent.

3. (Polysaccharide) Conjugate: add protein to activate MHC II, memory B cells. Ex: Meningitis, pneum., Hib

Why does US recommend 2 varicella vaccines?

Differences between varicella and zoster?

Second dose b/c 95% immune after 1 dose, 99% w/ 2 

Lowers risk of breakthrough

Boosts immunity

Zoster for adults: more concentrated version of varicella vaccine

CD4 and CD8 cells do not prevent infection but help clear and control it.

CD4: Antibody, humoral response. CD4 activated B cell differentiation into plasma cell produces the antibody response, Th1 supports cell mediated immunity. MHC Class II pathway.

CD8: Cytotoxic T cells more direct effect. Directly kill infected cells, also indirectly through release of cytokines. MHC Class 1 intracellular presentation.

Live vaccines -> yes CD8, inactivated no

Tetanus, diptheria, pertussis

Also, HPV for different strains

Grow bacteria in a vat, extract toxin, purify it, inactive with Formalin and add alum adjuvant.

Toxins work by entering cell, inactivating EF2

Ex. Tetanus, Diptheria, Pertussis

Serial passage through cell lines.

Ex. Measles, mumps, rubella, varicella, oral polio, BCG

Cold adapted - serial passage through cold temps

Ex. LAIV (Flumist), rotavirus

Reassortant.

Ex.: Cold adapted flu virus, rotavirus

Xenotropic - use related virus.

Ex. smallpox, Rotateq, BCG

Rubella, varicella

HPV - infected during birth

maybe more?

At birth: BCG, OPV, HepB  in US: Hep B

During pregnancy? Td, TIV, HepB? (double check)

Streptococcus Pneumoniae

Bacteria. Unique to humans.

Can have asymptomatic carriage

No cross reactivity between subgroups, some within, some cross protection.

2 verisons are available:

1. Pure polysaccharide  (Called PPSV14)

Only used in adults. Halsey predicts they're going to switch to 13-valent conjugate.

2. 13-valent PCV13 (polysaccaride conjugate vaccine)

Used in infants. (Highly immunogenic in infants.) 

3. PCV7 - conjugated vaccine (possibly used internationally?). Conjugated vaccines are conjugated to non-toxic diptheria toxin. Conjugated because they don't have as immunogenic of a response. 

Intramuscular

Duration of protection is unknown.

Not on EPI schedule.

US: 4 doses at 2,4,6,12-15 months

(minimum age is 6 weeks for conjugate, but 2 years for polysaccharide)

• Influenza (animal reservoir, reassortants)
• Tetanus (in soil)
• Pertussis because chronic state, low vaccine efficacy
• Hep A - it's in food, animals, etc.

Measles, varicella, Hep B, tetanus, diphtheria, pertussis

Not influenza!

Can be implemented when human efficacy trials not considered feasible or ethical, and use of animal efficacy data deemed appropriate. 

Does not apply if approval can be based on efficacy standards described elsewhere in FDA's regulations.

What is a vaccine? 

1.      intradermal: smallpox

2.      intramuscular: DTP

3.      subcutaneous: measles

4.      transcutaneous (in development)

5.      oral: polio vaccine

6.      intranasal: cold adapted influenza vaccine

7.      edible? (experimental)

1. Recognize the disease as a distinct entity: distinguished from other diseases

2. Identify the etiologic agent

3. Grow agent in lab

4. Establish animal model for disease

5. Identify immunologic correlate for immunity: what protects the animal from disease?

     -> usually a serum antibody

6. Inactivate or attenuate the agent in lab/ choose antigens

7. Prepare candidate vaccine (Good Manufacturing Procedure)

8. Test on animals and evaluate its ability of protection

9. Apply to FDA for IND approval

10. Phase 1: safety and immunogenicity

11. Phase 2: safety and immunogenicity, dose-response

12. Phase 3: efficacy (protection level in vaccinated compared to non-vaccinated)

13. Submit licensure application

14. FDA approval

15. Post licensure: Advisory committee review/ recommendations, marketing, Phase4 (surveillance for safety and effectiveness)

• Excision and repeated excision
• Tracheostomy may be necessary
• Young child with RRP takes about 7 treatments; # of treatments needed over time decreases

• Lag time from onset of infection to cancer is 10 to 20 years
• Persistent infection is used as a surrogate marker was used (primary outcome)
• CIN = secondary outcome
• Cancer must go through persistent infection

Annual cost of single case  = $42,920
Annual cost in US = $79 million
o   States have to pay a portion of the vaccine; some states cover everyone; some pay for none.
Costs much more to add male vaccination – less COST EFFECTIVE

Vaccinating females 12-26; est cost per QALY = $19,700 for cervical outcomes
Vaccinating males 12 est cost per QALY = $105,700 for cervical outcomes
Different laws require insurance to cover or not

GAVI, PATH, etc. are investigating new schedules to require less doses
o   If less doses are required it will lower the cost and keep much of the benefit!
o   key element of the decision making process:

o   Cost per quality adjusted life year
o   If the 3 doses provide life long – vaccination is cost effective
o   If there is waning immunity and a booster is needed – less cost effective
o   The price was close to the true value of protection

1902: Biologics Control Act of 1902
Requires licensure of product and manufacturing establishment

Authority to conduct unannounced inspections and withhold and revoke licenses

o   Development of rationale based on disease pathogenesis

o   Immunogen Identification

o   Development of manufacturing process; non-clinical studies

-Pre-IND Meeting

oProduct Manufacturing, Animal safety & Immunogenicity, Lot Release, Phase 1 protocol

oEfficacy trial protocol, Phase 1 and 2 data,  Update: product etc, Assay data

- Pre-BLA Meeting

oClinical data summary: Safety and efficacy, Update: product assays etc, Outline of BLA (Biologics License Application)

 Detailed manufacturing procedures to ensure consistency of production
- Defined compatible components
-Intermediate and final product testing and lot release specifications
- Adventitious agent testing
-       Examination for extraneous materials

-  Stability, including genetic stability
- Source and quality of starting materials
- Selection/characterization of cell substrate
-  Viral or bacterial seed history and characterization

  Validation of manufacturing process for removal and/or inactivation of viruses/bacteria
- In process testing
-  Release testing of bulk and final products
-       Stability studies (shelf life)

-       Challenge protection studies

o   Provides rationale for use in humans

o   Determination of optimal dose

o   Phase 1: Safety and immunogenicity

o   Phase 2: Safety, immunogenicity, dose ranging

o   Phase 3: Efficacy, safety, immunogenicity

o   Review of data to support licensure

o   Pre-approval inspection

o   Phase 4 studies

o   VAERS (passive surveillance)

o   Lot release

o   Biennial inspections

-      testing efficacy
-       double blinded, randomized, controlled
-       background epi needed for sample size
-       case definition well defined

-       prospective primary and secondary endpoints
-     monitoring: case surveillance, safety, duration, immunogenicity and correlates of protection, data monitoring committee
-       data analysis plan

- safety is relative
- risk tolerance influenced by

- risk of vaccine-preventable disease vs. risk of adverse event associated with vaccine     - alternative vaccines

- intended population

- size of safety database for routinely administered childhood vaccines

if new vaccine recommended on the same schedule as other vaccine - obtain data to support simultaneous administration
-bridging studies - support manufacturing change
-clinical lot consistency studies - support physiochemical assessment of manufacturing consistency

Drugs and biologicals that reduce or prevent serious or life threatening conditions caused by exposure to lethal permanently disabling toxic chemical, biological, radiological or nuclear substances.

    - human efficacy trials not feasible or ethical
    - use of animal efficacy data scientifically appropriate
    - dose not apply if appoval can be based on efficacy standards described elsewhere         in FDA’s regulations

    - Not feasible if there is no valid animal model of disease
    - Confidence may be an issue, even in valid models

8 health maintenance organizations across country have linked database for:

• Vaccination (exposure)
• Outpatient, ER, hospital, and lab data (health outcomes)
  • Demographic variables (confounders)
  • • Covers about 3% of US population
    • Hypothesis testing studies can be performed from here

Good:

• All medical encounters available at most sites
• Allows calculation  of background rates of various conditions
• Medical chart reviews is easily accessible
  Bad:
• • Sample size may be inadequate for very rare events
  • Lack of Demographic diversity in HMO practices
  • Variability in accuracy of coded data used for studies
  • Unvaccinated population may be small
• Ugly: YOUR MOM.

• Convergence on data needed to evaluate the vaccines
• Drafted WHO Guidelines on Regulatory Preparedness for Human Pandemic Influenza Vaccine (2007)

• Assesses competencies of National Regulatory Authorities (NRA) around world
• Training to help build NRA capacities to evaluate vax devo and licensure

• Pediatric Research Equity Act, increased Safety measures
• Safety labeling changes: trigger specific timelines for safety label negotiations/implementation
• Risk Evaluation and Mitigation Strategies: FDA can enforce this requirement based on safety info
• Active Post-Market Risk Identification and Analysis System (mentioned earlier): links vaccine safety data from multiple source
• • Safety has always been stressed by CDC/FDA, but these measures sought to increase the accountability of the manufacturers to uphold importance of safety

• IND: Review with 30days of receipt (fast!) and study may proceed after 30 days of not placed on hold by FDA

• End-of-Phase 2 and pre-BLA meetings strongly encouraged
• FDA can place a hold on study anytime during Phase 2 or Phase 3 for safety reasons or clinical design reviews
• BLA: Review completed within 10months. Priority review is within 6months

Plasma Derived Vaccine: Purified and concentrated sera, inactivated by formalin, urea and 2 others.

Recombinant Vaccine: DNA (plasmid) inserted into cytoplasm of producer cells (yeast/insect cells) which serve as a “factory” to make antigen. Grown in large vats and purified.

 Late 1800s organism isolated from pus (gram negative rods).
-      Originally named Pfeiffer’s bacillus & attributed as cause of influenza.
-      Recognized in 1918 that Haemophilus Influenzae was not cause of influenza.
-      Established in 1933 that influenza was caused by virus and H. influenza was a cause of secondary infection.

-      Non-spore forming coccobacillus that is unique to man.
-      Very difficult to grow – requires X factor (hemin) and V factor (nicotinamide adenine dinucleotide NAD) on chocolate agar.
-      2 types – Encapsulated (6 capsular types designated a through f) and nonencapsulated.
-      Frequently colonizes upper respiratory tract.
-      Capsule type b (Hib) particularly virulent – allows organism to evade immune system, proliferate & cause disease.

Type b capsule composed of polyribosyl-ribitol phosphate (PRP) which is responsible of virulence and immunity.

-      Opsonophagocytic antibodies - present via maternal Abs and are developed from 4+ years old - protect against Hib.
-      BPIG study - polyvalent Ab given to Native American infants - protected infants from invasive and non-invasive disease by encapsulated bacteria.
-      Next step: deliver antigen itself to the host and allow Ab production à using polysaccharide sugars alone makes Ab BUT is T cell independent (delayed ontogeny, no memory, no maturation, depletion of B cell pool).

-      Early 1900s - whole pneumococcal cell ground up and injected into African gold miners - efficacy not clearly established.
-      1985 - Hib-PRP vaccine licensed à tested as “control” for a meningococcal outbreak in Finland in children (3mths – 5yrs).
-      Hib-PRP efficacy studies - for young children (3-17months) Hib-PS antigen alone NOT sufficiently immunogenic - how to induce immunity to PS antigens?

The routine introduction of Hib vaccine has led to the near-elimination of the disease in US.

-      Issue 1:  concern that removing type b allows for the other strains (types a, c, d, e and f) to invade - they can become more common and cause more disease - so far, they have remained fairly low level and stable (Particularly concerned about Hia).

-      Issue 2: In GAVI-eligible countries, financing for vaccines not a big problem anymore à 

-      Issue 3: dosing and scheduling for greatest effect - US uses 3 doses + 1 booster; low-income countries use 3 doses (no booster) - BUT since there is no long term protection in low burden setting, waning immunity, and increased susceptibility, a booster is needed.routine use now occurring.

-      Occurrence: world wide

-      Reservoir: humans

-      Transmission: respiratory droplet although no firm evidence exist.

-      Communicability: limited. Secondary attack rate of 0.3%. Depend on age.

-      Exposure risk factors: crowding, large household size, child care attendance, low socioeconomic status, low parental education, school aged siblings.

-      Host risk factors: race/ethnicity, chronic disease.

-      Gram negative diplococcus

-      Polysaccharide capsule helps to resist phagocytosis and complement mediated lysis.

-      13 serotypes based on capsule - A, B, C, X, Y and W135 most invasive & cause epidemics - classified according to immunologic reactivity to capsular polysaccharides.

-      Relative importance of serotypes depends on geographic location and other factors such as age - B, C & Y cause most US cases and A causes most cases in African meningitis belt.

-      Only bacterium capable of generating large epidemics of meningitis.

-      Serogroup distribution varies globally and regionally and varies over time.

-      Potential for global spread.

-      Emergence of new serogroups.

-      Meningococcal polysaccharide vaccines effective in high-risk populations.

-      Multiple doses of polysaccharide vaccine lead to less and less concentrations of antibody.

-      Unique features:

-      Hyporesponsiveness seen - clinical implications unknown.

-      Unique features:

-      Disease prevalence decreases as bactericidal activity increases.

-      Correlates of protection

-      3 vaccines licensed in the UK without efficacy studies

-      Reservoir: humans

-      Transmission: droplet spread or by direct contact

-      Incubation period: 3-4 (2-10) days.

-      Communicability: low, 2-4 cases per 1000 household members at risk.

-      Host risk factors: complement pathway deficiency, asplenia, genetics, HIV.

-      Exposure risk factors: household exposure, upper respiratory tract infection, active and passive smoking, crowding.

BELT:       Africa, Ethiopia to Senegal

-      Gram positive diplococcus/chains.

-      Isolated in 1881 by Pasteur.

-      Unique to humans.

-      Polysaccharide capsule is primary basis for pathogenicity. Organisms without capsule non-pathogenic.

-      >90 serotypes (~45 serogroups) based on the capsule antigenicity (identified by quelling reaction or PCR).

-      Antibodies and complement interact to opsonize the organism and make it available for phagocytosis and clearance.

-      No cross-reactivity between serogroups, but some within serogrpups and some cross-protection

-      Some antibodies have cross reaction with other capsules or related bacteria.

-      Most serotypes cause serious disease but only a few produce the majority of infections.

-      The ranking and serotype prevalence differ by age and geographic area.

-      Disease incidence: high in first 2 yrs and last few yrs of life.

-      Colonization decreases with age (up to ~45yo).

-      Global burden: 14.5 million cases of pneumo in children <5; ~830,000 deaths.

-      Occurs in Sub-Saharan Africa, SE Asia and S Asia.

-      High mortality rates in Latin America, Africa, S & SE Asia.

-      Pneumococcal polysaccharide vaccine: 2 types - 14-valent & 23-valent.

-      Multiple doses of polysaccharide vaccine lead to less and less concentrations of antibody.

-      Unique features:

-      Hyporesponsiveness seen - clinical implications unknown.

-      Unique features:

-      Disease prevalence decreases as bactericidal activity increases.

-      However, pneumococcus has many serotypes to immunize against.

-      Lots of vaccine trials - in general, about 80% efficacy.

-      Protection against some influenza because it recognizes the disease.

-      Currently use 13-valent vaccine in US.

-      Reservoir: humans (Nasopharynx)

-      Transmission: direct contact, droplets, autoinoculation.

-      Communicability: presumably transmission can occur as long as it is in respiratory secretions.

-      Host Risk factor: pulmonary disease, decrease immune function, asplenia, asthma, smoking, cerebrospinal fluid leak, child care attendance, race/ethnicity (in children) and cochlear implant.

-      Environment risk factors: crowding, season