DISEASE
Occurrence of Disease
Wild Animals Involved in Wild Animals Involved in MPXV Transmission (USA, 2003)MPXV Transmission (USA, 2003)
Gambian Giant Rat(Crycetomys sp.)
Prairie Dog(Cynomis sp.)
Ghana
TX
WI
IL*
IA
15/4
09/04
Entry and Distribution Route of Entry and Distribution Route of Crycetomys spCrycetomys sp. and . and Cynomys sp.Cynomys sp. Involved in MPXV Outbreak (USA, 2003) Involved in MPXV Outbreak (USA, 2003)
Source: MMWR 52 (23), CDC, 2003.
15/4
Index case in Marshfield, 26 May 2003:
Disseminated lesions.
Distribution of MPXV Cases in the USA
WI
IL IN OH
KSMO
Number of cases = 87WI = 38IN = 24IL = 19
OH = 4KS = 1MO = 1
Source: MMWR 52 (23), CDC, 2003.
Signs & Symptoms of Disease
FeverFatigueWhite Blood Cell CountPainMuscle AchesBlood Pressure
Protective Responses General protection – skin, stomach acid, mucous membranes, cilia, macrophages, enzymes.
Protective Responses Specific protection – immune response cells recognize one special organism at a time.
Specific Protection Cooperation of immune response cells
• Immune response- recognition of antigen (invader) as foreign and different
- introduction (presentation) to and activation of immune response cells
- protective responses: antibodies, immune cells
- Memory (booster) responses to provide future antibodies
Antigen Presentation
Vaccine Development Most vaccines do not make it to market
Some make it but do not reach original product goals
A few make it and perform as designed
Vaccine Development Is a large risk and investment.
Key Issues Target group Immunogenicity Efficacy Safety Cost 10 years to completion
Phases of Development Preclinicals – animals• Toxicity• Immunogenicity• Combination potential- Stability data- Potency
- Protection (if model is available)
Phases of Development Investigational New Drug (IND)Filing*Phase I – weeks to months- 10 to 40 human volunteers- Safety- Dose size and administration route- Mode of action of immune response- Characterization of vaccine
Phases of Development• Phase II – months to several years- 50 to 500 volunteers- Rates and severity of common adverse effects- Immune response to target group• Phase III – 2 – 5 years- several thousand to 20,000-50,000 volunteers- Placebo-controlled- Safety- Efficacy (if combo., correlates to protection)
- BLA filing – 1-2 years
Post-Market Surveillance Monitoring after licensure• Safety• Efficacy• New indications
2005 - Rubella declared no longer endemic in the US
Types of Bacterial Vaccines Whole cell Acellular Toxoids Polysaccharides Conjugates Combinations
Whole Cell Vaccines
Pertussis Whooping cough – is an acute infectious disease caused by Bordetella pertussis.
First isolated in 1906 Prior to 1940’s over 200,000 cases per year
3,700 cases per year since 1980. In unimmunized populations – 300,000 deaths per year
Bordetella pertussis Small aerobic gram negative rod
Fastidious and requires special media for isolation
Acellular Vaccines
Pathogenesis Pertussis antigens allow invasion of host defenses
Local tissue damage in respiratory tract
ADACEL (0.5ml)
Contains pertussis toxin (PT) 2.5 µg filamentous hemagglutinin (FHA)
5 µg pertactin (PRN) 3 µg fimbriae types 2 and 3 (FIM)5 µg
Bacterial Toxins Toxins that lyse cells – hemolysins and leukocidins
Toxins that elevate cAMP Toxins that block protein synthesis
Toxins that block nerve function
Vibrionaceae
Vibrio – isolated in 1884
Vibrionaceae Curved or straight bacilli
Aerobic or anaerobic growth
Oxidase positive, non spore formers
Primarily found in water
Produce GI disease Vibrio, Aeromonas, & Plesiomonas
Vibrio Grow on alkaline media but not acidic media
Polar flagella
Physiology & Structure Broad temperature range: 18C to 37C
Gram - negative
Vibrio choleraeSix groups based on somatic O antigens
O1 group: 2 biotypes - el tor & cholerae
2 serological subgroups: ogawa, inaba
Strains with both ogawa & inaba = hikajima
Pathogenesis Toxin binds to specific receptors in the small intestine
Enters the mucosal cells Effects a series of reactions that result in the rapid secretion of Na, K and bicarbonate into the intestinal lumen
Transmission
Pathogenesis 1 liter of fluid loss per hour Vibrio penetrates through the mucous covering the surface of the intestine and adheres to the mucosal cell layer
Virulence Factors – V. cholerae
Cholera enterotoxin, cytotoxin, flagellum, adhesions, mucinase
Cholera Cot – Cholera Facies
Treatment
Because death from cholera is a consequence of dehydration, the disease is treated using oral rehydration therapy (ORT), which consists of large volumes of water mixed with a blend of sugar and salts.
Antibiotics. While antibiotics are not a necessary part of cholera treatment, some of these drugs may reduce both the amount and duration of cholera-related diarrhea. A single dose of doxycycline (Adoxa, Monodox) or azithromycin (Zithromax, Zmax) may be effective.
Toxin Producing Bacteria
• Tetanus – lockjaw (risus sardonicus)
• Diphtheria – upper respiratory & cardiac problems
TetanusTetanus is an acute, often fatal, disease caused by an exotoxin produced by Clostridium tetani.
Clostridium tetani Spores found in soil, dust, animal feces; may persist for months to years
Multiple toxins produced with growth of bacteria
Tetanospasmin estimated lethal dose = 150ng
Clostridium tetani Grown in hamburger!
Peptone based medium.
Neonatal Tetanus Generalized tetanus in newborn infant
Infant born without protective passive immunity
High fatality rate without therapy
Estimated 500,000 deaths worldwide in 2004
Tetanus cases reported worldwide 1990-2004. Ranging from strongly prevalent (dark red) to very few cases (in light yellow) (grey data).
Tetanus
Tetanus Complications Laryngospasm – spasms of vocal cords and respiratory muscles
Fractures – spine and long bones due to muscle spasms and seizures
Formalin-inactivated tetanus toxin
Schedule: 3 or 4 doses + booster, booster every 10 years
Efficacy: approximately 100% Duration: approximately 10 years
Antibiotics help kill the bacteria. Penicillin G is the most commonly used antibiotic for tetanus infection. You might receive it orally or intravenously.
Diphtheria Diphtheria is an acute, toxin mediated disease caused by Corynebacterium diphtheriae. Diphthera – Greek for leather hide.
Antitoxin developed in 1891. Toxoid developed in the 1920’s.
Diphtheria Cultures are grown in a modified Mueller and Miller medium.
Purified by serial ammonium sulfate fractionation and diafiltration.
C. diphtheriae Aerobic gram-positive bacilli Toxin production occurs only when the bacillus is itself infected (lysogenized) by a specific virus carrying the genetic information for the toxin (tox gene). Only toxigenic strains can cause severe disease.
Diptheria
Treatment is with erythromycin orally or by injection (40 mg/kg/day; maximum, 2 gm/day) for 14 days, or procaine penicillin G daily, intramuscularly (300,000 U/day for those weighing 10 kg or less and 600,000 U/day for those weighing more than 10 kg) for 14 days.
The disease is usually not contagious 48 hours after antibiotics are instituted. Elimination of the organism should be documented by two consecutive negative cultures after therapy is completed.
Polysaccharides Bacteria with capsules• Haemophilus influenzae, type b• Neisseria meningitidis• Streptococcus pneumoniae
Capsules
Polysaccharides Bacteria with capsules• Evade APCs – no T-cells activated- children & older adults make few or no antibodies, or short-lived antibodies
- No memory cell production- Antibodies working with APCs are important for bacterial disease protection
Neisseria meningitidis Encapsulated Gram-negative diplococci
Colonize nasopharynx
Cause meningitis
Neisseria meningitidis Bacterial Strains: A/B/C/Y/W-135
Signs and Symptoms Stiff neck Nausea Vomiting Discomfort around bright light Confusion Sleepiness High fever Seizures (as the disease progresses)
Commonly used meningitis treatments include cephalosporins, especially Claforan (cefotaxime) and Rocephin (ceftriaxone). Various penicillin-type antibiotics, aminoglycoside drugs such as gentamicin, and others, are also used
Menomune A/C/Y/W-135 Injected subcutaneously.
Do not inject ID, IM or IV
Conjugate Vaccines Capsule bonded to a protein. Stimulate a more vigorous immune response. More antibody is produced along with memory.
Conjugate Vaccine Conjugate vaccines work much better in young children whose immune systems are immature.
Conjugate Vaccines Haemophilus influenzae type b infections – ActHIB
Streptococcus pneumoniae – Prevnar
Neisseria meningitidis - Menactra
Menactra This vaccine provides protection against bacterial strains A, C, W135, and Y but not against B
Menactra This is the new meningococcal conjugate vaccine from Sanofi-Pasteur licensed in January 2005. It is licensed for 2 to 55 year olds.
Haemophilus influenzae B
Act-HIBHaemophilus influenzae type b (Hib)
Act-HIB ® (Haemophil
us b conjugate vaccine, tetanus protein - conjugate)
01959034 5 x 0.5 mL
Haemophilus influenzae produces beta-lactamases, and it is also able to modify iHaemophilus influenzae produces beta-lactamases, and it is also able to modify its penicillin-binding proteins, so it has gained resistance to the penicillin family of antibiotics.
In severe cases, cefotaxime and ceftriaxone delivered directly into the bloodstream are the elected antibiotics, and, for the less severe cases, an association of ampicillin and sulbactam, cephalosporins of the second and thirdgeneration, or fluoroquinolones are preferred. (Fluoroquinolone-resistant Haemophilus influenzae has been observed.)
Macrolide antibiotics (e.g., clarithromycin) may be used in patients with a history of allergy to beta-lactam antibiotics.[citation needed] Macrolide resistance has also been observed
Combination Vaccines – should be- stable for 18 to 24 months
- Recommended at same age - age appropriate vaccine cocktail
- Adverse effects equal to < separate vaccines
- Immune response at protective levels
- Benefit fewer injections