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Flashcards in *M40: Vaccines Deck (33)
1

a. Vaccine: a suspension of microorganisms (live attenuated or killed) or fractions of microorganisms, administered to induce immunity and prevent disease.

b. Immunization: artificially inducing an immune response or providing protection against an infectious disease.

c. Active immunization: inducing the body to mount a protective immune response.

d. Passive immunization: transferring exogenous antibody for temporary protection.

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e. Toxoid: Bacterial toxin rendered non-toxic and used to stimulate anti-toxin antibodies.

f. Adjuvant: a substance sometimes mixed with the vaccine components to induce a stronger immune response; particularly important when a subunit antigen is used (“danger” signal).

g. Sterilizing immunity: an immune response that completely eliminates the infection.

h. Herd immunity: the resistance of a population to an infectious agent due to the immunity of a high proportion of the population

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Effectiveness of vaccination:

Example: In the US, measles killed 3000 people per year and caused 48,000 hospitalizations prior to immunization. When immunization rates declined a decade ago, there was an outbreak of 55,000 cases, with 11,000 hospitalizations and 125 deaths. Following introduction of a vaccine in the US, a number of infectious diseases were reduced so far as to be virtually eliminated within 5-10 years (e.g. polio, diptheria, neonatal tetanus, measles, rubella).

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Immunologic responses to vaccines

a. The primary immune response to an antigen takes 7-10 days—T cells must be primed and proliferate, help is then provided to B cells or CD8 T cells, and these cells proliferate. In the absence of an actual infection, the cells become memory cells. Upon challenge with a microbe, a secondary response, which is much faster and more robust, is mounted and the infection is eliminated or disease is averted.

b. Best case scenario for developing a vaccine: prior infection (once) protects against subsequent infection.

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Immunologic responses to vaccines

c. Live vaccines can induce antibodies as well as effector T cells, while subunit or killed vaccines primarily induce antibody responses. Most vaccines that are used today work by inducing a strong antibody response that can inactivate the toxin or prevent viruses from entering cells. There are many infectious diseases for which an effective vaccine has yet to be developed. These infections are often complex, with protection dependent on various aspects of the immune response, and have immune-subverting mechanisms. Also, chronic infections, which can persist in the face of the immune response, are very difficult to vaccinate against.

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Vaccines not available for some of the world’s biggest killers

Vaccines urgently needed for diseases such as:
Tuberculosis
Malaria
HIV
Worm infections
Diarrheal diseases
Respiratory infections
Sexually transmitted diseases (gonorrhea, Chlamydia, syphilis)
Trypanosomal infections

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Safety issues:

Modern vaccines are safe and effective, but there are risks. Each vaccine is associated with some adverse effects, mostly mild, but occasionally severe. There has been substantial controversy regarding safety of vaccines, and some parents choose not to vaccinate their children because of fears about vaccine safety. Overall, the benefits of vaccination far outweigh any risks. Vaccine use comes under frequent review, and modifications to reduce risk occur. For example, the acellular pertussis vaccine is now used instead of the killed whole pertussis vaccine, because there are many fewer side effects. Inactivated polio vaccine is used now instead of live attenuated polio vaccine, because the only polio cases (~5/year) that were seen in the US in recent years were due to the vaccine.

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Herd immunity: effects of vaccination on the public

a. When a large group of people (i.e. school-age children) are vaccinated, there is little reservoir for the infectious agent. Thus, even those children not vaccinated are “protected” from disease, simply due to the fact that there is less chance to be infected.

b. Some live vaccines can be passed to other, non-vaccinated individuals

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Live attenuated microorganisms

a. microbe is rendered relatively avirulent (frequently by repeated passage in vitro).

b. replicates in the recipient, inducing a strong immune response. Frequently, protection is long-lived and only one dose is necessary.

c. A more comprehensive immune response may be induced by live vaccines.

d. Examples: measles, mumps, rubella, smallpox, BCG, oral polio. Some safety issues.

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Killed/inactivated microorganisms

a. organism is killed, and used as a vaccine. Usually requires more than one dose to induce strong responses, and boosters are also necessary.

b. Usually induces an antibody response.

c. Examples: whole pertussis, inactivated polio vaccine, hepatitis A.

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Subunit vaccines

a. Purified components of microorganisms, such as toxoids, recombinant antigens, polysaccharides conjugated to carrier proteins.

b. Usually repeated doses are needed, with adjuvant, and antibody responses are induced.

c. Examples: hepatitis B vaccine, tetanus, diptheria, Hib, acellular pertussis.

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Other vaccines

a. Other vaccines available and used as needed

Some vaccines are delivered to travelers to other countries as protection
• e.g. typhoid vaccine

Some vaccines are delivered to at risk subpopulations in the US
• rabies vaccine, pneumococcal vaccine, anthrax

Some vaccines are commonly used in other countries, but not in the US
• e.g. BCG (vaccine against tuberculosis)

Booster for tetanus and pertussis (pertussis as booster for adults is relatively new)

b. Future vaccines
DNA immunization
Heterologous vectors (viral or bacterial)
More subunit and recombinant vaccines

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13

MMR vaccine: Mumps, measles, rubella
Mumps:

a. Virus characteristics: Family Paramyxoviridae, Genus Rubulavirus
- Single stranded negative sense RNA virus
- One serotype known

b. Disease
- Acute viral infection with swelling and tenderness of the parotid and salivary glands
- Symptoms: fever, malaise, headache, involvement of parotid and salivary glands
- Usually fairly benign; complications can include meningitis and epididymo-orchitis (rare before puberty).

c. Vaccine (1967)
- Attenuated virus grown in chick embryo cell culture
- Single immunization produces anti-mumps neutralizing antibody in >95% children
- Given at >12 months of age, to avoid maternal antibodies

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MMR vaccine: Mumps, measles, rubella
Measles:

a. Virus characteristics: Family Paramyxoviridae, Genus Morbillivirus
- Rubeola virus (also called measles virus)
- Single stranded negative sense RNA virus
- Important membrane glycoproteins include hemagglutinins and the F (fusin) protein

b. Disease: extremely contagious, still a major killer of children in the developing world
- Respiratory transmission
- Incubation period 10-14 days
- Clinical manifestations: malaise, fever, runny nose, respiratory symptoms (cough) precede the rash. Koplik spots also precede rash (bluish gray specks on a red base inside the mouth).
- Rash: usually begins on face, proceeds down body, with extremities last. Erythematous and maculopapular; usually lasts 5 days.
- Entire illness 7-10 days

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MMR vaccine: Mumps, measles, rubella
Measles:

c. Complications:
- Respiratory tract complications (secondary bacterial infection) neurologic (encephalitis) with possible long term effects
- Long term immunosuppression, resulting in enhanced susceptibility to other infections

d. Vaccine (1963)
- Live attenuated virus grown in cell culture
- Immunity is probably antibody and T cell-mediated
- Long lasting immunity
- Given at 12-15 months of age because of maternal antibodies
- Can be a problem in other countries where measles is still prevalent—vaccination of younger children is sometimes performed, but these children may be less protected

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MMR vaccine: Mumps, measles, rubella
Rubella (German measles):

a. Virus characteristics: Family Togaviridae, Genus Rubivirus
- Positive sense single stranded RNA virus

b. Disease
- Respiratory transmission
- Incubation period 12-23 days
- Age determines severity of disease: postnatally acquired infection is usually mild.
- However, infection of a fetus during maternal rubella is likely to have severe consequences.
- Postnatal: many are subclinical infection, rash develops in symptomatic individuals
- Congenital rubella: infection in early gestation very dangerous, can lead to fetal death, premature delivery and congenital defects, such as deafness, myopia, heart disease, mental retardation

c. Vaccine (1969)
- Live attenuated virus
- Rationale: prevent congenital rubella by controlling postnatal rubella
- No major epidemics in the US in the past 35 years

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Chickenpox (Varicella zoster virus--VZV):

a. Transmission is via the respiratory route
- 1-4 million cases yearly

b. Primary infection causes varicella (chicken pox)
- Incubation period is ~14 days, with fever headaches, malaise preceding a exanthematous rash. Rash begins on the face, scalp or trunk, and the vesicular lesions are very itchy. Usually self-limiting. Complications happen in some cases, most commonly in adults and immuno-compromised children
- Secondary bacterial infection of the lesions can occur from scratching
- Patient is infectious 48 hr before rash and 4-5 days after rash onset.

c. Reactivation of latent infection results in herpes zoster (shingles)
- Occurs in ~15% of infected individuals (~500,000 cases per year)
- Lesions are clustered and dermatomal (affecting area of skin supplied by branches from a single spinal nerve)
- Lesions can be very painful

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Chickenpox (Varicella zoster virus--VZV):

Virus characteristics
- Herpesvirus (DNA virus)
- Similar to Herpes simplex virus genetically
- Establishes latency in sensory ganglia, but is disseminated so multiple ganglia are
infected

Treatment

a. Varicella: treatment is designed to reduce risk of complications.
- Hygiene, bathing, topical dressings if necessary.
- Acyclovir, but not generally used

b. herpes zoster
- acyclovir or other drugs are sometimes used

Vaccine
- Live attenuated vaccine Varivax introduced in 1995
- 86% effective against varicella, 100% against severe disease
- also used to prevent shingles (reactivation of varicella) in older persons

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Smallpox:

1. Disease was eradicated worldwide—last case was in Somalia in 1977.
- Vaccination caused eradication. Routine vaccination in the US was discontinued in ~1972.

2. Virus characteristics; pox virus Family Poxviridae
- Variola virus
- Double stranded DNA virus
- Replication proceeds entirely in the cytoplasm with virus providing all the necessary enzymes for DNA replication and gene expression
- Very similar to vaccinia virus, but less is known about variola because it is not studied due to laboratory hazards
- Variola infection is limited to human (and perhaps monkeys)
- Variola strains: variola major and variola minor.
- Variola major is most virulent, with mortality of 20-50%.

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Smallpox:

3. Disease characteristics
- Virus infects upper respiratory tract, then spreads to regional lymph nodes and throughout body. Can be isolated from the blood easily before rash occurs.
- Requires close contact to spread
- Incubation period of 12 days
- Rash progresses in a uniform pattern from maculopapules to vvesicles to pustules and scabs over 1-2 weeks
- Death can occur even before a rash appears in the most severe form, but also occurs up to a month after infection.
- Death can be caused by bleeding, cardiovascular collapse, secondary infections

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Smallpox:

4. Vaccine
- Vaccinia virus used as the vaccine against smallpox
- Factors contributing to the success of vaccination
--> One antigenic type
--> No persistent carriers or asymptomatic infections
--> No animal reservoir
--> Highly lethal, disfiguring disease: frightening to people, which was a strong induction to be vaccinated

5. Smallpox as a biological weapon
- Estimated that >40% of the US population is unprotected against smallpox
- Respiratory route of transmission and a fairly stable virus
- Highly contagious with a high fatality rate

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Human Papilloma virus vaccine:

1. HPV is non-enveloped, encapsulated, doubles stranded DNA virus.
- Common sexually transmitted infection: 22.5% prevalence in US women, ~43% in some parts of Africa

3. >100 different HPV genotypes, ~40 infecte genital mucosa
- Low risk: HPV6, HPV 11 produce genital warts
- High risk (15 known oncogenic HPV genotypes): HPV16 (~50% of all cervical cancers,
- HPV18 20% of all cervical cancers)

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Human Papilloma virus vaccine:

4. Vaccine newly approved by FDA “Gardasil” (Merck)
- Virus like particle (VLP) non-infectious capsid like particle, no nucleic acids,
--> Composed of L1 capsid of 4 HPV genotypes: HPV 6, 11, 16, 18
--> Capsid protein is produced in yeast, and assumes native conformation
--> Induces strong nuetralizing antibody response (adjuvant for Gardasil is alum)
- Trials indicate infection with these 4 genotypes or HPV-associated genital warts in vaccinated group was decreased by 90%, and overall cervical cancer rates decreased 97-100%. A very effective vaccine

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Human Papilloma virus vaccine:

2. Cause of genital warts and cervical cancer; only a small percentages of infections lead to cancer

5. Additional vaccine in human trials is also a recombinant capsid, made in insect cells, with AS05 adjuvant, that only targets HPV16 and 18 (Glaxo-Smith-Kline)

6. Vaccination issues: target vaccine to 11-13 year old girls (before they are sexually active)
- Now approved by some insurance programs for teenage boys
- Access in developing countries?

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Bordetella pertussis:

Causative agent of whooping cough

a. gram negative coccobacillus

b. strict aerobe, nutritionally fastidious (need complex media containing blood)

c. very sensitive to environment and don’t survive outside the body for long

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Bordetella pertussis:
Whooping cough:

a. severe childhood disease, highly communicable—still a disease of worldwide importance

b. adults generally get a much milder version of disease, but adults with mild disease (similar to a cold) are reservoir for transmission. Even asymptomatic adults that are infected can transmit infection.

d. course of disease: tracheitis and bronchitis, with accumulation of mucus, cells, and bacteria in the airways. Mucociliary elevator is impaired, cough is easily triggered because of sensitization of cough receptors by a toxin produced by the bacteria. Intense coughing can lead to hemorrhages or vomiting.

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Bordetella pertussis:
Whooping cough:

c. can be life-threatening or lead to neurologic sequelae

e. Early infection, symptoms look like common cold, but this is the most infectious phase

f. Complications include secondary infections (such as pneumonia) and physical sequelae from the paroxysmal cough. CNS abnormalities can occur—e.g. convulsions (febrile or afebrile)

g. Antibiotic treatment at stage of severe coughing doesn’t have a major effect, but may prevent some transmission.

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Bordetella pertussis:
Pathogenesis—virulence factors:

a. pertussis enters the trachea and bronchi by inhalation and attach to the cilia of epithelial cells of the large airways. The organisms do not invade tissue, but remain on the mucosal surface. There are specific adhesins for attaching to these cells:
- Filamentous hemagglutinin (FHA) binds to glycolipids (sulfatides)
- Pertussin toxin (PT) functions as an adhesin and a toxin
- Pili also facilitate binding to cells
- Can also bind to neutrophils via CR3

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Bordetella pertussis:
Pathogenesis—virulence factors:

b. Spread and multiplication
- Bacteria multiply rapidly and spread along the mucosa of the lower respiratory tract
- Large numbers of bacteria become trapped in cilia and mucus, the submucosa becomes inflamed, and destruction of epithelial cells can occur
- The intense and uncontrollable cough has a distinctive “whoop” noise, and persists for ~2 months—the body is trying to clear the airways of the material that accumulates because the mucociliary elevator function is impaired.

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Bordetella pertussis:
Pathogenesis—virulence factors:

c. Damage to host
- A number of toxins are produced by B. pertussis that contribute to the disease
i. Pertussis toxin (PT): A-B exotoxin composed of the B (binding) domain which has 5 non-identical subunits and the A (active) portion that ADP ribosylates host cell G proteins resulting in a rise in host cell cAMP levels and disrupting cellular signaling functions.
ii. Adenylate cyclase: secreted by B. pertussis and penetrates host cells, where it is activated by a mammalian calmodulin—also increases intracellular cAMP
iii. tracheal cytotoxin derived from peptidoglycan—specifically kills ciliated cells and induces local damage
iv. heat-labile (aka dermonecrotic) toxin: may also be involved in local damage

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Bordetella pertussis:
Pathogenesis—virulence factors:

d. Transcriptional regulation of virulence gene expression
- Bvg system (bvgA, bvgS) two component regulatory system
- BvgS histidine kinase that senses environmental signals, bvgA transcriptional activator of virulence genes. BvgS is phosphorylated and transfers that phosphate to bvgA, which then acts to induce transcription of pertussis toxin genes, fha genes, etc. Actual signals not known, but temperature (37°C) and low Mg2+ can be used in lab to induce Bvg+ state. Bvg+ state is the in vivo relevant state, and the reservoir of Bvg- bacteria is unknown.

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Bordetella pertussis:
Vaccination:

Traditional vaccine was killed whole B. pertussis, given with purified diptheria and tetanus toxoid proteins (DPT). There were complications associated with the pertussis component, including: fever, malaise, pain at injection site (due to inflammatory response to the whole organism). Neurologic symptoms were observed in a small number of children, although not necessarily due to the vaccine. However, the perception was that the vaccine had the potential to be dangerous, and some parents didn’t want their children to have it.

An acellular version of the pertussis portion of the DPT vaccine is now routinely used (DtaP): contain PT (inactive), and may also contain FHA, pertactin (an adhesin), and fimbriae. Vaccines with 3-5 components are better than 1-2 components. Adverse reactions are much lower with the acellular version and it is now recommended for all 5 vaccinations of children in the US.

Adults should be boosted since they are major carriers—adult booster contains lower levels of the pertussis antigens

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Bordetella pertussis:
Recent outbreaks of pertussis could be due to:

a. poor vaccination rates…but in general vaccination rates are 85%, so likely not the cause of the recent outbreak

b. genetic changes in B. pertussis due to vaccine pressure
i. although there are changes in B. pertussis genes, they do not seem to result in immune evasion

c. Better diagnosis and reporting of cases
i. PCR based identification of cases increases case finding, but clinical disease is increased as well, so this is likely not the reason for the increased incidence in the past few years.

d. Reduced efficacy of acellular version of vaccine
i. Compared to whole cell version, does not appear to be as effective
ii. Protection wanes quickly after last dose of vaccine (NEJM, 2012)
iii. Better vaccine needed, with immunogenicity and long term protection of the original whole cell vaccine and fewer side effects.

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