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