Tuesday, October 11, 2022

 


 )Edmonston-Enders strain(

1971 Licensure of combined measles-

 mumps-rubella vaccine

1989 Two dose schedule

- Composition Live virus

- Efficacy 95% (range, 90%-98%)

- Duration of

- Immunity Lifelong

- Schedule 2 doses

- Should be administered with mumps and rubella as MMR

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MMR Vaccine

• First dose of MMR at 12-15 months

• Second dose of MMR at 4-6 years

• Second dose may be given any time >4 weeks after the first dose

Rabies

• Rhabdovirus family; genus Lyssavirus

• Enveloped, bullet-shaped virions(Figure 2-36)

• Slow, progressive zoonotic disease

• Primary reservoirs are wild mammals; it can be spread by both wild and domestic mammals

by bites, scratches, and inhalation of droplets.

• Virus enters through bite, grows at trauma site for a week and multiplies, then enters nerve

endings and advances toward the ganglia, spinal cord and brain.(Figure 2-37)

• Infection cycle completed when virus replicates in the salivary glands (Figure 2-38)

• Clinical phases of rabies:

• Prodromal phase – fever, nausea, vomiting, headache, fatigue; some experience pain,

burning, tingling sensations at site of wound

• Furious phase – agitation, disorientation, seizures, twitching, hydrophobia

• Dumb phase – paralyzed, disoriented, stuporous

Figure (2-36) Enveloped bullet shaped Rubies virus

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• Progress to coma phase, resulting in death

Figure (2-37) Rote spread of virus

Figure(2-38) Rabies virus inoculation and replication in infected person

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Rabies Virus diagnosis

Laboratory diagnosis

1. PCR

2. Serology (IFA)

3. Animal control

Rabid or suspected rabid animals are killed and examined by histopathology for Negri bodies and

viral antigen

• Vaccination of pets is required by law in most states

Immunity and protection

- Vaccines

- First one developed by Pasteur by using spinal cords from infected dogs

- Today’s principal vaccine is the human diploid cell vaccine (HDCV) made in the WI-38

fibroblast cell line

- Virus is inactivated by βPL

- Post-exposure prophylaxis

- One dose of hyperimmune antiserum

- Five immunizations over 28 days

Recommended prophylaxis in exposed individuals not previously vaccinated against rabies

Wound site(s)


Human Rabies

Immune Globulin

(RIG)

Rabies Vaccine

Laboratory diagnosis

• Diseased dog: viral antigen and Negri body in brain tissue (Figure2-39).

• Patient: IF assay, PCR.

• Immediate thorough cleansing of all wounds with soap and

water.

• Tetanus prophylaxis

- IU/kg body weight

- should be infiltrated in wound(s)

- The remainder should be given IM

 at a site distant from vaccine

IM (1 mL) in the deltoid area on days 0, 3, 7, 14, and 28

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ORTHOMYXOVIRUSES (Figure 2-40)(Figure2-41)

pleomorphic

influenza types A,B,C (Figure 2-42)

febrile, respiratory illness with systemic symptoms

Figure(2-41)Orthomyxoviruses

Figure(2-40) Orthomyxoviruses structure

A B

Figure (2-39) (A,B) Negri body brain tissue

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Wild aquatic birds are the main reservoir of influenza A viruses. Virus transmission has been

reported from wield waterfowl to poultry, sea mammals, pigs, horses, and humans. Viruses are

also transmitted between pigs and humans, and from poultry to humans. Equine influenza

viruses have recently been transmitted to dogs. (From Fields Vriology (2007) 5th edition, Knipe,

Figure (2-42)Influenza virus nomenclature

Figure(2-43) Influenza A reservoir

,

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DM & Hawley, PM, eds, Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia Figure(2-

43).

Hemagglutinin

• Required for virus binding to cell surface sialyloglygolipids and sialyloglygoproteins.

• Responsible for virus penetration.

• Antibodies to HA neutralize virus.

• Trimer in envelope.

• Cleavage to HA1 and HA2 required for infectivity.

• Fiviteen HA subtypes

1. Lowest homology is 25% (H1 and H3)

2. Highest homology is 80% (H2 and H5)

3. Less than 10% variation within subtype(Figure 2-44).

Neuraminidase

- Removes sialic acid from any glycoconjugate.

- Aids virus spread

Figure(2-44) structural and non-structural coding by influenza virus genome

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- May remove “decoy” receptors on irrelevant cells during infection

- Prevents virus clustering at cell surface upon release

- High concentration of anti-NA antibody are necessary for virus neutralization(Figure 2-45).

Different species harbor different strains of the flu virus:

Table(2-3)and figure(2-46)

• Human flu (Table2-3)

• Bird flu

• Swine flu

• ………………

Figure(2-45)Influenza replication

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Influenza A virus: HA subtypes

Figure(2-46) NA subtypes in different animal species

Table(2-3) Influenza A virus : HA subtypes

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Binds to cell surface carbohydrate - sialic acid

Ubiquitous receptor

Can be present as part of glycoprotein or glycolipid

Specific requirement for  2-3 and  2-6 linkages gives different tropism for avian vs. human cells

(pigs have both)Figure(2-48)

Figure (2-47) Influenza A virus , receptor of AH

Binds to cell surface carbohydrate - sialic acid

Ubiquitous receptor

Can be present as part of glycoprotein or glycolipid

Specific requirement for  2-3 and  2-6 linkages gives

different tropism for avian vs. human cells (pigs have both)

Figure(2-48) Influenza A virus: attachment

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• On the surface of influenza virus reside two major proteins; Haemagglutinin (HA) and

Neuraminidase (NA). Sixteen subtypes of HA (H1 to H16) and nine subtypes of NA (N1 to

N9) are recognized in aquatic birds.

• Death mostly occurs as a consequence of primary viral pneumonia or of secondary

respiratory bacterial infections, especially in patients with underlying pulmonary or

cardiopulmonary diseases which causes death in different outbreak time( Figure2-50).

Figure(2-49) Type A influenza cannot be eradicated

Figure(2-50) Eras of human Influenza A virus

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Viruses undergo genetic change by several mechanisms

• Genetic drift where individual bases in the DNA or RNA mutate to other bases.

• Antigenic shift is where there is a major change in the genome of the virus. This occurs as a

result of recombination(Figure2-51).

Seasonal flu/ Pandemic flu

• Epidemic (seasonal) influenza which occurs annually and is attributable to minor changes in

genes that encode proteins on the surface of circulating influenza viruses. These are known

as interpandemic epidemics.

• Pandemic influenza which occurs when more significant changes in the influenza A virus

arises when human virus strains acquire genes from influenza viruses of other animal

species. When this happens, everyone in the world is susceptible to the new virus, and a

worldwide epidemic or pandemic can result.

Reassortment of Gene Segments

• Influenza has 8 separate gene segments that encode 10 different proteins

• When a host cell is infected with two different influenza viruses, the progeny virus can be a

mixture of both “parent” viruses

Figure(2-51)Antigenic variation of influenza virus envelope proteins

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• Reassortment provides for increased biological variation that increases the ability of the virus

to adapt to new hosts (figure 2-51) which result a pandemic influenza (Figure 2-53)

Figure(2-52)genetic mutation of influenza A-Antigenic drift B-Antigenic shift

A

B

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Avian Influenza

• Avian influenza is an infectious disease of birds caused by type A strains of the influenza

virus.

• These viruses occur naturally among wild aquatic birds worldwide and can infect domestic

poultry and other bird and animal species. The disease, which was first identified in Italy

more than 100 years ago.

• Fifteen subtypes of influenza virus are known to infect birds, thus providing an extensive

reservoir of influenza viruses potentially circulating in bird populations.

• H5N1; the strain of avian flu known as has been behind outbreaks of deadly avian flu.

• Migratory water birds, especially wild ducks. They may do not show clinical disease. The

virus colonizes the intestinal tract and is spread in the feces . They act as a reservoir for the

infection of other species .

• Pigs can be infected by bird influenza (as well as by the form of influenza that affects

humans) and can pass on the flu to humans.

Figure(2-53) Generation of pandemic influenza virus strains

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Swine Flu

- Influenza in swine was first recognized as an epizootic disease in 1918.

- Swine influenza virus was first isolated from humans in 1974. Serologic evidence of

infections with a swine influenza virus in humans has also been obtained. Viruses of swine

may be a potential source of epidemic disease for humans.

Avian Influenza

- Avian influenza transmitted by birds usually through feces or saliva.

- Avian influenza is not usually passed on to humans, although it has been contracted by

people who have handled infected birds or touched surfaces contaminated by the birds.

Swine Flu

• Swine influenza (swine flu) is a respiratory disease of pigs caused by type A influenza virus

that regularly cause outbreaks of influenza in pigs.

• Like human influenza viruses, there are different subtypes and strains of swine influenza

viruses. The main swine influenza viruses circulating in U.S. pigs in recent years are: H1N1

influenza virus, H3N2 virus, H1N2 virus.

Figure(2-54) Influenza virus: the immune response

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Influenza Prevention

 Vaccination before the start of influenza season

• Northern Hemisphere: October-November

• Southern Hemisphere: April-May

 Antiviral treatment

• Therapeutic

• Prophylactic

Vaccination

 Trivalent: two current A strains and one current B strain.

 For 2010 season (Figure 2-55)

• A/California/7/2009 (H1N1)–like virus

• A/Perth/16/2009 (H3N2)–like virus

• B/Brisbane/60/2008–like virus

 Formalin fixed “wild type” virus approved for parenterally administered vaccination.

 Live attenuated vaccine (“Flumist”)

 Temperature sensitive recombinant bearing relevant HA and NA genes.

 Must anticipate shift and drift in order to identify appropriate vaccine strain.

Figure(2-55) General steps for influenza vaccine production

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5.Hepatitis B Virus

Hepatitis (Liver-Attacking) Viruses

Hepatitis A – fecal/oral, contaminated food, vaccine available

Hepatitis B – blood, semen, vertical (mother-child), vaccine available

Hepatitis C – blood (IV drug use, transfusion, organ donation, unsterile injecting equipment, sexual

intercourse)

Hepatitis D – survives only in cells co-infected with hepatitis B

Hepatitis E* – contaminated food or water, fecal/oral(Table 2-3)

*causes short-term disease and is not a chronic carrier state

Table (2-3)Characteristics of hepatitis viruses

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Hepatitis B

- Hepatitis B is caused by infection with the Hepatitis B virus (HBV), the prototype member of

the hepadnavirus family

- It has a circular DNA genome of 3.2 kb (Figure 2-56)

- Currently, eight genotypes (A−H) are identified by a divergence of >8% in the entire genom

(Figure 2-57)

Hepatitis B Characteristics

• A Hepadnaviridae – partially double-stranded DNA virus

• HBsAg – stimulates protective antibodies, a marker for current infection

• HBcAg – localized within liver cells, identifies acute infection, anti-HBcAg persists for life

and is a marker of past infection

• HBeAG – a marker of active replication and infectivity

Hepatitis B Virus :

- Hepadnaviridae family (DNA)

- Numerous antigenic components

- Humans are only known hosts

- May retain infectivity for more than 7 days at room temperature

Figure(2-56)Hepatitis B

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Hepatitis B virus infection :

- More than 350 million chronically infected worldwide

- Established cause of chronic hepatitis and cirrhosis

- Human carcinogen – cause of up to 80% of hepatocellular carcinomas

- More than 600,000 deaths worldwide in 2002

-

Epidemiology

• Worldwide, HBV is the primary cause of liver cancer

1. For males, it is the third leading cause of cancer mortality

2. For females, it is the sixth leading cause of cancer mortality

Epidemiology

• The incubation period from the time of exposure to onset of symptoms is 6 weeks to 6

months.

• HBV is found in highest concentrations in blood and in lower concentrations in other body

fluids (e.g., semen, vaginal secretions, and wound exudates).

Figure(2-57) Geographic distribution of Hepatitis virus

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• HBV infection can be self-limited or chronic.

• In adults, only approximately half of newly acquired HBV infections are symptomatic, and

approximately 1% of reported cases result in acute liver failure and death.

Diagnosis

• Hepatitis B is detected by looking for a number of different antigens and antibodies:

Hepatitis B surface antigen (HBsAg):

- A protein on the surface of HBV; it can be detected in high levels in serum during acute or

chronic HBV infection.

- The presence of HBsAg indicates that the person is infectious.

- The body normally produces antibodies to HBsAg as part of the normal immune response to

infection.

- HBsAg is the antigen used to make Hepatitis B vaccine.

Hepatitis B is detected by looking for a number of different antigens and antibodies:

Hepatitis B surface antibody (anti-HBs):

• The presence of anti-HBs is generally interpreted as indicating recovery and immunity from

HBV infection.

• Anti-HBs also develops in a person who has been successfully vaccinated against Hepatitis

B.

Total Hepatitis B core antibody (anti-HBc):

• Appears at the onset of symptoms in acute Hepatitis B and persists for life.

• The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined

time frame.

Hepatitis B is detected by looking for a number of different antigens and antibodies:

IgM antibody to Hepatitis B core antigen (IgM anti-HBc):

• Positivity indicates recent infection with HBV (≤6 months).

• Its presence indicates acute infection.

Hepatitis B e antigen (HBeAg):

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• A secreted product of the nucleocapsid gene of HBV that is found in serum during acute and

chronic Hepatitis B.

• Its presence indicates that the virus is replicating and the infected person has high levels of

HBV.

Hepatitis B is detected by looking for a number of different antigens and antibodies: (Table 2-4)

Hepatitis B e antibody (HBeAb or anti-HBe):

• Produced by the immune system temporarily during acute HBV infection or consistently

during or after a burst in viral replication.

• Spontaneous conversion from e antigen to e antibody (a change known as seroconversion) is

a predictor of long-term clearance of HBV in patients undergoing antiviral therapy and

indicates lower levels of HBV. (Figure 2-58)

Table (2-4) Hepatitis B

Typical interpretation of serologic test results for hepatitis B virus infection

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Figure(2-58)Immune response of hepatitis B virus A-Chronic hepatitis B , B-Acute of hepatitis B virus

A

B

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Hepatitis B complication :

- Fulminant hepatitis

- Hospitalization

- Cirrhosis

- Hepatocellular carcinoma

- Death

Chronic Hepatitis B virus infection :

- Chronic viremia(Figure 2-59)

- Responsible for most mortality

- Over risk 5% (Figure 2-60)

- Higher risk with early infection

Hepatitis B perinatal transmission :

 If mother positive for HBsAg and HBeAg

- 70%-90% of infected

- 90% of infected infants become chronically infected

 If positive for HBsAg only

Figure (2-59) Hepatitis B virus multiplication

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- 5% - 20% of infants infected

- 90% of infected infants become chronically infected

Global patterns of chronic HBV infection :

 High (> 8%) : 45% of global population

- Lifetime risk of infection >60%

- Early childhood infections common

 Intermediate (2%-7%):43% of global population

- Lifetime risk of infection 20%-60%

- Infections occur in all age groups

 Low(<20%):12% of global population

- Lifetime risk of infection <20%

- Most infections occur in adult risk groups

Adult at risk for HBV infection :

 Sexual exposure

- Sex partners of HBsAg-positive persons

- Sexual active persons not in a long – term , mutually monogamous relationship.

- Persons seeking evaluation or treatment for a sexually transmitted disease.

- Men who have sex with men.

adults at Risk for HBV Infection

Figure (2-60) Risk of chronic HBV carriage by age of infection

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 percutaneous or mucosal exposure to blood

- current for recent IDU

- household contacts of HBsAg-positive person

- residents and staff of facilities for development disabled persons.

- Healthcare and public safety workers with risk for exposure to blood or blood-contaminated

body fluids.

- Persons with end-stage renal disease

- Persons with diabetes mellitus.

Hepatitis B Treatment

 For acute infection, no medication is available; treatment is supportive.

 For chronic infection, several antiviral drugs (adefovir dipivoxil, interferon alfa-2b, pegylated

interferon alfa-2a, lamivudine, entecavir, and telbivudine) are available.

- Persons with chronic HBV infection require medical evaluation and regular monitoring to

determine whether disease is progressing and to identify liver damage or hepatocellular

carcinoma.

Hepatitis B Elimination

 CDC’s national strategy to eliminate transmission of HBV infection includes:

1. Prevention of perinatal infection through routine screening of all pregnant women for

HBsAg and immunoprophylaxis of infants born to HBsAg-positive mothers and infants born

to mothers with unknown HBsAg status

2. Routine infant vaccination

3. Vaccination of previously unvaccinated children and adolescents through age 18 years

4. Vaccination of previously unvaccinated adults at increased risk for infection

Hepatitis B Vaccine

 Composition Recombinant HBsAg

 Efficacy 95% ( Range , 80%-100%

 Duration of Immunity 20 years or more

 Schedule 3 Doses

 Booster doses not routinely recommended

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6.Enteroviruses

 Enteroviruses are a genus of the picornavirus family which replicate mainly in the

gut.(Figure2-61)

 Single stranded naked RNA virus with icosahedral symmetry

 Unlike rhinoviruses, they are stable in acid pH

 Capsid has 60 copies each of 4 proteins, VP1, VP2, VP3 and VP4 arranged with icosahedral

symmetry around a positive sense genome.

 At least 71 serotypes are known: divided into 5 groups

1. Polioviruses

2. Coxsackie A viruses

3. Coxsackie B viruses

4. Echoviruses

5. Enteroviruses (more recently, new enteroviruses subtype have been allocated sequential

numbers (68-71) Figure(2-62)

History

 Poliovirus - first identified in 1909 by inoculation of specimens into monkeys. The virus was

first grown in cell culture in 1949 which became the basis for vaccines.

 Coxsackieviruses - In 1948, a new group of agents were identified by inoculation into

newborn mice from two children with paralytic disease. These agents were named

coxsackieviruses after the town in New York State. Coxsackieviruses A and B were identified

on the basis of the histopathological changes they produced in Newborn mice and their

capacity to grow in cell cultures.

 Echoviruses - were later identified which produced cytopathic changes in cell culture and

was nonpathogenic for newborn mice and subhuman primates.

 More recently, new enterovirus types have been allocated sequential numbers (68 - 71).

Figure(2-61)Enterovirus Particles

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Table(2-5) Categories of Enteroviruses

Figure(2-62)

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Poliovirus

- 3 serotypes of poliovirus (1, 2, and3) but no common antigen.

- Have identical physical properties but only share 36-52% nucleotide homology.

- Humans are the only susceptible hosts.

- Polioviruses are distributed globally. Before the availability of immunization, almost 100% of

the population in developing countries before the age of 5.

- The availability of immunization and the poliovirus eradication campaign has eradicated

poliovirus in most regions of the world except in the Indian Subcontinent and Africa.

- Poliovirus is on course of being eradicated worldwide by the end of 2000 or 2001.

Pathogenesis

The incubation period is usually 7 - 14 days.

Following ingestion, the virus multiplies in the oropharyngeal and intestinal mucosa.

Figure(2-63)Pathogenesis of enterovirus infection

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The lymphatic system, in particular the tonsils and the Peyer's patches of the ileum are invaded and

the virus enters the blood resulting in a transient viraemia.

In a minority of cases, the virus may involve the CNS following dissemination. (Figure 2-63)

Figure (2-64) Population infection A-Indene children with poliomyelitis B-outbreak au early 20th country C- Evidence of poliomyelitis in

the pharaohs

B

A

C

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Born in 1882 at Hyde Park, New York--now a national historic site--he attended Harvard

Universityand Columbia Law School. On St. Patrick's Day, 1905, he married Eleanor Roosevelt .

Following the example of his fifth cousin, President Theodore Roosevelt, whom he greatly admired,

Franklin D. Roosevelt entered public service through politics, but as a Democrat. He won election to

the New York Senate in 1910. President Wilson appointed him Assistant Secretary of the Navy, and

he was the Democratic nominee for Vice President in 1920 .

In the summer of 1921, when he was 39, disaster hit-he was stricken with poliomyelitis.

Demonstrating indomitable courage, he fought to regain the use of his legs, particularly through

swimming. At the 1924 Democratic Convention he dramatically appeared on crutches to nominate

Alfred E. Smith as "the Happy Warrior." In 1928 Roosevelt became Governor of New York .

He was elected President in November 1932, to the first of four terms.)Figure2-65)

Immunity

 Antibody is the major protective immune response to the enteroviruses . Secretory antibody

can prevent the initial establishment of infection in the oropharynx and gastrointestinal tract,

and serum antibody prevents viremic spread to the target tissue and therefore disease.

 Cell-mediated immunity is not usually involved in protection but may play a role in

pathogenesis.

Clinical Manifestations

Figure(2-65)Franklin D. Roosevelt

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There are 3 possible outcomes of infection:

1. Subclinical infection (90 - 95%) - inapparent subclinical infection account for the vast

majority of poliovirus infections.

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