II Flashcards

Question

EVD Impacts on the Fragile Healthcare Systems of the Worst Affected Countries

Answer 1

* Increase in infant and maternal mortality rates * Increase incidence of other infectious diseases * Death resulting from otherwise curable diseases * Increase rate of teenage pregnancy * Lack of trust between doctors and patients

Answer 2

* Enveloped, Single stranded RNA virus * contains envelope proteins E and M * Positive sense non-segmented RNA genome * Flaviviridae family * Virus genome is 1079 bases long * Open reading frame codes for a polyprotein that is cleaved into capsid, membrane and non-structural proteins

Answer 3

* mosquito-borne disease * Zika is primarily spread by the female Aedes aegypti mosquito which is active mostly in the daytime. The mosquitos must feed on blood in order to lay eggs * Vector: Aedes genus of mosquitoes * Little is known about ZIKV host factors * May affect neural progenitor cells * Detection of viral RNA in amniotic fluid * Most infections are asymptomatic

Answer 4

Early clinical symptoms: mild fever, myalgia (pain in muscles), fatigue, conjunctivitis, arthralgia (pain in joints), skin rashes Clinical complications: Microcephaly, Guillain–Barré syndrome (GBS)

Answer 5

Guillain-Barré syndrome (GBS) is a rare disorder in which a person’s own immune system damages their nerve cells, causing muscle weakness and sometimes paralysis. GBS can cause symptoms that usually last for a few weeks. Most people recover fully from GBS, but some people have long-term nerve damage.

Answer 6

* first identified in 1947 from rhesus monkeys in the Zika forest of Uganda * mostly endemic to tropical Africa & Southeast Asia * multiple outbreaks around the globe, including North and South America

Answer 7

* non-human primates (NHPs) | * 10 days incubation period in mosquitos

Answer 8

* Mainly transmitted by Aedes genus of mosquitoes * Can be sexually transmitted through semen * infect most mammals * Communicability: CAN be spread prior to, during and after onset of symptoms

Answer 9

* VACCINES: no licensed vaccines or cure * Experimental therapies: Fluids through IV, antiviral drugs, Inovio's DNA vaccine * Public Health measures: quarantine infected individuals, controlling mosquito populations

Answer 10

* Developed by Inovio Pharmaceuticals * DNA based vaccine * Use of multiple antigens * Robust antibody and broad T-cell responses in mice * Primate and human safety studies next * Inovio Pharmaceuticals Inc. recently stated that its pre-clinical testing for the company’s synthetic vaccine designed to protect people from the Zika virus has shown a robust, durable immune response in test subjects.

Answer 11

Diphtheria is caused by a bacterium, Corynebacterium diphtheriae. The actual disease is caused when the bacteria release a toxin, or poison, into a person's body.

Answer 12

Diphtheria bacteria live in the mouth, throat, and nose of an infected person and can be passed to others by coughing or sneezing. Occasionally, transmission occurs from skin sores or through articles soiled with oozing from sores of infected people.

Answer 13

The incubation period is short: 2–5 days, with a | range of 1–10 days.

Answer 14

Early symptoms of diphtheria may mimic a cold with a sore throat, mild fever, and chills. Usually, the disease causes a thick coating at the back of the throat, which can make it difficult to breathe or swallow. Other body sites besides the throat can also be affected, including the nose, larynx, eye, vagina, and skin.

Answer 15

Diphtheria is a serious disease: 5%–10% of all people with diphtheria die. Up to 20% of cases lead to death in certain age groups of individuals (e.g., children younger than age 5 years and adults older than age 40 years).

Answer 16

* In respiratory tract, there is formation of “pseudomembrane” interferes with breathing and may lead to suffocation * Heart and neurological damage also seen

Answer 17

* Pathology mediated by a secreted exotoxin * Injection of toxin in absence of bacteria replicates disease * Once internalized, toxin interferes with protein synthesis * A single toxin molecule may kill a cell * Pathogenic strains secrete an exotoxin * The toxin is actually coded for by a lysogenized bacteriophage (prophage) * Without the phage the bacteria cannot release the toxin or colonize the respiratory tract

Answer 18

* May be treated by passive immunization with antitoxin * Active immunization employs formaldehyde-inactivated toxoid, which retains the protective epitopes but cannot cause disease * Once a feared killer of children, vaccination against diphtheria has essentially eliminated disease from U.S.

Answer 19

*Gram-positive, rod-shaped bacteria that are aerobic and non-motile, with characteristic metachromic granules *metachromic granules are composed of polymerized inorganic polyphosphate, an energy rich compound that may act as a reserve of energy for cell metabolism *Discovered in 1884 by German bacteriologists Edwin Klebs and Friedrich Löffler *Member of the Corynebacterium genus, which are commonly found in the environment Some nonpathogenic species, such as C. glutamicum, are used in the food industry *Four subspecies of C. diphtheriae gravis, mitis, belfanti, and intermedius Varying severities between the four biotypes

Answer 20

Gram-positive bacteria are bacteria that give a positive result in the Gram stain test. This is because the thick peptidoglycan layer in the bacterial cell wall retains the stain after it is washed away from the rest of the sample, in the decolorization stage of the test.

Answer 21

Temperate viruses usually do not kill the host bacterial cells they infect. Their chromosome becomes integrated into a specific section of the host cell chromosome. Such phage DNA is called prophage and the host bacteria are said to be lysogenized. In the prophage state all the phage genes except one are repressed. None of the usual early proteins or structural proteins are formed. in a few situations, the prophage supplies genetic information such that the lysogenic bacteria exhibit a new characteristic (new phenotype), not displayed by the nonlysogenic cell, a phenomenon called lysogenic conversion. Lysogenic conversion has some interesting manifestations in pathogenic bacteria that only exert certain determinants of virulence when they are in a lysogenized state. Hence, Corynebacterium diphtheriae can only produce the toxin responsible for the disease if it carries a temperate virus called phage beta.

Answer 22

1. Diptheria toxin's receptor-binding domain (B) binds host membrane 2. Membrane bound toxin (A+B) enters by endocytosis 3. catalytic subunit A is cleaved but held to the B subunit by disulfide bonds. Endosome vesicle acidifies; the disulfide bonds are reduced 4. The transmembrane domain facilitates the passage of the catalytic A peptide through the vesicle membrane 5. Te catalytic A domain ADP-riboslyates elongation factor 2 (EF2). This halts protein synthesis & kills the cell * The toxin inhibits translation of proteins by the cell * One of the most deadly toxins known * Lethal dose in is 0.1 μg/kg * One gram would be sufficient to kill more than 100,000 humans

Answer 23

* The respiratory symptoms caused diphtheria to be known as the “strangling angel of children” * Incubation period of 1-5 days * Major clinical feature is the formation of a pseudomembrane in the throat: comprised of dead host cells, dead bacteria and fibrin & can lead to death due to airway obstruction * Lymphadenopathy: Enlarged lymph nodes; characteristic “bull throat" that is often associated with more serious disease * Other symptoms: cardiac arrhythmias, myocarditis, cranial and peripheral neuropathies

Answer 24

* Cutaneous diphtheria: A second type of diphtheria can affect the skin, causing the typical pain, redness and swelling associated with other bacterial skin infections. * Common in tropical nations * More contagious than respiratory diphtheria

Answer 25

* historically worldwide, with more temporal patterns (winter/spring) * 1921: the US recorded 200,000 cases with 16,000 deaths-->antitoxin was available then, but not antibiotics * in the last 5 years, only 2 cases reported in US * transmission of the disease in the US was thought to be interrupted by the mid-1990s, but further studies showed that endemic cases were still circulating in small, impoverished communities

Answer 26

RESERVOIR * Humans are only natural host and reservoir * Asymptomatic carrier state exists TRANSMISSION * Airborne respiratory droplets * Direct contact

Answer 27

* As additional information regarding vaccine efficacy and correlates became available, improved scheduling and boosting has led to a major decrease in cases of diphtheria worldwide (fewer than 5,000 cases/yr over past 5 years) * The large increase in Europe (EUR) in the 1990s is a direct result of the dissolution of the Soviet Union – by 1994 157,000 cases and 5,000 deaths had been reported

Answer 28

* Antibodies to diphtheria toxin correlate with protection*Following active immunization >95% of persons will reach a protective level of 0.1 IU/mL * 1.0 IU/mL level of antitoxin often associated with long-term protection * Protection is not necessarily absolute even with high antitoxin levels; fatal diphtheria has been reported in patients with antitoxin levels as high as 30 IU/mL * Neither immunization nor natural infection convey lifelong immunity due to waning antibody titers

Answer 29

In the 1890s von Behring and Kitasato demonstrated that antiserum against diphtheria toxin could serve as a therapy for diphtheria; techniques were quickly developed to prepare large quantities of diphtheria antitoxin from horses *antiserum is created from putting a small amount of virus in horses and then collecting horse antibodies

Answer 30

Worked with Pasteur on cholera, anthrax and rabies Isolated C. diphtheriae Purified diphtheria toxin Developed methods to prepare antitoxin in horses Cofounder of the Pasteur Institute, served as its director for almost 30 years

Answer 31

*antibodies are made by hyperimmunizing horses with diptheria toxoid and toxin mixtures, then semi-purifying IgG to reduce the risk of serum sickness *Antibody purification involves selective enrichment or specific isolation of antibodies from serum (polyclonal antibodies) *In 1901, 10 children in St Louis died after receiving diphtheria antitoxin from a horse later found to be infected with tetanus. This incident led to the first federal regulation of biological products. In 1925, the “Great Race of Mercy” was run to save the children of Nome, Alaska The treatment of recent diphtheria cases in Haiti, Spain and Belgium has been complicated by the need to obtain antiserum. In each case the child died.

Answer 32

Nome, Alaska faced a crisis too terrible to imagine—an outbreak of diphtheria that could kill most of the region's population of about 10,000 people. Normally, Dr. Welch would have treated infected people with diphtheria antitoxin to fight off the effects of the poison that diphtheria releases into the body. But the town’s supply of antitoxin was not enough and it had expired. ams of mushers traveled day and night, enduring blizzards and temperatures of 50 degrees below zero, handing off the package to fresh teams. Leonhard Seppala’s team with lead dog, Togo, covered 91 miles —the most dangerous part of the relay — and Gunner Kaasen’s team and lead dog, Balto, finished the lifesaving race, reaching Nome on February 2. This Great Race of Mercy was completed in a record 5 days and 7 hours.The original “Great Race of Mercy” in 1925 occurred when dog mushers from around Alaska joined forces to carry life-saving diphtheria serum to Nome. Since 1973, the Iditarod Trail Race has been run annually in memory of this original sled dog relay.

Answer 33

Togo and his musher Leonhard Seppala; the two of them and the rest of the team covered 170 miles in three days – the hardest part of the route. Togo currently “resides” in the the Iditarod Trail Sled Dog Race Headquarters museum in Wasilla, Alaska

Answer 34

* First successful attempts at a vaccine by von Behring in the late 19th century * Widely used in the United States starting in 1914 (85% efficacy) * Involved using mixtures of active diphtheria toxin with antitoxin * Worked well, as shown by Schick testing and clinical observation * However, for obvious safety reasons, this approach could not be continued

Answer 35

The Schick test, invented between 1910 and 1911 is a test used to determine whether or not a person is susceptible to diphtheria. The test is a simple procedure. A small amount (0.1 ml) of diluted (1/50 MLD) diphtheria toxin is injected intradermally into one arm of the person and a heat inactivated toxin on the other as a control. If a person does not have enough antibodies to fight it off, the skin around the injection will become red and swollen, indicating a positive result. This swelling disappears after a few days. If the person has an immunity, then little or no swelling and redness will occur, indicating a negative result.

Answer 36

* Gaston Ramon (Pasteur Institute) discovered in 1924 that heat and formalin-treated diphtheria toxin lost its toxicity, but was shown to still induce protective immunity. * Treatment retained protective epitopes while destroying those that caused pathogenesis. * Functional definition of a “toxoid.” * Alum adjuvanted for higher immunogenicity. * Stored at 2-8˚C (inactivated by freezing or high, tropical temperatures). * Intramuscular route of administration. * Toxoids have traditionally been produced by treatment with heat or fixative, but can be engineered via recombinant DNA technology * toxins typically have a binding domain and a toxin domain (which is what does the damage), and so binding domain is fine but toxin domain is inactivated

Answer 37

*Diptheria combined with tetanus (also compatible with alum) and acellular pertussis (intrinsic adjuvants) for higher immunogenic effect. DTaP - Vaccine formulation for children Tdap - Adult/adolescent vaccine formulation TD - Adult booster vaccine formulation *Five doses of DTaP Dose 1 - 2 months Dose 2 - 4 months Dose 3 - 6 months Dose 4 - 15 to 18 months Dose 5 - 4 to 6 years (recently added) One dose of Tdap from 11 to 12 years old Catch-up immunization from 13 to 18 years of age. Boosters of Tdap recommended every 10 years

Answer 38

*Moderate to severe illness *Allergic response to vaccine *Nervous system disease within one week of a dose. *Seizure or high fever (>105˚ F) after a dose. “Cried non-stop for 3 hours or more after a dose.” Yes…it actually says this

Answer 39

* Moderate to severe illness * Allergic response to vaccine * Nervous system disease within one week of a dose. * Seizure or high fever (>105˚ F) after a dose.

Answer 40

Mild (common): * Fussiness (33%) * Fever (25%) * Redness, swelling, soreness, or tenderness at site of injection (25%) * Tiredness or poor appetite (10%) * Vomiting (2%)

Answer 41

Seizure (1 in 14,000) Non-stop crying for 3 hours or more (up to 1 in 1,000) High fever higher than 105˚ F (up to 1 in 16,000)

Answer 42

Serious allergic reaction (less than 1 in 1,000,000 doses) Long-term seizures Permanent brain damage The last two are so rare, it is unknown if they are actually caused by the vaccine.

Answer 43

* Caused by the bacteria Clostridium tetani * Pathology mediated by the secreted exotoxin tetanospasmin * Incredibly incredibly potent * Mobile and anaerobic. * C. tetani can form spores, which exist in the environment for a very long time * *Tetanus is a serious bacterial disease that affects your nervous system, leading to painful muscle contractions, particularly of your jaw and neck muscles. Tetanus can interfere with your ability to breathe and can threaten your life. Tetanus is commonly known as "lockjaw."

Answer 44

*Tetanus is caused by a toxin (poison) produced by the bacterium Clostridium tetani. The C. tetani bacteria cannot grow in the presence of oxygen. They produce spores that are very difficult to kill as they are resistant to heat and many chemical agents.

Answer 45

* C. tetani spores can be found in the soil and in the intestines and feces of many household and farm animals and humans. The bacteria usually enter the human body through a puncture (in the presence of anaerobic [low oxygen] conditions, the spores will germinate) . Tetanus is not spread from person to person.

Answer 46

*The further the injury site is from the central nervous system, the longer the incubation period. The shorter the incubation period, the higher the risk of death/ the more severe the disease. Incubation period can range from 1 day to several months. The spores that one is infected with germinate across a broad period of time

Answer 47

The symptoms of tetanus are caused by the tetanus toxin acting on the central nervous system. In the most common form of tetanus, the first sign is spasm of the jaw muscles, followed by stiffness of the neck, difficulty in swallowing, and stiffness of the abdominal muscles. Other signs include fever, sweating, elevated blood pressure, and rapid heart rate. Spasms often occur, which may last for several minutes and continue for 3–4 weeks. Complete recovery, if it occurs, may take months.

Answer 48

Tetanus has a high fatality rate. In recent years, tetanus has been fatal in about 10% of reported cases.

Answer 49

Laryngospasm (spasm of the vocal cords) is a complication that can lead to interference with breathing. Patients can also break their spine or long bones from convulsions. Other possible complications include hypertension, abnormal heart rhythm, and secondary infections, which are common because of prolonged hospital stays.

Answer 50

Yes! Tetanus disease does not result in immunity because so little of the potent toxin is required to cause the disease. People recovering from tetanus should begin or complete the vaccination series.

Answer 51

These vaccines are made by chemically treating the diphtheria, tetanus, and pertussis toxins to render them nontoxic yet still capable of eliciting an immune response in the vaccinated person. They are known as “inactivated” vaccines because they do not contain live bacteria and cannot replicate themselves, which is why multiple doses are needed to produce immunity.

Answer 52

* DTaP: Diphtheria and tetanus toxoids and acellular pertussis vaccine; given to infants and children ages 6 weeks through 6 years. In addition, three childhood combination vaccines include DTaP as a component. * DT: Diphtheria and tetanus toxoids, without the pertussis component; given to infants and children ages 6 weeks through 6 years who have a contraindication to the pertussis component. * Tdap: Tetanus and diphtheria toxoids with acellular pertussis vaccine; given to adolescents and adults, usually as a single dose; the exception is pregnant women who should receive Tdap during each pregnancy. * Td: Tetanus and diphtheria toxoids; given to children and adults ages 7 years and older. Note the small “d” which indicates a much smaller quantity of diphtheria toxoid than in the pediatric DTaP formulation.

Answer 53

* AB Toxin * B gets it into a neuron * A does “bad things” * Eventually degrades the protein synaptobrevin * Prevents the release of the inhibitory neurotransmitter GABA * End result is spastic paralysis

Answer 54

Three syndromes associated with tetanus: Localized Generalized (majority, 80% of cases) Cephalic (localized, to head)

Answer 55

Occurrence: worldwide Reservoir: one of the very few non-transmissible diseases for which vaccination is important-->Transmission and Communicability is Not a significant factor * capable of infecting almost any animal, and exists practically everywhere in the environment * this means that tetanus can NEVER BE ERADICATED

Answer 56

* Peaks in the late spring to mid-summer * Thought to correlate with soil and spore conditions * there has been a correlation with more frequency injury during these time points than at other times

Answer 57

* Antitoxin levels are the correlate of protection * 0.01 IU/mL level of antitoxin is protective * This was best shown in a human study (1942) of two scientists, K.L. Wolters and H. Dehmel, who immunized themselves and survived a lethal toxin challenge with antitoxin levels of 0.007 to 0.01 IU/mL * Similar to diphtheria, fatal tetanus was reported in patients who reported between 0.15 and 25 IU/mL * Passive antibodies made by hyperimmunizing horses with small doses of active toxin

Answer 58

* Some of the drop in tetanus disease can be attributable to better hygiene and the availability of passive antitoxin. * However, it is clearly evident that much of the drastic decrease in cases and fatalities is attributable to active immunization against tetanus toxoid.

Answer 59

* WANING immunity over time has been noted, with tetanus antitoxin levels lowering over time * Without boosting, there will be susceptible adult populations * However, because tetanus is omnipresent in our environment, adults who have lost their immunity cannot depend on high levels of childhood immunization, like they could in the case of diptheria * IMPORTANT to get a tetanus booster sometime in your twenties

Answer 60

* Known as the WHOOPING COUGH & is a highly contagious respiratory disease * Caused by the bacteria Bordetella Pertussis * pathology is mediated by an exotoxin, which, among other things, inhibits antibody production * it is immobile and aerobic * attaches to ciliated epithelial cells in the respiratory tract

Answer 61

Pertussis is spread through the air by infectious droplets and is highly contagious

Answer 62

* AB toxin * Both secreted & cellularly bound * secreted PT can target and mess up intracellular signaling by disrupting G protein coupled receptors * Cell bound PT seems important for adhesion to mucosal surfaces * Cell bound PT also seems to be involved in macrophage invasion

Answer 63

The AB toxins are two-component protein complexes secreted by a number of pathogenic bacteria. they interfere with internal cell function. They are named AB toxins due to their components: the "A" component is usually the "active" portion, and the "B" component is usually the "binding" portion *The B component binds to molecules on the surface of target cells. The toxins are then taken up into the target cells by endocytosis, at which point the A component enters the cytoplasm and (depending on the particular toxin) carries out some toxic enzymatic reaction inside the cell. There is thus a structural division between the cell-surface recognition function (B-subunit) and toxic enzymatic action.

Answer 64

* B Pertussis produces a specific adherence factor, and adheres to cells of the respiratory tract * Produces an exotoxin which induces cAMP production, as well as an endotixin * incubation period of 9 or 10 days * Cough worsens over two weeks, when it reaches the paroxysmal stage

Answer 65

A paroxysm is a burst of rapid, short coughs * this is when the cough is very severe and has the characteristic whoop sound associated with an attempt to breathe through an obstructed airway after a paroxysm * Paroxysmal stage slowly subsides over 2-6 weeks * Paroxysms can be extremely exhaustive, especially for children * some patients fracture their ribs during coughing

Answer 66

Occurrence: worldwide, endemic to the US Reservoir: humans are the only known reservoir, and there is no known chronic carrier state

Answer 67

Temporal Pattern: no consistent seasonal pattern Transmission: Large, airborne droplets expelled through coughing Communicability: Very contagious, with a reported 90% of household contacts and 50-80% of school contacts becoming infected *Most infectious during the early paroxysmal stage

Answer 68

There was an alarming rise in pertussis cases among adolescents and adults in the early 21st century *This prompted use of Tdap as a booster in early adolescence

Answer 69

* Correlates of protection are unknown * It is currently thought that antibodies against all components of current vaccine formulations are weak relative correlates. * Some studies show that an IFN-γ response aids in clearance.

Answer 70

* Passive Immunization with purified IgG exists * Was originally shown to have no clinical benefit and was discontinued. * More recent results showed attenuation of disease in humans. * Purified from the serum of humans who had been immunized with only pertussis toxoid. * Studies discontinued because of “expiration and lack of product.” (i.e., nobody cared enough).

Answer 71

* whole killed vaccine: earliest pertussis vaccine heavily used in the 1940s; shown to be efficacious in the early 20th century; improvements on the amount of antigen & gentler activation utilized to retain protective epitopes: it is very effective but has a lot of side effects * recently, have switched over to an acellular vaccine: it is less effective but FAR fewer side effects; duration of immunity is less than 10 years; recent outbreaks in RI thought to be caused by waning immunity

Answer 72

*Pertussis vaccine (both whole and acellular) have definitely lowered the incidence of disease and have aided in keeping it low.

Answer 73

Starting in the 1980s, there has been a consistent upward trend in the number of pertussis cases. Is resistance to the vaccine emerging? *in recent years, the number of cases has started to rise. By 2004, the number of whooping cough cases spiked past 25,000, the highest level it's been since the 1950s. It's mainly affected infants who are younger than 6 months old before they are adequately protected by their immunizations, and kids who are 11 to 18 years old whose immunity has faded. Recently recommended that kids who are 11-18 years old get a booster shot that includes a pertussis vaccine, preferably when they are 11 to 12 years old.

Answer 74

*Unlike the boosters of TD recommended every 10 years, there do not seem to be any pertussis-only boosters. *However, recently the ACIP recommendation has been to give Tdap when a tetanus booster is indicated *It would be great if we could find better markers for, or true correlates of immunity: this is the single major problem in development of better vaccines to pertussis, due to inability to determine effectiveness without clinical trials. *This also complicates the development of a bona fide adult booster for pertussis. Due to indications of waning immunity similar to that of diphtheria and tetanus immunity. It has been proposed (and implemented in some countries) that Tdap be used for adult boosting throughout life instead of DT.

Answer 75

Pertussis can be a very serious disease, especially for infants. Infants (6 months of age and younger) are the children most likely to die from this disease. Rates of hospitalization and complications increase with decreasing age. The breathing difficulties associated with this disease can be very distressing and frightening for the patient and his or her family

Answer 76

* inflammation of the liver * hepat=liver, itis=inflammation * in the USA, viral hepatitis is most commonly caused by Hep. A, Hep. B and Hep. C

Answer 77

* infectious disease: viruses, bacteria, fungi, parasites * drugs & toxins * autoimmune disorders (LUPUS) * metabolic diseases * heptatitis of less than six months duration is considered acute; chronic hepatitis persists longer

Answer 78

* A healthy liver is required to maintain bodily function * damage to the liver, especially chronic damage, may lead to serious symptoms in other organs and tissues * life-threatening diseases such as cirrhosis and cancer may result from chronic liver damage - brain damage, strokes, swollen muscles, jaundiced or yellow skin, inflammation and bleeding of stomach and esophagus, etc.

Answer 79

HEPTACELLULAR CARCINOMA (liver cancer) * alcohol, HBV and HCV can all cause inflammation, which can lead to regeneration and regrowth, hyperplasia cirrhosis, genetic mutations, and then HCC * HCC is the third largest cause of cancer deaths worldwide * more than half a million deaths per year & up to 80% are caused by HBV

Answer 80

Nearly 50% due to HBV & HCV

Answer 81

There are at least 5 recognized hepatitis viruses (ABCDE) * While each virus infects the liver and can cause hepatitis, each is a distinct virus, and there is no cross-protection * each presents unique challenge for vaccine development so far, only A and B have commercially available vaccines * Other viruses that can cause hepatitis include CMV, EBV, and Yellow Fever virus

Answer 82

* The Transient Fecal/Oral Infections | * "The vowels go out the bowels”

Answer 83

* Nonenveloped RNA virus of the Picornavirus family, which also includes Poliovirus * Single-stranded positive sense RNA genome * no serotypes * Humans are the only natural hosts * under suitable conditions HAV my be stable in the environment for months * Inactivated by high temperatures, formalin, and chlorine * You can get hepatitis A by eating food or drinking water contaminated with feces (stool) from a person infected with the virus or by anal-oral contact.

Answer 84

* Incubation period of 28 days * illness clinically similar to other forms of acute viral hepatitis * major symptoms include FEVER, MALAISE, ANOREXIA, NAUSEA, ABDOMINAL DISCOMFORT, DARK URINE, & JAUNDICE * clinical symptoms usually resolve within 2 months * likelihood of symptomatic illness directly related to age (the older you are, the more symptomatic you will be) * Most infected persons recover (Fatality rate is .3%) but some may progress to fulminant hepatitis, which may be fatal in up to 60% of cases (100 deaths per year in the US)

Answer 85

People who have fulminant hepatitis typically develop the symptoms seen in viral hepatitis. Then they rapidly develop severe, often life-threatening liver failure. This can happen within hours, days, or sometimes weeks.

Answer 86

ALL hepatitis infections leads to jaundice: note yellowing of skin and conjuctiva of eyes resulting from hyperbilirubinemia occurring as a result of virus-induced liver damage *Jaundice causes your skin and the whites of your eyes to turn yellow. Too much bilirubin causes jaundice. Bilirubin is a yellow chemical in hemoglobin, the substance that carries oxygen in your red blood cells. As red blood cells break down, your body builds new cells to replace them. The old ones are processed by the liver. If the liver cannot handle the blood cells as they break down, bilirubin builds up in the body and your skin may look yellow.

Answer 87

*early on have Viremia, HAV in feces, Jaundice and other symptoms of hepatitis ACUTE PHASE: IgM-->serum IgM anti-HAV levels rise first, and are detectable 5-10 days before onset of symptoms & may persist up to 6 months CONVALESCENT PHASE: IgG-->detectable for lifetime of patient, and confers lifelong immunity

Answer 88

Immunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. IgM is by far the physically largest antibody in the human circulatory system. It is the first antibody to appear in response to initial exposure to an antigen

Answer 89

Occurrence: Worldwide but highly endemic in Central & South America, Africa, Middle East, Asia, and Western Pacific (>80% infection in many of these regions by adulthood) Reservoir: Humans only No chronic carrier state

Answer 90

Transmission: fecal-oral, person-to-person, contaminated water or food (shellfish) Temporal Pattern: none Communicability: 2 weeks before to 1 week after onset; transmission is most likely 1-2 weeks before onset of symptoms

Answer 91

During the 90's, infection rates were highest in the west. Following introduction of Hep A vaccines, rates have been low throughout the USA.

Answer 92

* Administration of Immune Globulin (IG) was the major method for pre-exposure and post-exposure prophylaxis for Hep. A before active vaccines were developed * IG is produced from large pools of plasma prepared from many thousands of donors; traditionally there has been no need to purify HAV-specific antibodies since so many have been previously infected * Ironically, there is some concern that with the decline of Hep. A antibodies in the population due to lower incidence of infection, IG may become less effective * 80-90% effective if administered before exposure or within 2 weeks of exposure * Recommended for postexposure prophylaxis in persons younger than 12 months, older than 40, immunocompromised, with chronic liver disease, and for those whom active vaccine is contraindicated * can be used alone or in conjuction with active vaccines for those who need RAPID immunity (Travelers departing on short notice) * PAPA GINOS OUTBREAK ON MEETING STREET developed Hep. A so many had to get vaccinated

Answer 93

* formalin-inactivated whole virus produced by cell culture techniques * adjuvanted with aluminum hydroxide * two monovalent vaccines available: HAVRIX & VAQTA (monovalent vaccine contains a single strain of a single antigen) * HAVRIX (Hepatitis A Vaccine) is a sterile suspension of inactivated virus for intramuscular administration: Vaccine efficacy 94% * VAQTA is an inactivated whole virus vaccine derived from hepatitis A virus grown in cell culture * both vaccines approved for people over 12 months and requires 2 doses at least 6 months apart * vaccines are 95-97% immunogenic after 1 doe and 100% immunogenic after 2 doses

Answer 94

* Immune Globulin: lowest level of antibodies * attenuated vaccine: slightly higher antibody levels * inactivated Hep. A vaccine: higher antibody levels * WT infection: highest antibody levels

Answer 95

* International travelers * men who have sex with men (MSM) * Persons who use illegal drugs * Persons with chronic liver disease * Close contacts of adopted children from endemic areas * Persons with occupational risk * Persons working with Hep A in laboratory settings * Of interest, Hep A vaccination is NOT routinely recommended for healthcare workers, child care workers, sewer workers, plumbers, or food handlers since these populations have not been shown to be at increased risk of infection * In 2006, routine vaccination of all children was recommended by ACIP and AAP * Now part of RI’s “vaccinate before you graduate” program

Answer 96

*All children should receive hepatitis A vaccine at 12-23 months of age *Vaccination should be integrated into the routine childhood vaccination schedule Children who are not vaccinated by 2 years of age can be vaccinated at subsequent visits Efforts focused on routine vaccination of children 12-23 months of age should enhance, not replace, ongoing vaccination programs for older children and high-risk adults

Answer 97

* HEP A infections of children are often MILD or asymptomatic * infected children (symptomatic or not) shed high levels of virus and serve as an important soruce of transmission to others * immunization of children has been shown to provide herd immunity to populations as a whole * current goal is to achieve a national immunization rate >90%

Answer 98

ADVERSE RXNS * local: pain/swelling in 20-50% * systemic: malaise/fatigue in

Answer 99

* non-enveloped * Positive sense single stranded RNA (ssRNA) * Icosahedral (polyhedron w/ 20 faces) * Only 1 serotype * Clinically very similar to HAV * Major concern: high mortality rate (20%) in pregnant women

Answer 100

* Fecal-oral route (common cause of water-borne epidemics in Asia, Africa, India, and Mexico) * No chronic state (except in the immunocompromised) * Same acute symptoms

Answer 101

* Hep E is most common in developing countries. Epidemics have been reported in Asia, the Middle East, Africa, and Central America, some involving tens of thousand of persons over a short period of time. People living in refugee camps or overcrowded temporary housing after natural disasters are at particular risk. * Hep E is believed to be uncommon in the U.S. and usually results from travel to a developing country. However, rare cases have been reported among persons with no history of travel to hyperendemic countries and recent studies have found a high prevalence of antibodies to HEV in the general population.

Answer 102

* Symptoms of are most common among older adolescents and young adults (aged 15–44 years) * Children infected with HEV usually have mild or no symptoms * Pregnant women, particularly those in their third trimester, are more likely to experience severe illness, such as fulminant hepatitis and death * The overall case-fatality rate is ≤4% * For infection acquired in developed countries, symptoms are more common among older people (>45 years), particularly men.

Answer 103

* Symptoms usually develop 15 to 60 days (mean: 40 days) after exposure * Period of communicability has not been determined, but virus excretion in stool has been demonstrated up to 14 days after the onset of jaundice. * Chronic infection appears very rare, and are so far reported only in organ transplantation patients.

Answer 104

* Currently a HEV recombinant protein vaccine is in a phase II trial * Vaccine consists of purified polypeptide produced in cells infected with a recombinant baculovirus containing a truncated HEV genomic sequence encoding the capsid antigen * People who took vaccine had a lower incidence rate and a higher antibody response * Vaccine efficacy was in the high 80's or mid-90s

Answer 105

* Efficacy in the general population? This population was almost entirely male military personnel. * Duration of the induced immunity remains unknown beyond the 804 day mean followup period * Efficacy of the vaccine in preventing asymptomatic HEV infection was not determined, thus the vaccine might not prevent transmission

Answer 106

* Design: Randomized, double-blind, placebo controlled * Subjects: 112,604 healthy adults 16-65 years old in Jiangsu Province, China were assigned to vaccine or placebo group * Vaccine: 3 doses of HEV 239 (30 μg of purified recombinant hepatitis E antigen adsorbed to 0.8mg aluminium hydroxide suspended in 0.5 mL buffered saline) given intramuscularly at 0, 1, and 6 months * conclusion: HEV vaccine was well tolerated and effective in prevention of hep E in the general population in China, including both men and women: Adverse effects attributable to the vaccine were few and mild

Answer 107

* The Bloodborne Oncogenic Viruses | * “The consonants mean donate blood you can’t”

Answer 108

* Formerly called “serum hepatitis” * First recorded cases in German recipients of a smallpox vaccine containing human lymph * In early and mid 20th Century the link to contaminated needles/syringes and blood was recognized: Jaundice reported among recipients of human serum and yellow fever vaccines * “Australia antigen” (Hepatitis B surface antigen; HBsAg) was described in 1965 * “Dane particle” (complete Hep B virion) described in 1970 * Serologic tests developed in 1970s * HBsAg was purified from infected humans for use in the first vaccine, later it was expressed in yeast via recombinant DNA

Answer 109

* Double-shelled DNA virus of the Hepadnaviridae family (A capsid is the protein shell of a virus) * Small circular DNA genome that is partially double-stranded * DNA encodes 4 genes: S, P (polymerase), C (Core & e) and X (unkown) * Antigenic components include surface (HBsAg), core (HBcAg), and e (HBeAg) antigens * Four major serotypes (at level of HBsAg) and eight genotypes

Answer 110

HBeAg (Hepatitis B e-Antigen) - This is a viral protein that is secreted by hepatitis B infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a patient's degree of infectiousness.

Answer 111

* Humans are only known host for HBV, although similar viruses have been described in ducks, squirrels, and woodchucks * May retain infectivity on surfaces for more than 7 days at room temperature

Answer 112

Hepadnaviridae is a family of viruses. Humans, apes, and birds serve as natural hosts. There are currently seven species in this family, divided among 2 genera. Its most well-known member is the Hepatitis B virus. Diseases associated with this family include: liver infections, such as hepatitis, hepatocellular carcinomas (chronic infections), and cirrhosis

Answer 113

* most common cause of chronic viremia * More than 2 billion (1/3 of the global population) have been infected at some time, with over 350 MILLION chronically infected * established cause of chronic hepatitis and cirrhosis * HUMAN CARCINOGEN: cause of up to 80% of hepatocellular carcinomas * More than 600,000 deaths worldwide

Answer 114

* Aside from being found in complete virions, excess HBsAg may be found in serum in noninfectious spherical and tubular particles * HBcAg not generally detectable in serum, but anti-HBcAg can be readily detected and is indicative of current or past infection * HBeAg is detectable in serum in persons with high viral titers

Answer 115

*Incubation period 60-150 days (average 90 days) *Nonspecific prodrome (preicteric phase) Malaise, fever, headache, myalgia, dark urine, etc. Lasts for 3-10 days before onset of jaundice *Icteric (jaundice) phase Usually lasts 1-3 weeks Illness not specific for hepatitis B At least 50% of infections asymptomatic, although virus may still be transmitted to others * Most acute infections in adults resolve completely, with elimination of HBsAg from the blood and production of anti-HBsAg, which conveys lasting immunity * Fulminant hepatitis may occur in 1-2% of cases

Answer 116

* Often asymptomatic in early stages * Chronic viremia, able to transmit infection to others * Risk of chronic infection variable with age * 90% of infants who acquire from mothers * 30-50% of children 1 to 5 years * 5% of adults * Causes most HBV-associated morbidity and mortality * Chronic hepatitis, often progresses to cirrhosis * Cirrhosis (liver scarring): >3,000 deaths in U.S. per year * Liver failure * Hepatocellular carcinoma (liver cancer): 12-300 fold elevated risk in chronic Hep B infection * 1000-1500 deaths associated with Hep B annually in U.S.

Answer 117

ACUTE INFECTION: Anti-HBc followed by anti-HBs CHRONIC INFECTION: Anti-HBc but NO anti-HBs response

Answer 118

Occurrence: WORLDWIDE; half of global population lives in areas of high prevalence, and half of population live in areas of moderate prevalence Reservoir: HUMANS ONLY

Answer 119

TRANSMISSION: contact with blood (direct or via IV drugs/transfusion), SEXUAL (most important in USA), Perinatal (risk depends on level of maternal viremia), nonsexual person-to-person contact over long periods COMMUNICABILITY: acute cases are 1-2 months before and after onset of symptoms CHRONIC: ongoing risk due to persistent viremia

Answer 120

PREVACCINE ERA: estimated 300,00 people infected annually 2006: nearly 50,000 new infections, and 1 million chronic infections

Answer 121

*Administration of hepatitis B immune globulin (HBIG) was the major method for pre-exposure and post-exposure prophylaxis for Hep B before active vaccines were developed *HBIG is produced from the plasma of selected donors with high anti-HBsAg titers This distinguishes it from “regular” IG (used against HAV), which has relatively low ant-HBsAg titers and is of limited use for this purpose *Approximately 75% effective when given soon after exposure to HBV, with efficacy increased if used in conjunction with active vaccine *The cost of HBIG precludes its use in much of the developing world

Answer 122

HBIG is indicated for post-exposure prophylaxis in persons without demonstrated protection against HBV * Perinatal exposure of an infant born to an HBsAg-positive mother * Household exposure of an infant younger than 12 months to a primary caregiver with acute Hep B * Percutaneous or mucous membrane exposure to HBsAg-positive blood * Sexual exposure to an HBsAg-positive person * To reduce the risk for recurrent HBV infection after liver transplantation

Answer 123

* Plasma-derived Hep B vaccine: prepared from HBsAg subviral particles purified from the plasma of infected humans: safe and effective but not well accepted, removed from U.S. market in 1992 (still produced in some countries) * Recombinant Hep B vaccine: first licensed vaccine to be produced by recombinant DNA technology: Recombinant HBsAg is produced in Saccharomyces cerevisiae yeast cells, purified, and adjuvanted with alum * Two monovalent vaccines available, as well as various combination vaccines * Hep B vaccine is now the first immunization that most infants in the U.S. receive; it is generally administered before discharge from the hospital following birth

Answer 124

1. discovery of Australia antigen (HBsAg) 2. Dane particles (complete HBV) described 3. Successful HBV infection of Chimps 4. Licensure of plasma-derived vaccine 5. Licensure of Recombinant Vaccine 6. Universal infant vaccination 7. Plasma-derived vaccination withdrawn 8. universal adolescent vaccination

Answer 125

* 3 Doses (0, 1-2, 6-18 months) * Efficacy 95% (Range, 80%-100%) * Duration of 20 years or more Immunity * Booster Doses are not routinely recommended

Answer 126

* Despite availability of Hep B vaccines, the impact of such vaccines has not been optimal * Vaccination was targeted to high risk groups, however 25% to 30% of persons with HBV infection deny any risk factors

Answer 127

* Lack of awareness of disease in at-risk populations * Lack of access to at-risk populations * Lack of public or private outreach * Vaccine cost * Low initial vaccine acceptance: first dose is less than 50% effective, second and third doses bring you up tov 100% efficacy * Rapid acquisition of infection in at-risk groups

Answer 128

* Prevent perinatal HBV transmission: screen pregnant women for HBsAg * Routine vaccination of all infants * Vaccination of children and adolescents not vaccinated as infants * Vaccination of adults in high-risk groups: sexual exposure, percutaneous or mucosal exposure to blood, international travelers to regions of high or moderate prevalence, persons with HIV * Protection is defined as an anti-HBsAg titer of 10 mIU/ml or greater

Answer 129

SINGLE ANTIGEN: recombinant HB, Energix B COMBINATION VACCINES: Twinrix: A&B Comvax: Heb B and Hib (meningitis) Pediarix: B, IPV, Diptheria-Tetanus-Pertussis

Answer 130

* Vaccine-induced antibody levels decline over time * Immunologic memory established following vaccination which allows for continued protection * Exposure to HBV results in anamnestic anti-HBsAg response: means a second rapid increased production of antibodies in response to an immunogenic substance after serum antibodies from a first response can no longer be detected in the blood * Chronic infection rarely documented among vaccine responders * For this reason booster doses or serologic testing not routinely recommended

Answer 131

Adverse Rxns: Pain at the injection site, fatigue, headaches, fever up to 99.9, severe reactions Contraindications & Precautions: severe allergic reactions to a vaccine component or following a prior dose. Moderate or severe acute illness. Hep B vaccinates have not specifically been evaluated in preggo women, but no safety issues have been reported and theoretical risk is LOW.

Answer 132

*Postvaccination testing of high-risk persons for whom knowledge of immune status is desirable does occasionally demonstrate nonresponse *Factors associated with nonresponse Vaccine factors (suboptimal dose, schedule, etc.). Host factors: >40 years, males, obesity, smoking, chronic illness *30-50% of nonresponders will respond adequately after a second three dose series *

Answer 133

* Antibodies to HBsAg (natural and vaccine induced) generally target a hydrophilic region referred to as the a determinant * Alterations in the amino acid sequence in this region may lead to conformational changes that can - -Allow infections in previously vaccinated persons - -Prevent detection of HBsAg by some antibody-based assays

Answer 134

* This mutation alters the projecting loop (aa 139-147) of the a determinant such that neutralizing antibodies are unable to bind * First identified in a group of Italian children that had HBsAg in their blood despite presence of vaccine-induced antibodies * Other mutations with similar effect have been identified in the aa 120-147 region * Despite the potential of such mutants to escape vaccine-induced protection and reduce the efficacy of immunization programs, currently the public health impact is thought to be low (but should be continuously monitored)

Answer 135

* Despite high efficacy of current recombinant subunit vaccines, there is room for improvement * “Third-generation” vaccines may provide benefit to current nonresponders and immunosuppressed persons * May also allow for fewer doses in immunocompetent persons, improving compliance

Answer 136

* Pre-S1, Pre-S2, and S proteins are produced from the S gene during infection * Pre-S1 and Pre-S2 have been shown to provide T cell help for production of anti-HBsAg antibodies during natural infection * Pre-S/S vaccines are highly immunogenic at lower doses than conventional vaccines, and have improved efficacy in nonresponders * Not yet available in the U.S.

Answer 137

* Alum is used in conventional Hep B vaccines * Other adjuvants that have been evaluated include MPL, MF59, and CpG-based synthetic oligonucleotides * Such vaccines have good efficacy in nonresponders and immunosuppressed persons * An MPL-adjuvanted vaccine is licensed in some countries for patients with renal failure or on dialysis, but not yet in U.S.

Answer 138

* Chronic infections notable for lack of anti-HBsAg response * Current therapies including IFN-alpha and nucleoside/nucleotide analogues are effective but not generally able to eradicate virus * Various strategies including conventional vaccine, cytokine therapy, transfer of primed APCs, novel adjuvants (e.g MPL and MF59) and DNA-based vaccines have had encouraging results in clinical trials

Answer 139

*Deltavirus *Enveloped but defective in that it doesn’t have its own genes for envelope proteins *Negative sense ssRNA *No virion polymerase *Only 1 serotype *CAN ONLY CO-INFECT WITH HBV! *Disease more serious with HBV + HDV *However, no HBV = no HDV *Therefore, covered by HBV vaccine

Answer 140

* It is estimated that 3% of the world’s population (up to 200 million people) are infected with HCV * Originally termed “non A non B hepatitis” when first recognized in the * Most infections (75-85%) become chronic * Chronic hepatitis C infection typically leads to cirrhosis which can lead to liver failure and HCC * Leading cause of liver transplantation worldwide * Current medical therapy for chronic hepatitis C eradicates the virus in a minority of patients and it is associated with serious side effects * No vaccine currently available

Answer 141

* Enveloped RNA virus of the Flaviviridae family * Single-stranded positive sense RNA genome * Six major genotypes * Error-prone RNA polymerase * Icosahedral shell surrounds core of genetic material; shell surrounded by lipid envelope * E1 and E2 are viral proteins in the envelope * Infects humans and chimpanzees

Answer 142

* Acute HCV infection usually sub-clinical * 15-50% of acute hepatitis C infections spontaneously resolve within 6-12 months; 50–85% of infected individuals develop chronic infection * Up to 20% of chronically infected HCV patients may develop progressive liver damage leading to end-stage disease, usually over a period of 20–30 years * Co-factors for disease include male sex, alcohol use, co-infection with HIV or HBV, obesity, age at infection (younger people have a slower course of disease) and iron levels in the liver * HCC occurs in approximately 2.5% of chronic infections * Also linked with development of autoimmune and immune complex diseases

Answer 143

* In chronic infection, anti-HCV levels remain high, HCV RNA remains detectable, and ALT levels fluctuate in and out of normal range * ALT: The alanine aminotransferase (ALT) test is typically used to detect liver injury. It is often ordered in conjunction with aspartate aminotransferase (AST) or as part of a liver panel to screen for and/or help diagnose liver disease.

Answer 144

* spontaneous recovery (15) * chronic Hepatitis (85) * Cirrhosis (15); caused by chronic hep. * Decompensation or HCC (caused by cirrhosis) * DEATH (due to decompensation or HCC)

Answer 145

* Current or former injection drug users * Recipients of clotting factor concentrates made before 1987 * Recipients of blood transfusions or solid organ transplants before July 1992 * Chronic hemodialysis patients * Persons with known exposures to HCV, such as Healthcare workers after needlesticks involving HCV-positive blood * Recipients of blood or organs from a HCV-positive donor * Persons with HIV infection * Infants born to HCV-positive mothers

Answer 146

* Epidemiological and experimental data indicate the existence of effective adaptive immune responses as well as evasion strategies on the part of the virus * Recovery from acute HCV infection is associated with the induction of Th1-type CD4+ T helper responses as well as CD8+ CTL T cell responses to the virus * Role of virus-specific antibodies in recovery from infection is less clear but various epidemiological and experimental studies have indicated a role for neutralizing antibodies directed at E1 & E2 proteins * HCV evades innate and adaptive immune responses * Inhibition of natural killer (NK) cell activity * Suppression of type 1 interferons * Escape mutants to cytotoxic T lymphocytes (CTLs) as well as to neutralizing antibodies directed to the N-terminal region of gpE2 * Down-regulation of effector T cells specific for the virus as a consequence of persistent HCV infection

Answer 147

PERSISTENCE: Suppression of type 1 intereferons, inhibition of NK activity, inhibition of HCV effector T cells, T cell escape mutants,, antibody escape mutants, masking of virion from antibody ERADICATION: optimal NK receptor repertoire, early, broad, HCV T cell responses, early neutralizing antibody

Answer 148

* Induce broadly neutralizing antibodies (watch out for those mutating regions!) * Induce strong functional virus-specific CD4 and CD8 T-cell responses * Immune responses should be induced in the liver as well as the blood * Target multiple viral antigens/epitopes * Target all major serotypes * Must target conserved regions of the virus to avoid viral escape * Should be compatible with broad range of host HLA molecules * Should be therapeutic (or at least not enhance pathogenicity) in those already infected

Answer 149

* Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes. * People with malaria often experience fever, chills, and flu-like illness. Left untreated, they may develop severe complications and die. * The vast majority of cases in the United States are in travelers and immigrants returning from countries where malaria transmission occurs, many from sub-Saharan Africa and South Asia.

Answer 150

*If drugs are not available or if the parasites are resistant to them, malaria infection can develop to anemia, hypoglycemia or cerebral malaria, in which capillaries carrying blood to the brain are blocked. Cerebral malaria can cause coma, life-long-learning disabilities, and death.

Answer 151

``` Central: headache Systemic: FEVER Muscular: fatigue & pain Back: pain Skin: chills & sweats *respiratory: dry cough Spleen: enlargement Stomach: nausea, vomiting ```

Answer 152

Patients can often be misdiagnosed with influenza, and advised to rest, drink plenty of fluids, and take tylenol for muscle pain and headaches *Patient feels much better after going home, but a few days later these symptoms present: Pt calls and speaks to a different doctor: Felt worse, had diarrhea, vomiting Patient is diagnosed with gastroenteritis, same treatment recommendations ``` *Patient returns by ambulance 2 days, this time with more severe symptoms: Hematuria (blood in the urine) Severe anemia Low blood pressure Acute kidney failure Hypoglycemia (low blood sugar) Ataxia (movement trouble) Patient dies soon after admission ```

Answer 153

*1 million deaths a year *250 million cases/year 85% (212.5 million) are in Africa Greatest morbidity/mortality in children under 5 and pregnant women

Answer 154

Descriptions of Malaria like illness date back to 2700 B.C. 1880 – Malaria Parasite discovered 1897 – Discovery of the mosquito as parasite vector 1951 – Malaria considered ‘eliminated’ from the United States but still see cases that are ‘imported’

Answer 155

Malaria caused by a parasite called PLASMODIUM: has 5 distinct species *FALCIPARUM species is the one responsible for most of malaria deaths and is most prevalent in Africa

Answer 156

* Anopheles mosquitoes * 60 different species can transmit malaria * Females only (males feed on plant nectar) * Found throughout the world, including 48 states * Mosquitoes are required for transmission * Females are the only ones who can transmit malaria as they feed on blood, while their male counterparts feed on plant nectar

Answer 157

* Half the world’s population is at risk in 109 countries. | * Most prominent in countries with warmer climates, and swampy regional landscapes.

Answer 158

*(of a disease or condition) regularly found among particular people or in a certain area. "areas where malaria is endemic"

Answer 159

*Parasitic disease causes 1 million deaths annually and 250 million cases annually *Greatest morbidity/mortality in children under 5 and pregnant women *Large risk for travelers coming from areas with little or no malaria transmission *Notice specific common disease associated genes in malaria-endemic countries. Example: Sickle Cell Trait

Answer 160

*Symptoms begin within 15 days of infection Uncomplicated Malaria - -Fever Cycle - -Periodic cycle based on rupture of red blood cells: Case study – symptoms onset every 48 hours Severe (Complicated) Malaria - -Severe Anemia - -Hematuria (blood in urine) * RBC sticky-ness leads to: - - Cerebral Malaria (mostly in children) - -Organ Failure - -Death

Answer 161

* Symptoms are often non-specific * Blood smear is diagnostic standard, but there are limitations: - -Rural settings aren’t equipped to perform the test - -Accuracy depends on skill and level of parasites in the blood - -Sensitivity can be as low as 50% and as high as 90% “Fever equals malaria unless proven otherwise”…but this is problematic! --Leads to overdiagnosis of malaria, mismanagement of symptoms& Allocation of limited resources

Answer 162

In humans, the parasites grow and multiply first in the liver cells and then in the red cells of the blood. In the blood, successive broods of parasites grow inside the red cells and destroy them, releasing daughter parasites ("merozoites") that continue the cycle by invading other red cells. The blood stage parasites are those that cause the symptoms of malaria. When certain forms of blood stage parasites ("gametocytes") are picked up by a female Anopheles mosquito during a blood meal, they start another, different cycle of growth and multiplication in the mosquito. After 10-18 days, the parasites are found (as "sporozoites") in the mosquito's salivary glands. When the Anopheles mosquito takes a blood meal on another human, the sporozoites are injected with the mosquito's saliva and start another human infection when they parasitize the liver cells. Thus the mosquito carries the disease from one human to another (acting as a "vector"). Differently from the human host, the mosquito vector does not suffer from the presence of the parasites. *https://www.youtube.com/watch?v=A2-XTlHBf_4

Answer 163

1. Mosquito bites host (human) and injects sporozoites * Sporozoites migrate to liver 2. Sporozoites infect liver cells and become schizonts 3. Schizonts reproduce asexually inside the liver cell 4. Schizonts generate large numbers of merozoites & Eventually, the large number of merozoites ruptures the liver cell

Answer 164

5. Merozoites migrate back to the circulation and infect healthy red blood cells - -Merozoites become trophozoites (the activated, intracellular feeding stage of an apicomplexan) 6. After feeding, the trophozoite becomes a schizont, later releasing merozoites This cycle occurs every 48 hours in a cyclical manner

Answer 165

7. After traveling back to the circulation and infecting RBCs, some trophozoites develop into gametocytes instead. * Gametocytes can stay in the blood for several days * During this time, gametocytes can be taken up by mosquitoes during a feeding, transferring the parasite back to the vector

Answer 166

8. Gametocytes are taken up by mosquito during feeding 9. Gametocytes migrate to gut 10. 1 male and 1 female gametocyte fuse and form an ookinete (fertilized and motile) 11. Ookinetes develop into oocysts and begin to produce sporozoites 12. Oocysts eventually rupture and release sporozoites, which migrate to the salivary glands of a mosquito for transmission to a host during a subsequent feeding

Answer 167

* Does not confer sterile immunity, thus immunity does not prevent infection * There is some naturally acquired immunity for those who have had years of Plasmodium exposure * This partially protective immunity decreases the intensity of infection and severity of the disease * Natural Acquired Immunity is only maintained by ongoing exposure * Naïve Populations more likely experience complicated malaria * Both antibodies and T cells may be important for expression of immunity. We need more research!

Answer 168

*Sickle Cell anemia is caused by a single point mutation, causing glutamic acid to be replaced by valine *abnormal hemoglobin forms strands that cause this sickle shape *Leads to loss of blood cell elasticity and destruction of mis-shapen RBCs *sickle cells will often block blood flow *This occlusion of vessels can lead to several serious symptoms, including acute chest syndrome, spleen ischemia, and vaso-occlusive crises of various organs (vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organs)

Answer 169

he malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle-cell trait (selection for the heterozygote).

Answer 170

* Sickle cell anemia is a dominant trait, with homozygous dominant individuals suffering from the worst symptoms (HbSS) * Heterozygotes (HbS) have “sickle cell trait,” but only mild symptoms * Due to premature death of RBCs, malaria is unable to reproduce properly during the erythrocytic stage * Because of this, HbS individuals actually have a higher likelihood of survival and the trait has been selected for over time

Answer 171

* Sequestration in tissue * Antigenic variation * Antigenic diversity/polymorphism * Adherence to epithelial walls * State of immune suppression

Answer 172

* It’s a parasite * Highly polymorphic genome * Lack of immune correlates * Problematic animal models * Parasites have immune evasion mechanisms * Need adjuvants that generate extremely high antibody titers

Answer 173

Sporozoites: (Humoral) - -Ab to block invasion - -Ab to kill sporozoites via Opsonization / C’ Hepatocyte: (Cell Mediated) - -CTL mediated lysis - -CD4+ help for activation/ differentiation of CTL - -Localization cytokine release by T cells or APCs - -ADCC of C’mediated lysis

Answer 174

* Localized of cytokine release that directly kill infected erythrocytes or intracellular parasite * Abs kill pRBC via opsonization or phagocytotic mechanism * Abs stop schizont rupture * Abs block merozoite invasion * Abs prevent cytoadherence of pRBC

Answer 175

* Cytokines will kill gametocyte w/in pRBC * Abs that kill gametocytes w/ in pRBC via C’ * Abs interfere w/ fertilization * Abs that inhibit transformation of the zygote into the ookinete * Abs that block the ookinete from the midgut or into salivary glands

Answer 176

1. People living in endemic areas present some degree of acquired immunity (semi-immunes) 2. Passively transmitted serum from semi-immune adults can confer protection in sick kids 3. Genetic and other factors exist that alter the severity of the disease – we just need to find what they are!

Answer 177

Sub-Unit - -Pre-erythrocytic - -Erythrocytic - -Sexual stage (transmission blocking vaccine) Whole Killed - -Pre-erythrocytic (prophylatic) - -Erythrocytic (altruistic)

Answer 178

* Goal: Prophylactic Vaccine to prevent infection | * Major Challenge: Limited amount of time (sporozoites travel to liver

Answer 179

*Infected mosquitoes are gamma- irradiated which attenuates the sporozoites within them, allowing them to infect hepatocytes but not develop into mature schizonts *problem: This technique requires >1000 immunizing bites to achieve maximal protection That’s a LOT of mosquitoes! Not cost effective and impractical but it works

Answer 180

*Identified circumsporozoite (CS) protein as antigen of choice for vaccine development – but it is not immunogenic on its own. RTS,S: Hybrid construct of the hepatitis B surface antigen (HBsAG or S antigen) fused with a recombinant antigen derived from part of the circumsporozoite (CS) protein Adjuvant System: AS01 or AS02 required for immunogenicity Induces very high antibody titers Can be improved by combining with erythrocytic vaccine and better adjuvants. * Major findings: 55. 8% efficacy against malaria infection in children 5-17 months of age 47. 3% efficacy against severe malaria in this group

Answer 181

* Full Phase III trial results will be available by late 2014 * Most recent study updates with different age group children are showing similar efficacy * Potential concern: Waning protection – level of protection was lower at the end of the 12-month surveillance period than shortly after vaccination. Next steps: WHO review Regulatory review by European Medicines Agency in 2014-2015 Licensure!

Answer 182

* The Phase 3 trial of RTS,S enrolled over 15,000 infants and young children in seven sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and the United Republic of Tanzania). * The trial sites within these countries represented a range of malaria transmission settings (low, medium and high) in order to determine the vaccine’s efficacy in these different settings.

Answer 183

Over the full duration of the trial, vaccine efficacy against clinical malaria in infants was 27% in the group that received four doses of RTS,S (3 doses at 6, 10 and 14 weeks of age, and a fourth dose 18 months later); and 18% in the group that did not receive the fourth dose of the vaccine. In these infants, no significant efficacy was noted against severe malaria, with or without a fourth dose. Among children aged 5-17 months who received four doses on a 0, 1, 2, 20 month schedule, vaccine efficacy against clinical malaria was 39% over the full duration of the trial. With a four-dose schedule, the overall efficacy against severe malaria among children in this age group was 31.5%, with reductions in severe anaemia, malaria hospitalizations and all-cause hospitalizations also seen.

Answer 184

Among children in the older age group, there was an excess risk of febrile seizures within 7 days after any of the vaccine doses. Among infants, this excess risk was only apparent after the fourth dose. Among children in the older age group, an increase in the number of cases of meningitis and cerebral malaria was found in the group receiving the malaria vaccine compared to the control group. The significance of these findings in relation to the vaccination is unclear. An excess of meningitis and cerebral malaria was not seen in infants aged 6–12 weeks.

Answer 185

* The European Medicines Agency (Europe’s version of the FDA) provided a scientific opinion that was positive towards licensing the drug. It is up to respective African countries to consider using the vaccine in their jurisdictions –as of yet not country has licensed RTS, S. * WHO: Strongly supportive of the need to proceed with these pilots in children aged 5-17 months as the next step for the world’s first malaria vaccine. WHO is now actively working with financing bodies, and the malaria vaccine clinical trials partnership (including PATH and GSK) to mobilize the financial support for the pilots, and to finalize design of the pilot implementation programme.

Answer 186

* Goal: Block disease progression: Therapeutic vaccine * Challenges: polymorphism and immune evasion Examples: MSP-1 protein, AMA-1 and Combination B

Answer 187

*Current focus is on identifying target antigens Examples of past antigens of interest: - -MSP-1 (Merozoite Surface Protein-1) - -AMA-1 (Apical Membrane Antigen) – type 1 integral membrane protein - -Combination B Vaccine – mixture of 3 blood stage antigens delivered in water-in-oil emulsion. None of these have proved as effective as originally hoped because of polymorphism!

Answer 188

Goal: Prevent transmission, altruistic vaccine Advantages: avoids polymorphism and immune selection pressure Challenges: need a high antibody titer Current Targets: Pfs25, AnAPN1

Answer 189

*Recently, there has been a trend to return to the whole parasite approach Challenges: --Logistics of Production --sterile, hand dissection, liquid nitrogen storage Only protects the immune naïve – not our target population…because really how many living in certain African countries are immune naïve?!

Answer 190

* Need to better utilize mapped genome of P. falcipurum in order to identify more protective antigens * Need better adjuvants * Need to identify target audience in order to tailor vaccine to specific demographic * Continue awareness and funding

Answer 191

* HIV stands for human immunodeficiency virus. * HIV is a virus that gradually attacks the immune system, which is our body’s natural defense against illness. If a person becomes infected with HIV, they will find it harder to fight off infections and diseases. The virus destroys a type of white blood cell called a T-helper cell and makes copies of itself inside them. T-helper cells are also referred to as CD4 cells. * If left untreated, it can take around 10 to 15 years for AIDS to develop, which is when HIV has severely damaged the immune system. * Unlike some other viruses, the human body cannot get rid of HIV. That means that once you have HIV, you have it for life.

Answer 192

*With proper medical care, HIV can be controlled. Treatment for HIV is often called antiretroviral therapy or ART. It can dramatically prolong the lives of many people infected with HIV and lower their chance of infecting others. Before the introduction of ART in the mid-1990s, people with HIV could progress to AIDS in just a few years. Today, someone diagnosed with HIV and treated before the disease is far advanced can have a nearly normal life expectancy.

Answer 193

* First described by Ellerman & Bang in 1908, who reported that they could transmit Leukemia from one chicken to another with an infectious extract of blood cells * Rous: transported tumor from one chicken to another & also prepared an extract of tumor cells, passed them through a filter and found that there were "filterable agents" * The isolation of the first oncogenic retroviruses by Ellermann and Bang (1908) and by Rous (1911) created the founding paradigm of the field. These discoveries were of absolute novelty, without anticipatory predecessors, and in many respects, they were far ahead of medical science of their times. * first retrovirus seen was HTLV-1, which is Human T-cell leukemia virus type 1 (HTLV-1)

Answer 194

* Virologist and immunologist * 1960 Nobel prize winner * Clonal Selection Theory * Discovered there existed multiple, non-cross-protective strains of Polio * Wrote Natural History of Infectious Disease & said that to write about infectious disease… “is almost to write of something that has passed into history...the late 20th century would be witness to the virtual elimination of infectious disease as a significant factor in social life.”

Answer 195

* The theory states that in a pre-existing group of lymphocytes (specifically B cells), a specific antigen only activates (i.e. selection) its counter-specific cell so that particular cell is induced to multiply (producing its clones) for antibody production. * When a soluble antigen is present, it binds to the antibody on the surface of B cells that have the correct specificity. These B cell clones develop into antibody-producing plasma cells or memory cells. * Following initial exposure to antigen, the plasma cells stop producing antibody and die. Memory cells remain in greater numbers than the initial B cells, allowing the body to quickly respond to a second exposure of that antigen.

Answer 196

*HIV is a retrovirus +RNA-->-DNA-->dsDNA-->integration into host genome From host genome to mRNA Retroviruses are special in that they can undergo reverse transcription (RNA to DNA) When in the host genome, it is referred to as a provirus

Answer 197

Retroviridae is a family of enveloped viruses that replicate in a host cell through the process of reverse transcription. A retrovirus is a single-stranded positive-sense RNA virus with a DNA intermediate and, as an obligate parasite, targets a host cell. Once inside the host cell cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome — the reverse of the usual pattern, thus retro (backwards). This new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, translating and transcribing the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. It is difficult to detect the virus until it has infected the host. At that point, the infection will persist indefinitely.

Answer 198

Three steps in viral entry: 1. Attachment: “bumping” into the susceptible cell, non-specific 2. Binding: interaction with a specific receptor; defines tropisms 3. Entry: fuses with host membrane to gain entry Integration: 1. ssRNA undergoes RT 2. Forms the pre-integration complex (PIC) 3. Integrase (within PIC) mediates entry into the nucleus and integration into host dsDNA

Answer 199

1. Activation of provirus 2. Transcription of proviral DNA into genomic ssRNA, processed into mRNA 3. Transported to cytoplasm 4. Host ribosomes translate viral proteins 5. Assembly of HIV virions 6. Host membrane buds out, forming the viral envelope 7. Release of viral particles

Answer 200

* HIV tropism refers to the cell type that the human immunodeficiency virus (HIV) infects and replicates in. * HIV-1 entry to macrophages and T helper cells is mediated not only through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells but also with its chemokine coreceptors. * HIV infects CD4+ T cells and macrophages/monocytes * Both require the binding of a co-factor *CD4 is NOT sufficient for binding and entry * T cell infecting (or T tropic) strains require CXCR4 binding * Macrophage/monocyte infecting (or M tropic) strains require CCR5 binding * Dual infecting (D/M tropic) can infect both T cells and macrophages

Answer 201

*Goal: Keep viral loads down and T cell counts high. Current drugs and targets: AZT (nucleoside RT inhibitor; NRTIs) (1984) Protease Inhibitors (PIs) (1995) Non-nucleoside RT inhibitors (NNRTIs) (1998) Entry inhibitor (2006) Integrase inhibitor (2007) HAART: highly active anti-retroviral therapy (1996)

Answer 202

``` 1. HIV-1 Most prevalent form Most pathogenic form Target of vaccine development Many different sub clades ``` 2. HIV-2 Less Pathogenic form 3. Animal HIV most likely to enter the human population with SIV (simian) Feline, bovine, and murine viruses have also been described

Answer 203

``` HIV disease burden rose rapidly from 1982 to 1994 *35M infected globally Only 50% know 23.5M in Sub-Saharan Africa (1 in 20) Only 8M on therapy ``` Overall 60M infections and 25M deaths

Answer 204

Blood Babies “Boinking” Sexual contact 85% of global infection due to heterosexual contact Infected blood Intravenous drug use Before 1985, patients receiving blood transfusions or pooled blood products were at high risk Mother-to-Child transmission Can occur during pregnancy, labor, or breastfeeding Without intervention, transmission rates about 15-45% With intervention, under 5%

Answer 205

1. HIV is a retrovirus; integrates its genetic material into human chromosome inside the cells it infects; very brief window for vaccine-mediated immune responses to act 2. HIV does not induce protective immunity: no documented case of recovery from HIV infection & the correlates of protection in HIV infection remain unknown 3. HIV is hypervariable: HIV has an error-prone reverse transcriptase and a rapid replication rate; so high mutation rate; enables immune escape; HIV is a "moving target" because by time vaccine made, the virus might have significantly mutated 4. HIV has immune evasion mechanisms: HIV targets the very immune cells necessary to keep infections at bay; virus outer surface protein gpi20, is adapted to avoid immune system; decorated with matrix of carbohydrates to shield it from neutralizing antibodies, it has decoys to shift immune response away 5. HIV infects HUMANS: no ideal animal models for HIV infection & AIDS 6. HIV is a sexually-transmitted infection: because HIV infects by multiple routes, robust mucosal immunity may be required for protection; also sexually active adolescents through the elderly can be infected

Answer 206

* Recombinant protein (gp120) * synthetic peptides (V3) * naked DNA * Live-recombinant vectors * whole-inactivated virus * live-attenuated virus

Answer 207

1. Expression of gp120; failed in all systems where it was attempted 2. Inactivated Vaccine: Salk attempted to do what he had done with Polio 40 years prior; he grew HIV, killed it, and injected it with an adjuvant. PROBLEM: the envelope proteins were lost during preparation & had no statistical efficacy

Answer 208

* Newer vaccines were designed to produce T cell responses * Multi-center, randomized, double-blind, placebo-controlled phase 2b test-of-concept clinical trial * 3,000 HIV-negative participants between 18 and 45 years old * 34 clinical trial sites in North and South American, Caribbean and Australia Trial objectives Would the vaccine reduce HIV infections? In those who became infected, would vaccine reduce viral load? * Employed the Merck Ad5 trivalent HIV vaccine * The vector was engineered to express single HIV genes, either Gag, Pol, or Nef * Placebo: dilution buffer without Ad5 * Vaccine or placebo given at 0,1 and 6 months

Answer 209

* Data and safety monitoring board recommended halting vaccinations for lack of efficacy * Vaccine efficacy was -25%; the DNA/rAd5 vaccine regimen did not reduce either the RATE of HIV-1 acquisition or the viral load set point in the population studied

Answer 210

*Used a “prime—boost” method Combine two failed vaccines ALVAC: Canarypox expressing Gal-Pol and Env at 0, 4, 12, and 24 weeks (“prime”) AIDSVAX: recombinant gp120 at 12 and 24 weeks (“boost”) Very large trial, with 16,000 HIV-negative participants ``` Findings: Over 3 years, 125 people became infected 74 in the placebo arm 51 in the vaccine arm 31% efficacy This is the first human trial to demonstrate ANY protective effect ```

Answer 211

Analysis of participants provided clues for future vaccine directions Individuals with a strong IgG response to the V2 loop of gp120 were 43% less likely to become infected Individuals with a strong IgA response to another region of gp120 were 54% more likely to become infected

Answer 212

32 bp deletion in CCR5 - -Results in a non-expressed mutant protein - -Major co-receptor of M-tropic HIV strains - -M-tropic strains tend to be the most likely transmitted BERLIN PATIENT Diagnosed with both AIDS and acute myeloid leukemia Received a bone marrow transplant from a 32 bp deletion donor Left the hospital with neither AIDS nor cancer Since the Berlin Patient, the same treatment has been attempted both with AND without 32 bp donors. Both protective?!

Answer 213

*Mississippi baby born with HIV was treated with aggressive anti-retroviral treatment just after birth *24 months after birth, researchers found a single copy of HIV RNA in plasma But when researchers mixed blood with uninfected CD4 cells, no new virus was produced *Hypothesis: The drugs prevented formation of viral reservoirs of long-lived CD4 cells that harbor latent HIV infections These cells avoid immune detection and are impervious to anti-retroviral drugs. *But how do we develop an immunological response as opposed to a pharmaceutical approach?

Answer 214

Broadly-Neutralizing Antibodies (BnAbs) *Induction of HIV-1 envelope BnAbs that target conserved regions is a key goal of vaccine development * 20% of patients evolve BnAbs against variants of the founder virus (that initially established infection) * Early neutralization by Abs triggers virus escape but rapid virus evolution was followed by acquisition of BnAbs that could neutralize a wide breadth of viruses *Although neutralizing breadth generally isn’t observed until chronic infection, a better understanding of the interaction between virus evolution and maturing of BnAb lineages may lead to BnAb development

Answer 215

``` siRNA (short interfering RNA) miRNA (micro RNA) Ribozymes RNA aptamers RNA decoys ``` John Rossi’s approach Lentiviral vector for modification of stem cells for bone marrow transplants Vector expresses shRNA (tat and rev), TAR decoy, and ribozyme targeting CCR5

Answer 216

Poliomyelitis, often called polio or infantile paralysis, is an infectious disease caused by the poliovirus.

Answer 217

Poliovirus is a member of the enterovirus subgroup, family Picornaviridae. *Enteroviruses are transient inhabitants of the gastrointestinal tract, and are stable at acid pH. *Picornaviruses are small, ether-insensitive viruses with an RNA genome. *RNA+ Virus *Three serotypes: aptly named 1, 2, and 3 *No cross-protection between serotypes *Fecal-oral transmission *Easy to inactivate: Heat, formaldehyde, chlorine, and UV light *Resistant to many normal cleaning supplies: Low pH’s, soaps, ethanol, chloroform

Answer 218

* Polio has been around for a long time - -Thought to date back to prehistory - -First official medical report in 1789 - -Nervous system involvement first hypothesized in 1840 *Widespread epidemics are a recent development: Began around 1900 *epidemics are result of improved sanitation Improved sanitation → later and less common exposure No maternal antibodies to “attenuate” infection No constant “boosting” → Large susceptible populations

Answer 219

Binds to CD155 * CD155 is also known as the “poliovirus receptor” * Viral RNA enters the cell * RNA+ translated into polyprotein: One long strand of proteins * Gets chopped up into individual proteins RNA+ → RNA- → RNA+ * RNA+ combined with protein capsid to form virions * Eventually, the cell is lysed and the baby virions are released

Answer 220

The virus enters through the mouth (INHALATION), and primary multiplication of the virus occurs at the site of implantation in the pharynx and gastrointestinal tract (IMPLANTATION SOMEWHERE IN THE GI TRACT). The virus is usually present in the throat and in the stool before the onset of illness. One week after onset there is less virus in the throat, but virus continues to be excreted in the stool for several weeks. RELEASE INTO LYMPHATIC SYSTEM VIA LACTEALS: The virus invades local lymphoid tissue, enters the bloodstream(lymph dumps into bloodstream-->VIREMIA), and then may infect cells of the central nervous system. Replication of poliovirus in motor neurons of the anterior horn and brain stem results in cell destruction (lysis) and causes the typical manifestations of poliomyelitis (paralytic polio); then spreads to next neuron and heads "towards" the CNS *Paralysis caused by polio is typically asymmetric *The pathophysiology was determined by Albert Sabin

Answer 221

6-20 day incubation period * EVERYONE infected with polio sheds the virus * Highest rate of viral shedding 7-10 days before and after initial symptoms * Virus continues shedding for up to 6 weeks * Highly infectious * >90% of susceptible household contacts become infected

Answer 222

Polio is diagnosed by isolating the virus, detecting anti-polio Abs, or by looking at the cerebrospinal fluid

Answer 223

Humans are the only known reservoir of poliovirus, which is transmitted most frequently by persons with inapparent infections. There is no asymptomatic carrier state except in immune deficient persons.

Answer 224

90% Asymptomatic: up to 90% of all polio infections in children are asymptomatic. Infected persons without symptoms shed virus in the stool and are able to transmit the virus to others. The majority of poliovirus infections are asymptomatic The majority of symptomatic poliovirus infections do not involve the CNS 7% minor, non-CNS illnesses: This clinical presentation is known as abortive poliomyelitis, and is characterized by complete recovery in less than a week. This is characterized by a low grade fever and sore throat. 2% Aseptic meningitis: Nonparalytic aseptic meningitis (symptoms of stiffness of the neck, back, and/or legs), usually following several days after a prodrome similar to that of minor illness 1% Paralysis: Many persons with paralytic poliomyelitis recover completely and, in most, muscle function returns to some degree. Weakness or paralysis still present 12 months after onset is usually permanent.

Answer 225

Flu-like symptoms: Sore throat, fever GI tract infection symptoms: Nausea, vomiting, abdominal pain

Answer 226

Virus makes it’s way to the CNS: Provokes inflammatory response * Stiffness in neck, back, and legs * Often completely reversible

Answer 227

* Paralytic symptoms begin ~1 week after non-paralytic aseptic meningitis symptoms * Eventually motor neurons are destroyed * Recovery is possible, but unlikely * 10x more likely to progress to paralytic polio in adults

Answer 228

* Paralysis of diaphragm → inability to breathe → death: Occurs in 5-10% of paralytic polio cases * The iron lung was a machine that would mechanically compress/decompress the thorax, which allowed individuals who lost control of their diaphragms to breathe * Some individuals were eventually able to be taken off the iron lung: others were not so lucky

Answer 229

* Condition in which survivors of paralytic polio become even weaker * Occurs in 25-40% of survivors ofparalytic polio * Affects an estimated 300,000 survivors * Occurs 30-40 years later * Note that no virus is shed * Upon death of some motor neurons, other motor neurons strengthen to compensate: which allows for better than expected mobility * Over time these hypertrophic neurons fail due to overuse, which leads to feebleness * Risk Factors: More time since onset of paralysis, more paralysis, and having two X chromosomes

Answer 230

* 13,000-20,000 cases of paralytic polio annually in the US alone * 500,000 cases of paralytic polio and death worldwide * Leading cause of permanent disability in children * Parents living in constant fear * Unlike most infectious diseases of the time, polio affected countries with the best public health symptoms * “Surveys showed that, apart from the atomic bomb, America’sgreatest fear was polio”- The Polio Crusade (PBS Special)

Answer 231

The biggest hindrance to developing a polio vaccine turned out to be culturing the virus in the first place *1909 – Karl Landsteiner cultured the virus in monkey neural tissue: Impractical for large scale vaccination campaigns 1936 – Albert Sabin cultured the virus in human embryonic neural tissue: Sabin deemed his culturing method not suitable for vaccine development as he was afraid it would be too virulent

Answer 232

* 1949 – John Enders cultures virus in non-neural tissue * Enders’ group managed to culture the virus in multiple types of non-neural embryonic tissue * Allowed for large-scale production of virus without sacrificing thousands of monkeys * Proved that poliovirus wasn’t exclusively neurotrophic * According to Enders himself, this discovery was completely accidental * As with all accidents that lead to scientific breakthroughs, Enders and his colleagues won the 1954 Nobel Prize in Physiology or Medicine for their work

Answer 233

* 1949 – Enders cultures virus * 1950 – passive immunization successful * Since then the correlates of immunity have been determined - -IgA prevents infection: Mucosal antibodies prevent the virus from ever colonizing the host * IgM and IgG prevent CNS involvement - -Serum Abs - -Neutralize the virus during the viremia phase - -Individuals with serum antibodies but without mucosal antibodies STILL EXCRETE THE VIRUS

Answer 234

*1952 – Salk develops IPV *1954 – IPV tested --1.8 million children were vaccinated nationwide…and the vaccine hadn’t even been licensed yet --These children are the “polio pioneers” in the background of every one of Dr. B’s slidesets This should give you an idea of how dire the situation was at the time *1955 – IPV licensed

Answer 235

* Whole-killed vaccine * Protects against all 3 serotypes * Grown in monkey kidney cells * 2 years after Enders’ pioneering research, Salk used Enders’ culturing technique to culture the virus in monkey kidney cells * Inactivated with formaldehyde * Produces strong serum antibody responses * NO mucosal response

Answer 236

* A miscalculation by Salk and faulty equipment led to live poliovirus being incorporated into batches of vaccines * 10 individuals died and nearly 200 were left paralyzed * This event led to a mild reluctance to be vaccinated with IPV * Opened the door for another vaccine to be developed

Answer 237

* 1957-1959 – Sabin develops monovalent OPVs against all 3 strains and tests them in the USSR * 1961 & 1962 – monovalent OPVs licensed * 1963 – trivalent OPV licensed * In actuality, multiple formulations of OPV were developed by multiple scientists. Sabin’s was chosen by an independent NIH panel as the best live-attenuated vaccine candidate.

Answer 238

* Live attenuated vaccine * Given orally * SUGAR CUBE!!!! * Protects against all 3 serotypes * Ratio of inclusion is 10:1:3 * Virus grown in monkey kidney cells * Attenuated through cold-adaptation * AKA exactly what Enders alluded to in 1954 * Elicits both IgG and IgA responses: is mucosal protection * A vaccine that is cheaper, easier to administer, more efficacious, protects multiple individuals, and comes with a sugar cube?!?! This seems too good to be true!!!

Answer 239

IPV: Given by needle, prevents against disease, protects only the vaccinee, costs 3$ a dose OPV: given orally, prevents against INFECTION, protects the vaccinee and others, cost 0.14$ a dose

Answer 240

*“VAPP” = “vaccine-associated paralytic polio” *In some cases, the attenuated virus reverts back into its pathogenic form *We call this “Vaccine Derived Poliovirus” or “VDPV” *VDPV behaves just as the actual virus does --It can cause paralysis (VAPP) --It can transfer to other humans --It can cause epidemics --1 out of every 1-3 million doses of OPV led to VAPP --7000x more likely in immunodeficient individuals --7-21x more likely to occur following the 1st dose *A few cases of VAPP a year was deemed an acceptable risk Most countries switched to OPV The US made the switch in 1963

Answer 241

Dose #1: 2 months Dose #2: 4 months Dose #3: 6-18 months Dose #4: 4-6 years Note that this is the schedule used in the United States through 1996.

Answer 242

Precautions: Moderate/severe acute illnesses (like always) Contraindications - -Anyone with an immunosuppressive condition - -Congenital immunodeficiency - -Leukemia or lymphoma - -Chemotherapy - -AIDS - -Anyone in close contact with an individual with the above immunosuppressive conditions *Everyone contraindicated for OPV was instead given IPV

Answer 243

After 1980 all cases of paralytic polio were either VAPP or imported

Answer 244

1987 – enhanced-potency IPV developed *2 doses Enhanced IPV = 3 doses regular IPV *1996 – ACIP recommends joint IPV-OPV schedule

Answer 245

* We had reached a point where the only cases of paralytic polio in the US were caused by the vaccine * VAPP was no longer an acceptable risk * ACIP recommended a joint IPV-OPV schedule * 2 doses of IPV followed by 2 doses of OPV * Hoped this would allow for all of the benefits of OPV without the risk * The data are really, really messy and inconclusive: “Ah screw it, let’s just do IPV” * 2000 – OPV use discontinued in US * According to the CDC, Poliovirus was last detected in the US in an Amish community in Minnesota in 2005

Answer 246

``` 4 shots: 2 months 4 months 6-18 months 4-6 years ``` * Typically given in combinationwith other vaccines such as DTaP or Hep B * Once-in-a-lifetime booster shot recommended for individuals traveling to high-risk countries who will be working in healthcare environments

Answer 247

*As of 2013, 92.7% of the population in the United States has received at least 3 doses of IPV (or OPV) Coverage varies by state Ranges from 87.6% in New Mexico to 97.9% in Massachusetts *Precautions include moderate/severe acute illnesses *Contraindications: Allergies to certain antibiotics used in vaccine formulation & Severe allergic response following a previous dose

Answer 248

1988 – WHO establishes GPEI: The Global Polio Eradication Initiative 350,000 cases of paralysis every year at this point Set year 2000 as a goal for global eradication *didnt happen BUT significant progress has been made

Answer 249

“Endemic” means WPV (wild poliovirus) transmission has never been interrupted in the region

Answer 250

“Polio-free” means no cases of any type of polio over a three-year period

Answer 251

* western hemisphere is declared polio-free * poliovirus 2 is declared eradicated * western pacific declared polio-free * Europe declared polio-free * WHO pushes deadline of polio eradication back to 2018 * *2012: no cases of polio observed in India: BIG achievement; in 1988, India was responsible for half of the worldwide cases of paralytic polio; currently India is POLIO FREE

Answer 252

2012 – Wild poliovirus 3 is last seen in Nigeria “The 10th of November is an opportunity to mark three years with no child paralysed [sic] by wild poliovirus type 3 (WPV3)…With no sign of type three of the virus anywhere in the world for three years, it’s very likely that it has been eradicated” - WHO, November 10th, 2015

Answer 253

Number of cases worldwide doubled Polio resurged in countries where it had been eliminated *Somalia Hadn’t had a single case since 2007 Accounted for 47% of all cases worldwide *Syria Hadn’t had a case since before 2005 4th most cases of polio for any country worldwide Cameroon No cases since 2009 Multiple cases due to virus spreading from neighboring Nigeria ``` 2014 Cases in Pakistan spiked up over 300% Nigeria had some problems Cases spilled into Cameroon and Equatorial Guinea 30 cases of cVDPV2 in Nigeria ```

Answer 254

* Remember when I said poliovirus could theoretically circulate in a population of IPV-vaccinated individuals without anyone showing symptoms so long as enough people were vaccinated? * In 2013, Pakistani poliovirus was detected circulating in Israel, Gaza, and the West Bank * It continued to be detected in Israeli sewage for two years during which time no cases of paralytic polio were observed * Israel had 94% coverage with IPV at the time

Answer 255

* WHO declared polio a “Public Health Emergency of International Concern” * Recommended that certain governments require individuals to show proof of vaccination in order to leave the country - -PHEIC applied to Pakistan, Syria, and Cameroon - -Called for all refugees to be vaccinated at the border * For perspective, only fourPHEICs have been issuedsince the WHO was giventhis authority in 2007: H1N1 (2009), Polio (2014),Ebola (2014), Zika (2016)

Answer 256

* The last two years have been phenomenal for WPV - -NO cases in Nigeria - -Nigeria is no longer considered “endemic” * Only 74 cases worldwide last year - -Every single one of them confined to Pakistan and Afghanistan - -Only 10 cases so far this year - -22 cases at the same point last year

Answer 257

* Eradication is possible * Only infects humans (Although there has been a documented case in a turtle) * No asymptomatic carrier state * Significant support and desire to get the job done * As of 2013, over 84% of the global population has received 3 doses of OPV or 4 doses of IPV

Answer 258

Unfortunately, complications exist Won’t be done using OPV alone - -VDPV (vaccine-derived poliovirus) - -OPV less effective on individuals living in poorer countries Won’t be done using IPV alone - -Harder to administer - -Doesn’t prevent infection (see: Israel) - -$$$

Answer 259

*Back in 2013, the WHO looked at the data and saw an troubling trend with poliovirus 2 WPV2 eradicated in 1999 cVDPV2 responsible for 97.6% of cVDPV (Circulating vaccine derived poliovirus) cases between 2008 and 2012 Responsible for 84% of cVDPV cases since 2013 “Why the hell are we still vaccinating for WPV2???” The costs outweighed the benefits

Answer 260

Recommended a switch from trivalent OPV (tOPV) to bivalent OPV (bOPV) tOPV protects against types 1, 2, and 3 bOPV protects against types 1 and 3 In fact, studies have shown that bOPV protects against types 1 and 3 more effectively than tOPV

Answer 261

* In order to prevent this, the WHO recommended three things * A global, synchronized switch from tOPV to bOPV * The stockpiling of mOPV2 in case of an emergency * The addition of one dose of IPV to the vaccination schedule a year in advance of the switch * The goal of the use of IPV is to provide immunity to PV2 in case of a cVDPV2 outbreak * Even if an individual’s response isn’t fully protective, at the very least it provides some memory that can be built on by mOPV

Answer 262

``` *Dose of bOPV at birth 3 doses of bOPV at 6 weeks or older 4 weeks between doses 1 dose of IPV at 14 weeks or older Can be administered concurrently with bOPV ``` “To mitigate the risk of undetected transmission, WHO recommends that endemic countries and countries with a high risk of WPV importation should not switch to an IPV-only or a sequential IPV–bOPV schedule at this time”

Answer 263

Either an IPV-bOPV schedule or an IPV-only schedule IPV-bOPV Schedule 1 or 2 doses of IPV followed by 2 or more doses of bOPV 4-8 weeks between each dose IPV Only Schedule 3 or 4 doses of IPV 4-8 weeks between each dose

Answer 264

*Before travelling abroad, persons residing in countries with active transmission of a wild or vaccine-derived poliovirus should have completed a full course of polio vaccination in compliance with the national schedule, and received one dose of IPV or bOPV within 4 weeks to 12 months of travel, in order to boost intestinal mucosal immunity and reduce the risk of poliovirus shedding. Travelers to endemic infected areas should be vaccinated according to their national schedules.

Answer 265

HPV is the most commonly sexually transmitted infection (STI)

Answer 266

Human Papillomavirus is a small icosohedral DNA virus; scientists have identified more than 130 subtypes of HPV, many of which infect the genitals, mouth, and throat *40 types infect the mucosal epithelium

Answer 267

* Transmitted through direct contact, almost always sexually transmitted * Other forms of transmission have been demonstrated, such as mother to child during active birth, but these are far less frequent * Communicability is high, in both acute and persistent infections * HPV can be passed even when an infected person has no signs or symptoms. * 130+ strains - 40+ of these types spread through skin-to-skin contact during sexual activity

Answer 268

* The most common STI in the US * Prevalence rate among American women aged 15-59 is an estimated 26.8% * Estimated 20 million currently infected * 6.2 million new infections/year * More than 80% of sexually active women will have been infected by age 50

Answer 269

* HPV is made up of an outer protein coat (the capsid) and double stranded circular DNA * Its genome encodes 8 proteins * 6 proteins early in the lifecycle (E1, E2, E4, E5, E6, E7) that help with viral replication, transcription and translation * E6 and E7 are the oncogenic proteins * 2 proteins late in the lifecycle (L1 and L2) which are structural, encoding the major and minor capsid proteins

Answer 270

For infection to occur, HPV enters through tiny cuts in the skin around or inside the penis, vagina, throat or anus. the virus makes its way down to the cells in the bottom or basal layer of skin and infects them. as the infected cells divide, the virus begins to make copies of itself. eventually the infected cells begin to move upwards through the skin layers, releasing new viruses that can spread the infection to other cells. for most, the cells of immune system can destroy infected cells and virus within two years. in some, the immune system isnt able to destroy all of the viruses, leading to an infection that doesnt go away. HPV infected cells may multiply over several weeks; if cells are infected with low-risk HPV, will form warts around genitals; if high risk, may damage cells genetic material, causing the cells to become pre-cancerous. over a period of years, a cancerous tumor may slowly form as the damaged cells continue to multiply. the most common cancer from high risk HPV is cervical cancer. no cure for HPV infection, but is vaccine that protects against 2 most common high-risk, and 2 most common low-risk.

Answer 271

* Sexual activity * Early age of onset of sexual activity * Multiple sex partners (or sex partners who have multiple sex partners) ``` Other possibilities: Young age (under 25) Smoking Increased parity (number of pregnancies) Inconsistent condom use Other genital infections genetic factors ```

Answer 272

High risk: oncogenic (cancer causing) HPV types 16 and 18 cause 70% of cervical cancer and the majority of all HPV-caused cancers 85% of all anal cancer and over 50% of cancer of the oropharynx (throat/mouth) are caused by HPV-16 Over a dozen high risk strains have been found High risk HPV causes 5% of all cancers worldwide

Answer 273

* Low risk: can cause skin warts | * HPV types 6 and 11 cause 90% of genital warts

Answer 274

mucosal/genital(~40 types) **high-risk types (16, 18, 31, 45) :low grade cervical abnormalities, cancer precursors, anogenital cancers **low-risk types (6, 11): low grade cervical abnormalities – usually regress spontaneously genital warts, laryngeal papillomas nonmucosal/cutaneous (~60 types)--> skin warts (hands and feet)

Answer 275

*Mostly asymptomatic ``` If there are symptoms, they include: Anogenital warts Recurrent Respiratory papillomatosis Cervical cancer precursors Cancer These vary by strain and by site of infection ```

Answer 276

A papilloma is a benign epithelial lesion characterized by small finger-like projections upon microscopic or macroscopic evaluation (so, basically, warts) Clearly, this virus was named before the link with cancer was determined.

Answer 277

CERVIX cancer the highest, followed by mouth, oropharynx, vulva, etc.

Answer 278

WOMEN: 70% of Cervical Cancer 70% of Anal/genital Cancer MEN:70% of Anal Cancer Transmission to women

Answer 279

WOMEN:: 90% of Genital Warts 90% of RRP (recurrent respiratory papillomatosis) lesions MEN:90% of Genital Warts 90% of RRP lesions Transmission to women

Answer 280

* The virus infects epithelial cells * Two of the proteins which HPV produces (E6 and E7) inside the cells interfere with normal cell functioning, causing extensive cell growth and preventing cell death * Often the immune system recognizes and destroys these cells, but if not there is persistent long-term infection * As these cells grow and proliferate, mutations can build up that cause more growth that eventually can cause a tumor * The whole process from infection to tumor can take decades * However, many high-grade lesions formed by HPV do not become cancerous

Answer 281

Within 1 year: initial HPVinfection\ within 1-5 years: persistent infecction/CIIN1 decades: cervical cancer

Answer 282

* CIN= cervical intraepithelial neoplasia * LSIL (Low-grade squamous intraepithelial lesions) = CIN1 - -Viral genome integration rare - -productive HPV infections (actively producing virions) * HSIL (High-grade squamous intraepithelial lesions) = CIN2/3 - - not producing virions (which require L1/L2 capsid proteins) but rather a focus on production of the non-structural proteins E6 and E7

Answer 283

Ability of the virus to persist within the host *However: persistent HPV16 infection carries a greater than ~5 fold risk of developing cancer than persistent infection with other types * Expression of E6 and E7 oncogenes - -Differ in sequence between low and high risk HPV - --Contribute to immune ignorance through interference with the normal interferon response - -Low level expression can also induce a state of tolerance in any responding T cells

Answer 284

* When the viral genome integrates into the host’s, it is shifting from a circular to a linear strand * This break occurs in the E2 gene, making it nonfunctional * The E2 gene is a negative regulator of E6 and E7, so they then become overexpressed

Answer 285

* Pap smears: collect a few cells from the cervix to look for precancerous cells - -Recommended for all women 21-65 * HPV DNA test - -Tests for the presence of the virus itself - -Very new, FDA approved in April 2014 *We have a good screening system in place, for those with access to care, regular pap smears are generally very successful for early detection Conclusion: If you have a cervix, get Pap smears!

Answer 286

Normally very low antibody response detected Possible reasons? --intracellular pathogen → more likely to induce a stronger cellular response (though antibodies are usually present in viral infections nonetheless) New Theory: HPV has evolved to avoid antibody responses What does this say about possible vaccine design?

Answer 287

* The link with cancer makes this virus an obvious target for a prophylactic, and perhaps even one day a therapeutic, vaccine. * More than 4 billion dollars are spent annually on treatments for HPV related diseases

Answer 288

* Anogenital HPV is the most common sexually transmitted infection in the US * Estimated 20 million currently infected * 6.2 million new infections/year * Common among adolescents and young adults * Estimated 80% of sexually active women will have been infected by age 50 * Infection also common in men

Answer 289

The American Cancer Society estimates that in 2012 12,170 new cervical cancer cases 4,220 cervical cancer deaths Almost 100% of these cervical cancer cases will be caused by one of the 40 HPV types that infect the mucosa It has been shown that HPV is necessary, but not sufficient, to cause cervical cancer

Answer 290

* Recommended during pre-adolescence in order to develop a strong immune response before becoming sexually active - -should get vaccinated through young adulthood if not yet done *3 shots over the course of 6 months (ideally) *2 varieties: Cervarix (GSK, bivalent, licensed in 2009 for females 10-25) and Gardasil (Merck, quadrivalent, licensed in 2006 for males and females 9-26) --Both protect against types 16 and 18 --Gardasil also protects against types 6 and 11 The CDC now recommends the vaccine for males and females!

Answer 291

* Both vaccines are subunit vaccines, using recombinant DNA to produce VLPs (virus like-particles) - -Just codes for the viral coat protein (HPV L1) - -The capsid with no viral DNA inside, so it cannot cause infection * HPV L1 major capsid protein of the virus is antigen used for immunization * L1 protein expressed in yeast cells using recombinant technology * L1 proteins self-assemble into virus-like particles (VLP)

Answer 292

With a virus that is known to be able to cause cancer, it is dangerous to use even inactivated whole viruses because of the possibility of injecting active oncogenes VLPs are noninfectious and non-oncogenic The virus was initially difficult to produce in vitro, precluding any large scale development of other vaccine types.

Answer 293

* None definitively identified as of yet * However, protection thought to be mediated by neutralizing antibodies, despite robust T-cell response induced by both vaccines - -Gardasil produced Th2 response while Cervarix produces Th1 response, and both are protective. This indicates T cell response itself is not as important - -Vaccines do not show any effectiveness in clearing current infections (and viral infections are cleared by activated T cells)

Answer 294

ACIP recommends vaccinating boys and girls ages 11-12, though can start as early as 9, and can catch up from 13-26 Routine schedule is 0, 2, 6 months (Gardasil) Minimum intervals 4 weeks between doses 1 and 2 12 weeks between doses 2 and 3 24 weeks between doses 1 and 3 Do not restart the series if the schedule is interrupted

Answer 295

HPV 16/18-related----------->97% efficacious CIN2/3 or AIS HPV 6/11/16/18-------------->95% efficacy related CIN HPV 6/11/16/18-------------------99% efficacy related genital warts

Answer 296

* High efficacy among females without evidence of pre-existing infection with vaccine HPV types * No evidence of efficacy against disease caused by active infections * Prior infection with one HPV type did not diminish efficacy of the vaccine against other vaccine HPV types * There is no indication as of yet of waning protection over time, but study populations continue to be followed

Answer 297

* 30% of cervical cancers are caused by HPV types not prevented by the quadrivalent HPV vaccine (Gardasil) - -HPV 16/18 are responsible for 70% of cervical cancers - -Vaccinated females could subsequently be infected with non-vaccine HPV types - -Sexually active females could have been infected prior to vaccination * Detection of dysplastic lesions allows for treatment that prevents them from becoming malignant – incidence of cervical cancer has decreased by 80% thanks to screening and subsequent treatment alone!

Answer 298

Contraindication Severe allergic reaction to a vaccine component or following a prior dose Precaution Moderate or severe acute illnesses (defer until symptoms improve)

Answer 299

``` Equivocal or abnormal Pap test Positive HPV DNA test Genital warts Immunosuppression (because it is a subunit vaccine) Breastfeeding ```

Answer 300

Local reactions: 20-90% (pain, swelling) Fever 10 to13% No serious adverse reactions reported

Answer 301

* An increase in the number of reports of syncope has been detected by the Vaccine Adverse Event Reporting System (VAERS) * 11-18 year old females have contributed most of the increase * And when they studied this further, they realized it was a side effect seen with any vaccine in this age group. AKA Pre-teen/teenage girls are fainters. * Serious injuries have resulted * Providers should strongly consider observing patients for 15 minutes after they are vaccinated

Answer 302

Protect from light Store at 2°C - 8°C Do not expose to freezing temperatures Remove from refrigeration immediately before administration

Answer 303

Affordable worldwide (

Answer 304

The vaccine has been available in the US for over 9 years, and yet : For girls 13-17 in the US, less than half have received one dose and about a quarter have received all three. For males the numbers are even lower. Compared to 76% of females aged 12–13 in England in 2009–2010 It seems that in the US there is complacency from the start

Answer 305

* Cost * Misunderstandings on need for male vaccination * Injected via needles * 3 dose schedule, and generally during pre-adolescence or adolescence (later than most other vaccines) * Misconstrued concerns about the vaccine itself

Answer 306

* Technical concerns: Unsafe, Ineffective, Too new to know it’s true safeness or efficacy. * Ideological concerns: Disapproval of adolescents engaging in sexual activity, idea that the vaccine will encourage young people to be more sexually active or to engage in riskier sexual behaviors

Answer 307

* Major problem is poor distribution of information and communication with providers - -Many providers are not fully comfortable discussion sexual topics with young patients and their parents * There are a few minor side effects but the risk of HPV greatly outweighs them - -The side effects and efficacy of the vaccine have been being studies since well before licensure (in 2006), and have continued to be studied - -This vaccine is no longer very new - --At this point, the lack of evidence for any major safety concerns indicate that this vaccine is safe

Answer 308

The concern of increased, younger, or riskier sexual activity is often referred to as “sexual disinhibition” or “risk compensation” Effects of these concerns: --Lack of vaccination (parents generally control what vaccines their kids get) --But also lack of communication and education (from doctors, from parents, and from schools) --A study of college women (old enough to not need parental consent) showed a positive correlation between vaccine status (or interest in getting the vaccine) and mother’s approval of the vaccine, communication with their mothers about sex, and perceived risk for HPV (Roberts, et al, 2010) So better communication and education=more vaccination

Answer 309

Risk compensation has repeatedly been shown not to actually exist: * *A cross-sectional study of 13–21 year old females after one dose saw a large majority recognized the need for continued safer sexual behaviors (Mullins et al., 2012) * *A longitudinal study of 16–17 year old girls before and after the vaccine was offered (Forster et al., 2012). Those who received vaccine were not more likely to have initiated sexual intercourse at the time of the follow-up survey. Of those who were sexually active, vaccination status was not predictive of frequency of condom use. * *A comparative study of 14–17 year olds recruited after HPV vaccine licensure and prior to licensure showed no difference in STI rates (Cummings et al., 2012). * *In fact, the pre-licensure group had more instances of unprotected sex than the post-licensure group, the opposite of what risk-compensation theory predicts. * **These studies indicate that not only is risk compensation a myth and not a reason to not vaccinate, but that it is a reason to ensure quality sex education

Answer 310

Reduce the cost Vaccine is most needed in places where screening is less common – underdeveloped countries and even poorer sectors of the U.S. Create ‘therapeutic’ vaccines that will treat women already infected – would have to produce more than neutralizing antibodies Add more subtypes L1 vs L2? L2 is involved with viral fusion and is more conserved amongst various subtypes, allowing the vaccine to cross-react with those subtypes not included in the vaccine – but less immunogenic

Answer 311

*Trials indicate that the valency of the vaccine did not affect antibody titers *Therefore, it would appear more is better! Especially since there hasn’t been significant proof of cross-protection against other HPV types not included in the vaccine

Answer 312

Merck has now made a 9-valent vaccine that is the same as Gardasil in every way except that it and additional 5 high risk strains (HPV 31, 33, 45, 52, and 58) The FDA approved this vaccine on Dec 10, 2014 In February 2015, ACIP recommended this 9vHPV vaccine as one vaccine that can be used for routine vaccination

Answer 313

Moralistic component: HPV is an STD Hard to propose compulsory HPV vaccination today because of the huge anticipated political backlash Rick Perry scandal: his ex-chief of staff was Merck’s chief lobbyist Biological Niche: will another serotype fill the gap? Evidence: 16 and 18 rarely co-infect Will women stop getting pap smears because of perceived protection? Longevity of protection? On the other hand, HPV causes other issues beyond cervical cancer including Anal, penile, and oral cancers Genital warts HPV vaccine is good (80-90%) at preventing these There is no one answer. Vaccination is a very complex debate that has components from many different areas including: Question for discussion: are vaccines the answer for HPV?

Answer 314

90% of people dying from Malaria live in Sub-Saharan Africa, and nearly all of the others occur in South-East Asia and South America * almost all malaria deaths are caused by Plasmodium falciparum * vaccine development efforts have thus been focused on preventing illness from P. Falciparum and to a lesser extent, P. vivax, which is the dominant plasmodium species in areas outside sub-Saharan Africa

Answer 315

The intensity of transmission generally varies as a function of the DENSITY and BITING and SURVIVAL RATES of the mosquito vector, which are strongly influenced by temperature and humidity, as well as by vector control measures * because of the variations in ecological and climate factors, which influence the abundance of vector breeding sites and the survival of musquitos, malaria transmission may be very heterogeneous within a country. * malaria is a vector-borne disease transmitted through the bites of Anopheles mosquitos, which breed and water * transmission is more intense in places where the lifespan of the vector is longer, allowing time for the parasite to complete its development within the mosquito, and where mosquitos prefer to bite HUMANS rather than other mammals

Answer 316

the long lifespan and strong preference for human blood of the principal African vector species, along with the predominance of P. Falciparum, are the main factors that explain why the burden of morbidity and mortality due to malaria is concentrated mainly in sub-saharan africa.

Answer 317

EIR: Entomological inoculation rate a measure of the malaria parasite transmission intensity is given by EIR, which is the estimated average number of times that an individual is bitten by a Plasmodium infected mosquito in a given period

Answer 318

Malaria infection is established in humans following the injection of the sporozoite form of the parasite by female anopheline mosquitos. subsequent development usually takes palce over 5-8 days, with multiplication of the parasite in liver cells, followed by release of parasites into the bloodstream and invasion of erythrocytes. replication within these cells and their subsequent rupture leads to the clinical manifestations of malaria. severe morbidity and mortality from falciparum malaria result from sequestration of infected erythrocytes and associated vital organ dysfunction sequesteration causes microvascular obstruction-related brain pathology, metabolic acidosis componded by severe anemia due to accelerated erythrocyte destruction, renal failure, hyperglycemia, etc.

Answer 319

frequency of episodes of malaria and the characteristics of malaria disease vary, depending on the infected individuals age, genetics, and immune response from previous malaria infections, and the intensity and seasonality of malaria transmission. morbidity due to infection with P. falciparum can range from mild febrile illness to life-threatening disease with coma, respiratory distress, severe anaemia or circulatory shock

Answer 320

Severe anemia, cerebral malaria, or metabolic acidosis, which may occur separately or in combination. Cerebral malaria is the syndrome which is associated with the highest fatality, particularly when combined with severe respiratory distress.

Answer 321

Malaria in pregnancy is a major cause of abortion, low birth weight, stillbirth and maternal anemia. severe falciparum malaria in non-immune women in late-stage pregnancy has a high mortality rate (50%)

Answer 322

widespread deployment of long-lasting insecticidal nets, the use of indoor residual spraying of insecticides, prompt diagnosis using rapid diagnostic tests, and treatment with highly effective artemisinin-combination therapies. these interventions are highly cost-effective. problem: insecticide resistance is rapidly spreading in malaria vectors, potentially compromising the effectiveness of nets and indoor residual spray, which rely heavily on insecticides.

Answer 323

ACTs are the first-line antimalarial treatment | monitoring for antimalarial drug resistance is important

Answer 324

acquired gradually with repeated exposure to malaria infection, and is acquired more rapidly for the more severe forms of the disease with increasing age, there is progressive protection first against severe malaria and ensuing mortality, then against illness with malaria, and much more slowly, against parasitemia wanes substantially if person leaves malaria-endemic regions and ceases to have regular exposure to malaria infection for a number of years

Answer 325

11 trial sites across sub-saharan Africa randomized to recieve 4 doses, 3 doses followed by control, or 4 doses of control.

Answer 326

pre-erythrocytic stage hybrid recombinant protein vaccine, based on the RTS,S recombinant antigen * comprises the hybrid polypeptide RTS in which regions of the P. Falciparum circumsporoziote protein known to induce humoral (R region) and cellular (T region) immune responses are covalently bonded to the hepatitis B surface antigen (S) * this recombinant fusion protein (RTS) is expressed in Sacharomyces Cerevisiae together with free hepatitis B surface antigen (S) to form RTS,S VLPs * w/ ASO1 adjuvant system: Contains MPL and a saponin and liposomes * Vaccine to be administered intramuscularly * NO preservative is included in the RTS,S formulation or ASO1 adjuvant system * Vaccine should be stored at 2-8 degrees celsius

Answer 327

* recently, incidence of malaria found to be inversely associated with concentration of anti-CS antibodies, so IgG response being proposed as a surrogate of protection; no generally accepted correlate yet * In phase III, RTS,S/ASO1 was immunogenic in children in both categories (6-12 weeks, 5-17 mnths) * 98% seropositivity for anti-CS antibody response in children * some infants still had materally-acquired anti-CS IgG; those who did had lower post-vaccination anti-CS IgG * SOME evidence for 6-12 weeks that there is an association between anti-CS antibody titers and incidence of clinical malaria * in 5-17 months, had 3-fold higher IgG antibody titres at first vaccination

Answer 328

Vaccine efficacy against clinical Malaria following first 3 doses was 51.3 % across all sites at 12 months * efficacy decresed with time, and for the whole trial period of 48 months, was 26.2 % * Vaccine efficacy was slightly higher among boys than girls in both the 3 and 4 dose group * vaccine efficacy was lower at every time point in those at 6-12 compared to those at 5-7 months

Answer 329

* the 3 doses alone had no effect on the overall incidence of severe Malaria * 4 doses: efficacy against severe malaria up to the end of the trial was 31.5%

Answer 330

Of solicited symptoms, pain, drowsiness, irritability, loss of appetite, and fever (>37.5 °C) were reported more frequently in the 7 days following RTS,S/AS01 than following the control vaccine. Fever was the most frequently reported solicited symptom The rates of systemic reactions (drowsiness, irritability, and fever) were higher for participants in the RTS,S/AS01 groups than for the control group.

Answer 331

A comparison of 4 mathematical models of the poten- tial impact of RTS,S/AS01 was carried out.41 The models assumed that vaccine implementation was added to existing levels of malaria control interventions and treatment.With an assumed coverage of 90% for the rst 3 doses and 72% for the 4th dose, all models predict a substantial additional public health impact of RTS,S/ AS01 in settings with PfPR2-10 between 10% and 65%.42 In these moderate to high malaria prevalence settings, median predictions range from 200 to 700 deaths averted per 100 000 vaccinees in a schedule with a 4th dose, and 10% to 28% of all malaria deaths averted in vaccinated children aged

Answer 332

Thus, the modelling predictions indicate a signi cant public health impact and high level of cost-effectiveness of RTS,S in moderate to high transmission settings, if implemented after achieving high LLIN usage, and high coverage of SMC (where this intervention is appropriate).

Answer 333

* Also known as sleeping sickness * Spread by infected Tstetse fly * In rare cases, can be spread through a blood transfusion, or from an infected mother to her baby during pregnancy/delivery * caused by two different parasite: T.b. rhondesiense, and T.b. Gambiense; most reported cases of sleeping sickness are caused by the second one, which tends to progress more slowly

Answer 334

* Millions of people are at risk in 36 countries of sub-Saharan Africa (found mainly in rural areas) * War and poverty may contribute to increased transmission * As a result of major efforts by WHO and other partner agencies in improving case detection and treatment, the figure was re-estimated to 50,000-70,000 cases in 2006. (was previously hundreds of thousands)

Answer 335

* Large sore will develop at the site of tsetse bite, fever, headache, muscle and joint aches, enlarged lymph nodes, and some may develop a rash * after a few weeks of infection, parasite infects the CNS: leads to mental deterioration, partial paralysis, nighttime sleep disturbance, problems with balance or walking, and eventually leads to coma & death. * If an infected person fails to receive treatment early on, death will most likely occur within a few months.

Answer 336

* Initially vaccine trails against trypanosomiasis started targeting the surface coat of the parasite * This coat is composed of 10 million copies of a single mole, the variant surface glycoprotein (VSG)

Answer 337

1. There are a countless number of possible molecules that the parasite could generate through gene rearrangements. so essentially the glycoproteins were constantly changing and so hard to target them. Antigenic Shift in Surface Proteins. 2. 2. The main immunoglobulin that VSG’s elicit are of the IgM isotype, which is short-lived.

Answer 338

* Vaccinate against invariant antigen localized at the Flagellar Pocket (FP) * A common architectural feature of trypanosomes is the flagellar pocket (FP). * This is an invagination of the membrane at the base of the flagellum. * This structure is readily involved in exocytic and endocytic processes, cell division, virulence, and immune evasion.

Answer 339

* A study from 1995 showed that immunization of cattle with an invariant antigen localized at the FP provided them with a partial protection against infections. * A similar experiment was performed in a murine model, where Balb/c susceptible mice were immunized with a FP preparation. * Partial protection was also achieved in this case, since 60% of the mice survived the parasite challenge. * The 40% that succumbed to infection exhibited a doubled survival time and a delayed parasitemia onset. * Regardless of these somewhat positive findings, subsequent challenges with higher parasite load (inoculum of 10^3 or more) demonstrated that the induced protection was temporary. * Gave only borderline immunity to low dose infection

Answer 340

There is a non-specific activation of immunoglobulin production. Cellular components of humoral response are no longer coordinated upon infection. The fact that the pathogen continuously changes its own antigen appearance. Pathogen prevents the host from mounting an efficient immune response and maintaining its immunological memory.

Answer 341

*The specific drug and treatment course will depends on the type of infection (T.b Gambiense vs T.b. rhodesiense) and the disease stage (whether the CNS has been invaded by the parasite). *Pentamidine is the recommended drug for first stage T.b. gambiense infection. *Suramin is used to treat first stage T.b rhodesiense There is no cure for African Trypanosomiasis. After treatment patients need to have serial examinations of their cerebral spinal fluid for 2 years, so that relapse can be detected if it occurs. *We rely mainly on control efforts such as reducing the disease reservoir and controlling the tsetse fly vector.

Answer 342

* While these drugs may interfere with the pathogenicity of trypanosomes and can mitigate the effects of infection, they have MANY side effects. * Side effects include: hypoglycemia, injection site pain, diarrhea, nausea, vomiting, bone marrow suppression, gastrointestinal symptoms, seizures, peripheral neuropathy…. And the list goes on.

Answer 343

TOTAL intestinal helminths have an extremely high number of life-years lost, clocking in at 39.0 million, which is above measles, malaria, TB, diabetes, etc. One of the most major causes of DALYs

Answer 344

BIG: Multicellular and mobile TOUGH: Resistant to digestion and immune effector mechanisms SMART: Thousands of genes * Millions of years of host- parasite co-evolution * Evade (and in many cases manipulate) the host’s immune response

Answer 345

* Because of rapid infection, anthelminthic treatment needs to be administered at least 3x a year. * Furthermore, it was found that increased delivery of anthelminthic treatment to endemic communities increased the risk of worms developing resistance.

Answer 346

Even if you don’t care about animal health in general, equine health is especially important to people in developing countries, where horses, mules, and donkeys are still commonly used as working animals. If a family’s horse isn’t healthy, they won’t be able to work and generate income, which then directly affects that family’s well being.

Answer 347

Mostly affect foals, and cause poor growth and airway inflammation. Are practically ubiquitous, and their eggs are very resistant to environmental conditions.

Answer 348

Are rarely associated with measurable disease, but are aesthetically unpleasant.

Answer 349

Affect horses of all ages, and can cause colic, emaciation, anemia, and diarrhea. Not commonly found in managed horse populations.

Answer 350

Are truly ubiquitous, and all grazing horses are infected. But they are relatively mild pathogens and only produce disease when infections reach extremely high levels.

Answer 351

Affect horses of all ages, and can sometimes cause colic. Infections are difficult to diagnose, since eggs are passed only intermittently with shedding of mature proglottids.

Answer 352

All of these parasites are transmitted by ingesting eggs or larvae. In the past, large strongyles were the most common infection in horses, but are now rare. Today, the most common infections are small strongyles and tapeworms in mature horses, and Ascarids in foals.

Answer 353

* Traditional parasite control programs involved rotational treatment with anthelminthic at regular intervals. The goal was to kill all of the worms before they could lay eggs and contaminate the environment. * This approach worked well against S. vulgaris, because it killed all the worms before they could mature and contaminate the environment with their eggs. That is why S. vulgaris infection and disease are now very rare in managed horse populations. * Unfortunately, the biology, life-cycle, and host parasite dynamics of Ascarids, small Strongyles, and Tapeworms are very different from those of S. vulgaris, and the traditional approach is not very effective at controlling these parasites, and has selected for high levels of resistance.

Answer 354

* Resistance is the ability of worms in a population to survive treatments that are generally effective against the same species and stage of infection. * With continued selection and reproduction of resistant worms, the frequency of resistance genes increases to the point where treatment fails. * Once resistance is present, the population of resistant parasites does not appear to revert to susceptibility.

Answer 355

* The current goal of parasite control in equids is to limit parasite infections so that animals remain healthy and do not develop clinical illness. The goal is NOT to eradicate all parasites from an individual. * To achieve good parasite control, one must prevent contamination of the environment with high numbers of eggs and larvae. * Eradication is impossible to achieve, and attempting to do so will accelerate the development of resistance.

Answer 356

* Many parasites begin their life as an egg in a manure pile, which then develop into infective larvae in the feces, and then move out into the pasture to be ingested by a horse. Thus, infection could be avoided if you remove feces from the pasture at least once a day. * Eggs hatch into larvae under moderate temperatures and moisture. Cold prevents development, and excess heat kills the eggs and larvae. Therefore, properly composting manure could also help parasitic infections. * Eggs hatch into larvae under moderate temperatures and moisture. Cold prevents development, and excess heat kills the eggs and larvae. Therefore, properly composting manure could also help parasitic infections.

Answer 357

* Evaluate the efficacy of dewormers on each farm at least every three years by analyzing the fecal egg count. * Give all horses one or two yearly treatments to target large strongyles, tapeworms, and bots. * All further treatment should be focused on high shedders in order to minimize environmental contamination. * Focus treatment during peak transmission season (spring and fall).

Answer 358

Even though there is no vaccine against worms, and worms are slowly becoming resistant to dewormers, all is not lost. By changing the goal of parasite control (from eradicating worms to limiting parasitic infection), and using environment-based and individualized approaches, resistance can be kept in check, and horses can be kept healthy.

Answer 359

*Definition - the price at which a new intervention is considered good value for your money *Affected by various factors – vaccine efficacy, disease burden *Differentiate from affordability; affordability more means low price while cost-effectiveness is more a question of whether the value of having the vaccine is worth the cost *Taboo for the public sector to refer explicitly to cost as a factor in health decisions. Vaccines – the exception? Old vs. new and in-the-pipeline drugs Full cost of vaccination: $2,192

Answer 360

Cost effective threshold: Less than $1000 per disability adjusted life year (DALY) averted A majority of vaccines cost less than $500 per DALY averted

Answer 361

* Currently, we focus on microeconomic analysis of vaccines - Quality Adjusted Life Years for the individual * Relevant for medical treatment – reduce individual pain and suffering * For vaccines there is much more at stake: positive externalities * Therefore, vaccines should be economically assessed at the population health level * Immunization is one of the most cost-effective ways of improving living standards, health, and economic properties * children will attend school more, leading to better outcomes; families economic outlook strengthens, leads to communities being more economically stable and produce, and more politically and economically stable countries

Answer 362

* Vaccines avert illness both directly and indirectly * Avert disease-associated disabilities, improve school enrollment and attainment * Improve productivity, life expectancy and reduced disease outbreaks * In the developing world, more investment in good health of the work force

Answer 363

The inappropriate response of the immune system against self antigens * Around 80 different autoimmune disease are known today * Most of the diseases affect women (75% of the cases) * Usually run in families * is the system of immune responses of an organism against its own healthy cells and tissues. * it is accepted that autoimmune responses are an integral part of vertebrate immune systems (sometimes termed "natural autoimmunity"), normally prevented from causing disease by the phenomenon of immunological tolerance to self-antigens.

Answer 364

CENTRAL TOLERANCE: * Self-reactive B cells are deleted in bone marrow during maturation * Self reactive T-cells are deleted in the thymus during maturation PERIPHERAL TOLERANCE: *(if any self-reactive T cells get into the periphery) *Anergy/deletion of self-reactive cells due to lack of co-stimulation T-regulatory cells suppress the self-reactive cells

Answer 365

Anergy: A state of immune unresponsiveness. Induced when the T cell's antigen receptor is stimulated, effectively freezing T cell responses pending a "second signal" from the antigen-presenting cell. The delivery of the second signal by the antigen-presenting cell rescues the activated T cell from anergy, allowing it to produce the lymphokines necessary for the growth of additional T cells. * Self-reactive T-cells will have signal 1, the TCR signaling, but there will be no signal 2, because the activation happens during anti-inflammatory conditions; without inflammation, and without signal 2, the cell will become anergized. * Costimulatory signal appears only if the environment is inflammatory; presence of inflammatory cytokines is crucial for activating T cells

Answer 366

Selected in the thymus for intermediate affinity for self-antigens * Bind to cells in such a way that instead of giving an activating signal, give an inhibitory signal * Treg secrete cytokines IL-10 and TGF-beta * Treg cells are defined as CD4+ T cells in charge of suppressing potentially deleterious activities of Th cells.

Answer 367

* The phenotype of the dendritic cells (APCs) + the environment they are in decides how the naive T-cell will respond: 1. deletion/ anergy - if the DC does not get enough co-stimulatory molecule expression from the environment or other innate cells 2. differentiation into effector T-cells - Th1, T2, Th17 3. differentiation into Tregs

Answer 368

The human immune system typically produces both T-cells and B-cells that are capable of being reactive with self-antigens, but these self-reactive cells are usually either killed prior to becoming active within the immune system, placed into a state of anergy (silently removed from their role within the immune system due to over-activation), or removed from their role within the immune system by regulatory cells. When any one of these mechanisms fail, it is possible to have a reservoir of self-reactive cells that become functional within the immune system. The mechanisms of preventing self-reactive T-cells from being created takes place through Negative selection process within the thymus as the T-cell is developing into a mature immune cell.

Answer 369

1. Anergize/deplete the self-reactive naïve T-cells 2. Differentiate the self-reactive naive T-cells into T-regs, instead of TH1 3. Anergize/delete memory T-cells * A potential vaccine should do pretty much what our peripheral immune tolerance should’ve done: anergize the self-reactive TH1s, and make them into T-regs.

Answer 370

1. FoxP3+ T-regulatory cells: * Contain the FoxP3 transcription factor * Produce anti-inflammatory TGF-beta and IL-10 * Can cytolyse effector T-cells * However, some T-cells have proven to be resistant to these Tregs, because of the cytokine IL15, which is produced during autoimmune diseases * It has been suggested that Foxp3 may act as a repressor of transcription with the function of regulating the amplitude of the response of CD4+ T cells to activation * The main evidence supporting Foxp3 as a critical factor for Treg functions comes from experiments showing that naïve T cells could be rendered suppressive by retroviral gene transfer of Foxp3 2. T-Helper-2 cells: * TH2 cells can actually inhibit TH1 cells, so for that purpose, they can be good. * However, can induce disease! 3. T-reg-1 cells: * Make a lot of TGF-beta, IL-10 * Their function is stable, and not affected by IL-15, like in FoxP3+ Tregs. *So the best option is T-reg1, although it depends on the disease we are talking about. What to remember from this slide is that all of these responses produce anti-inflammatory cytokines!

Answer 371

* Multiple sclerosis (MS) involves an immune-mediated process in which an abnormal response of the body’s immune system is directed against the central nervous system (CNS), which is made up of the brain, spinal cord and optic nerves. * Within the CNS, the immune system attacks myelin — the fatty substance that surrounds and insulates the nerve fibers — as well as the nerve fibers themselves. * The damaged myelin forms scar tissue (sclerosis), which gives the disease its name * When any part of the myelin sheath or nerve fiber is damaged or destroyed, nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing a wide variety of symptoms * Autoimmune, chronic disease caused by self-reactive T-cells against myelin * Disables the Central Nervous System * Can lead to paralysis, loss of cognition, and loss of vision * Affects 1 out of 1000 people, more women than men * Experimental Allergic Encephalomyelitis (EAE) - animal model for MS for research purposes

Answer 372

Structure of Myelin: * mostly lipids – sphingomyelin, glycolipids, etc. * 15% proteins - most important one is the Myelin Basic Protein (MBC) * Proteins are what our immune system recognizes! So for the purposes of vaccines we should take into consideration the protein parts of myelin: MBC.

Answer 373

* Myelin Basic Protein (Ag) phagocytosed by a macrophage * Presented on an MHCII molecule to a naive-T-cell * T-cell is activated, differentiates into TH1, and starts producing IFN-gamma. * IFN-gamma upregulates VCAM cell adhesion molecules on the endothelial walls of blood vessels near the brain. * Activated T-cells express a molecule called VLA-4, which bind to VCAM and hence cross the blood-brain-barrier. * T-cell produces cytokines inside the brain, causing increased permeability of the blood-brain-barrier. * Macrophages and MBC-specific B-cells cross the barrier. * Macrophages phagocytize myelin, causing demyelination. * Autoantibodies activate complement, ADCC and result in the destruction of myelin.

Answer 374

Copaxone is made of glatieramer acetate (GA) - a protein similar to MBP GA competes with MBP for binding the MHCII of the APC This results in fewer T-helper-1 cells, and therefore, fewer inflammatory cytokines Instead of TH1 cells, TH2 cells and T-regs are made, which suppress the TH1 - bystander suppression, and also produce anti-inflammatory cytokines Basically, the good guys outnumber the bad guys in the CNS, so there is less damage

Answer 375

However, the protection is only against EAE or MS, so this approach cannot be applied to other autoimmune diseases There will still be some TH1 cells and antibodies present in CNS, so it doesn't completely cure it, it only provides a longer time without any relapses.

Answer 376

*Take autoreactive T-cells from the patient *Attenuate them via irradiation (not pathogenic any more) *Inject back into the patient. *Patient develops "immunity" to the autoreactive T-cells T-regs will be formed which will suppress/delete the rest of the autoreactive T-cells in the patient. Might work better than copaxone, because the TH1 cells will not simply be suppressed, but also destroyed by the T-reg-CD8+ cells. *Might work better than copaxone, because the TH1 cells will not simply be suppressed, but also destroyed by the T-reg-CD8+ cells. I like this one better only because it is more applicable to other autoimmune diseases, and it has more of a potential of actually treating the disease than copaxone.

Answer 377

Studies since the 1980s have shown that despite spending enormous sums on health care, Americans are less healthy than their counterparts in other developed countries. Americans have a shorter life expectancy, higher rates of disease and the highest rates of infant mortality. It takes more than health care to make a country healthy.

Answer 378

Many important drugs are either unavailable in Cuba or so expensive that they are impractical. Specialized medical care is limited. Even basic supplies, like the chlorine used as a disinfectant, can be hard to come by. There was a time when anesthesia was so scarce that surgeons used acupuncture to control patients’ pain during operations. The government has focused efforts on ensuring access to public education, housing and nutrition — investments as important to health as medicine and doctors (social services). Heavy investment in primary care and public health measures. It has an unusually high number of doctors spread evenly across the country. Health care is government-financed and nearly every Cuban has equal access to the same health care system. The country has become much more self-reliant and has invested in its own biomedical research As a result Cuba’s citizens are more likely to die from the maladies that kill rich people -cancer and heart disease-than the communicable diseases that kill in most poor places.

Answer 379

The Cuban health system is recognized worldwide for its excellence and its efficiency Fidel and Raul Castro made biotechnology and medical research, particularly preventative medicine, a priority. *Cuba has managed to guarantee access to care for all segments of the population and obtain results similar to those of the most developed nations. With an infant mortality rate of 4.2 per thousand births, the Caribbean island is the best performer on the continent and in the Third World generally. *Annual health care costs average about $300 per person — more than 20 times less than that of American patients They do more hands-on training in community settings starting with their undergrad medical education.

Answer 380

* After the 1981 dengue fever outbreak struck nearly 350,000 Cubans, the government established the Biological Front, an effort to focus research efforts by various agencies toward specific goals. * Since then, Cuban immunologists made vaccination breakthroughs producing monoclonal antibodies for kidney transplants.

Answer 381

Cancer is the leading cause of death in the population aged 1-64 and the second cause of death in the population >65 after cardiovascular disease.

Answer 382

CimaVax, which is both a treatment and vaccine for lung cancer, has been researched in Cuba for 25 years and free to the Cuban public since 2011 First vaccine registered in the world for lung cancer therapy. So far, 5000 patients worldwide have been treated with CimaVax, including 1,000 patients in Cuba. Cimavax is also approved in Peru. This vaccine may be effective in both treating and preventing several types of cancer, including not only lung but breast, colorectal, head-and-neck, prostate and ovarian cancers. CimaVax offers an alternative treatment for these patients that have already received first line chemotherapy.

Answer 383

The Epidermal Growth Factor Receptor (EGFR) is an oncogene. EGFR overactivation can induce malignant transformation of a normal cell, signaling inhibition of apoptosis, cell proliferation, metastasis and tumor-induced proinflammatory and immunosuppressive processes. The EGFR signaling and transduction pathway can be efficiently interrupted by EGF deprivation with negative effects on cell proliferation, and consequently on tumor development Inducing EGF deprivation by active immunotherapy is an emerging concept developed by Cuban researchers which involves manipulating an individual’s immune response to release its own effector antibodies against EGF, thereby reducing tumor size or preventing its progress.

Answer 384

*Cimavax works the same as any other vaccine—each dose delivers an innocuous fragment of what we want the immune system to target (virus, bacteria, and so on) along with chemicals that amp up the immune system. *Blocking epidermal growth factor from reaching the cancerous cells won’t kill the cancer, but could stop it from growing and spreading. CimaVax doesn’t cure cancer. It’s a therapeutic vaccine. CimaVax induces people to build antibodies against the hormone EGF, which typically spurs cell growth but can also, if unchecked, cause cancer. For people who already have lung cancer, this response results in the body actually getting rid of the cancer cells And for people who are currently healthy but at high risk for lung cancer the treatment acts as a vaccine to prevent future relapse. it could one day be a standard preventive vaccine that a person gets in childhood, much like the way we get vaccinated against polio, measles, mumps and rubella.

Answer 385

Fever, Chills, Nausea, Vomiting, Headache, Tremor