MICR 4000 Unit 4

Why must an individual be vaccinated each year?

- Genetic diversity of the virus (constantly changing) - Short duration of immunity

What are the two types of flu vaccine?

- Inactivated vaccine (injection) - Nasal spray (live, attenuated form) - has had a few years where it was not recommended due to questions about its efficacy

Why is Whooping cough re-emerging?

- Increases awareness - Better diagnosis - Improved surveillance - Waning immunity from vaccines (acellular) - Mutations in B. pertussis antigens - Low vaccination rates (some due to exemptions)

When are the viruses to be included in the flu vaccine for the upcoming season decided upon? What are the decisions based upon?

- Made in February of each year for the next season (so the recommendations for the 2020-2021 flu season have already been made). Based on: ~ What is found year round ~ How the types are spreading ~ How well last year's vaccine protected against any new strains (if found)

Why is measles increasing in the United States and in other countries?

- Vaccine hesitancy plays a large role, but it isn't the only factor - There is also some current concern about the duration of measles immunity in people between the ages of about 30-65. Many people in this age group were vaccinated at a time when only one dose was recommended. It is possible they may not still have full immunity (it hasn't been well studied yet)

Be able to give one example of how each of the five agents discussed has been used negatively in the past.

- Yersinia pestis (causative agent of the plague) ~ Several cases during the 14th, 15th, and 18th centuries where the bodies of plague victims were catapulted into enemy troops ~ Some evidence that multiple times during WWII, the Japanese army may have delivered rice and grains mixed with plague-infected fleas to highly populated areas of China (this actually resulted in almost 2000 Japanese soldiers dying from plague) ~ Evidence that both the U.S. and the former Soviet Union worked on direct aerosolization of the plague - Bacillus anthracis (causative agent of anthrax) ~ Most concerns (and most of the history) surrounding this agent deal with pulmonary (inhalational) anthrax (there is also cutaneous and gastrointestinal anthrax - these will be described later in the lecture). ~ During WWI and WWII, anthrax was tested on livestock. In one instance, in 1941, Britain tested it on sheep in Scotland. Decontaminated proved to be very difficult, and the area was not considered to be safe again until 1990. ~ The accidental release of anthrax from a Soviet weapons facility in 1979 resulted in 68/79 individuals with inhalational anthrax dying and animal infections that were reported as far as 50 km away. ~ The Aum Shinrikyo cult released spores from the top of a building in Tokyo, but they used a nonpathogenic strain. ~ 2001 - the U.S. attacks - Variola major (causative agent of smallpox) ~ In the 18th century, large numbers of Native Americans were wiped out by smallpox, which allowed for the expansion of the British colonies. There are some suggestions/rumors that blankets and other items were deliberately seeded with the virus beforehand. ~ Since smallpox has been eradicated, any case would be investigated as a potential bioterrorism event. It is thought that we have a HUGE proportion of the population that would be susceptible. - Viral hemorrhagic fevers ~ Like Ebola, Marburg, and Lassa. Others, like yellow fever and Rift Valley fever, also have hemorrhagic presentations. ~ Former Soviet Union (typo on the slide - should not say "and Russia") - reports that they made large amounts of weaponized hemorrhagic fever viruses until the early 90s. ~ U.S. investigated the use of these viruses ~ Some suggestions that North Korea may have also weaponized some of these viruses ~ When you consider all of the viruses that can cause hemorrhagic fevers, there are a large range of transmission possibilities *Vectors (mosquito bites, for example) *Bodily fluids or contact with a reservoir host *Person to person transmission - Clostridium botulinum toxin ~ Inhalational route would be the most practical (toxin is not absorbed through intact skin, and the toxin is not spread person to person). Could be dosed in food, but that presents problems with large scale delivery. ~ Botulism neurotoxin A (well studied) ~ Japan - several aerosol attacks in Tokyo and at U.S. military bases in Japan (by the Aum Shinrikyo cult again). In the 1930s, there are reports that the Japanese army fed the toxin to prisoners. ~ WWII - both the U.S. and Germany are reported to have developed the toxin for use ~ Following the Persian Gulf War, Iraq admitted to producing thousands of liters of botulism toxin (enough to kill every person on Earth several times) - the toxin was never located.

What details regarding the spores were investigators quickly able to determine? (What strain was used? Were they weaponized? Etc). What did this tell investigators about the attacker?

- "Ames" strain ~ Spores came from a lab. (the strain had never been re-isolated in nature following it's original isolation in 1981). The original strain had been maintained at USAMRIID - United States Army Medical Research Institute for Infectious Diseases). - Highly purified ~ Someone with great technical skill had prepared the spores - Not weaponized (not resistant to antibiotics, not designed to be easily spread, etc). ~ Most likely not from a bioweapons research lab. More likely to be from a basic research lab or a vaccine development lab. - Envelopes/mailbox locations (where the letters were mailed) ~ Envelopes were only sold in Maryland and Virginia ~ Letters were sent from a mailbox in New Jersey - Forensic methods - Looked for DNA, performed handwriting analysis, looked for fibers, etc. - Still had no idea - Thought they were looking for a microbiologist with considerable experience and training. Thought the person was likely a U.S. citizen. They decided that the ASM (American Society for Microbiology) members might know the person - Two suspects came out of the investigation and recommendation of ASM members ~ At least 8 people named Dr. Steven J. Hatfill ~ A few people named Dr. Bruce Ivins (including a psychologist who had treated him earlier in his life)

What problems exist in regards to the ban set in place by the Biological and Toxin Weapons Convention?

- 1973 - worldwide Biological and Toxin Weapons Convention - banned development, production, stockpiling, and acquisition of biological weapons - supposedly implemented in 1975. BUT: ~ They did not include an effective international plan to actually challenge cases where countries were though to ignore the convention ~ Reportedly actually saw the number of countries engaged in such activities double over the decade following the convention ~ There are certainly reports of countries that are still actively developing and/or stockpiling bioweapons

Be able to outline the case against Dr. Bruce Ivins.

- Opportunity: ~ Worked alone the nights before the attacks - not really his usual behavior ~ Had access to the Ames strains - Motive: ~ Vaccine program that he had worked on for 20 years was failing - suddenly received a boost after the attacks - Language and codes: ~ Similarities in the language used in the letters sent with the spores and the language Ivins used in emails ~ Some overlap in codes that appeared to be in the letters and a book of codes Ivins had - Psychological problems/obsessive behavior: ~ History of hiding his identity (using pseudonyms) ~ History of driving long distances randomly to mail letters ~ Homicidal tendencies - death threats in therapy sessions, etc ~ Letters mailed from a box outside of the Princeton University chapter of a certain sorority (KKG) office building - he was obsessed with KKG *Turned down by a KKG sister (in college and graduate school?) - graduate school colleague that he was obsessed with (followed her career, stole her lab notebooks to "get back at her" for ignoring him) - sent her a picture of him holding plates of the Ames strain without any gloves on (Major bio-security breach) - she named him as a suspect during the investigation - Guilty behavior/inability to explain behavior: ~ Could not explain why he had been working late at night in the days leading up to both attacks ~ Book with codes - tried to hide it - on the night that he threw it out, he went to the street at 1:00 am in his long underwear (right after the garbage truck passed) to make sure that his trash had indeed been picked up that night. ~ Submitted questionable samples when asked (some reports say his initial submissions weren't even anthrax) ~Decontaminated his labs without reporting it - The spore preparation: RMR-1029 ~ A detailed phenotypic and genetic screen found that his lab was the only lab to have access to the exact spore prep used to make the spores for the letters.

What is meant by "flu season"?

- A period of time when there is sustained transmission of influenza - Can start as early as October and last through May - Flu season timing is not predictable and varies between seasons

How is Bacillus anthracis infection spread?

- Animals - can be from handling products (cutaneous) or breathing in spores from the products (inhalation). Could also be from eating undercooked meat from infected animals (gastrointestinal)

What sort of information is included in the "name" for a flu virus?

- Antigenic type - A or B - Host of origin - swine, chickens, etc. (if it is of human origin, the no original host is listed) - Geographical origin - location where the virus originated - Strain - a number - Year of isolation (2009, 1918, etc.) - Subtype, if type a - listed in parentheses - (H1N1), (H3N2)

Explain the two methods of antigenic variation for influenza viruses.

- Antigenic variation: change in the genetics of organism that changes the antigens - Two methods: ~ Antigenic drift - small changes that naturally occur (point mutations in the RNA due to errors in replication, etc.). Slow, gradual changes. ~ Antigenic shift - rare major changes (abrupt). Can result in entirely new surface proteins (new H or new N); can also allow for spill-overs into new hosts. Fast changes that happen occasionally.

What are some of the general concerns regarding vaccine safety?

- Attenuated live vaccines - have the potential to possibly cause disease due to reversion or in immunocompromised people. We've already discussed the oral polio vaccine and the problems with this - Immunocompromised individuals - cannot receive attenuated live vaccines - Allergic reactions - rare, but not impossible (for example, individuals with egg allergies cannot receive the influenza vaccine when the virus is grown in eggs) - Common mild side effects - redness and soreness at the injection site, fevers, etc. - Rare to more severe side effects - seizures (usually febrile) and high fevers. There can be a range of possible side effects here ~ There are some reports of really severe side effects such as permanent brain damage. These are generally so rare that determining whether the vaccine was a cause or contributor can be difficult.

What are the three stages of symptoms associated with Whooping cough?

- Catarrhal stage - 1 to 2 weeks. Generic cold-like symptoms (runny nose, low fever, mild cough, etc) - when antibiotics would help, but the diagnosis can be missed here to the generic symptoms. - Paroxysmal Stage - horrible coughing fits that result in most of the air being expelled from the lungs. The "whooping" sound can result as people desperately try to pull air back into their lungs. This is when whooping cough is often diagnosed, but very little can be done at this stage. The bacteria have been cleared from the body; antibiotics are not helpful. - Convalescent stage - recovery (very susceptible to secondary bacterial infections)

Why is there interest in developing a universal flu vaccine?

- Could protect people (potentially long term) against seasonal flu AND prevent pandemics (wouldn't have to constantly try to predict what flu strains/subtypes might emerge)

Describe the three types of disease caused by infection with Bacillus anthracis.

- Cutaneous - skin -less than 1% of infected people die with treatment; even without treatment, "only" around 20% of infected people die ~ Small sore - blister - ulcer with a black center area (none of these are painful) - Gastrointestinal - consumed (undercooked meat from infected animals) ~ Nausea, loss of appetite, bloody diarrhea, fever, and stomach pain - Inhalation - lungs - most severe. (at least 80% of people die without treatment) ~ Cold or flu-like symptoms (sore throat, fever, etc) - progressing to cough, shortness of breath, muscle aches, etc

What factors are important in preparation for a possible biological weapons attack?

- Detect the outbreak - Diagnose infections - Differentiate between cases from a biological attack vs naturally occurring cases - Defend against the infections through effective treatments and vaccines - Disperse those effective treatments and vaccines - BioShield Act - set to develop and purchase medical treatments, etc to counter bioterrorism attacks. For example, they funded: ~ Modified anthrax vaccines and therapeutics ~ Mass production of botulism antitoxin ~ Development of new smallpox vaccines.

What symptoms are associated with measles infections? What complications are possible? Include the possible longer-term complications.

- Fever - 3 "C"s - cough, coryza (inflammation of mucus membranes in the nose - leads to a runny nose), and conjunctivitis - Koplik spots (spots inside of the mouth) - Rash (usually starts on the head, then moves to the trunk and lower extremities) - Complications: ~ Short-term - ear infections, pneumonia, diarrhea, and encephalitis (that can result in permanent brain damage) ~ Long-term *SSPE - a very rare, but always fatal degeneration of the central nervous system. It can develop around 7-10 years after a measles infection. There is no successful treatment. *Some really interesting literature in the past few years has found evidence of short-term immunosuppression and even an impact on immune memory (for 2-3 years! Suggests that it makes the adaptive immune system "forget" the infectious agents it has previously seen). *A number of studies have separately found that when measles cases increase in a country, other childhood illnesses also increase. Is this due to the damage to the adaptive immune system?

Know some desirable traits of organisms or toxins that might be used as biological weapons.

- High morbidity and mortality rates - Potential for person to person transmission - Low infective dose - Ability to cause large outbreaks - Lack of effective vaccine or treatment (not yet developed or available in limited quantities) - Potential to cause anxiety and disrupt social stability - Large-scale production is possible - Stability (in storage and in the environment) - Release is difficult to detect (silent, invisible, odorless, tasteless) - Induces a disease that is difficult to diagnose

How do the types of influenza viruses (A and B) differ? (in terms of characteristics that we discussed in class)

- Influenza A ~ Virus subtypes and strains ~ Also strain variations ~ Can change by genetic drift or shift ~ Hosts - lots of variety here (why they are prone to antigenic shift) - humans and animals (ducks, chickens, and pigs...but others like whales, seals, dogs, bats, cats, etc.) - Influenza B ~ Only strains, not subtypes ~ Are changed by antigenic drift (normal mutations) ~ Hosts - humans

Reading: Why is the measles outbreak in Madagascar so bad? (What factors are contributing?)

- Measles cases are rising in the United States and elsewhere, in part because of: ~ Misinformation that makes some parents balk at receiving a vaccine (lack of resources) ~ Only 58% of people on Madagascar's main island have been vaccinated against measles (with measles one of the most infectious diseases, immunization rates need to be 90% to 95% or higher to prevent outbreaks) ~ Some cases of resistance to vaccinations exist because of the influence of religion or of traditional health practitioners ~ Nearly 50% of children in Madagascar are malnourished (malnutrition is the bed of measels) ~ Many people in Madagascar cannot afford to see a doctor or buy medicine, and health centers often are understaffed or have poorly qualified workers *As a result, information about health issues can be unreliable. Some parents are not aware that vaccines are free, at least in public health centers ~ Lack of resources for care, monitoring and social mobilization

How is B. pertussis thought to cause the disease symptoms associated with Whooping cough? How does this impact the effectiveness of antibiotics if given three weeks after infection?

- Mechanism of disease (simplified) - bacteria attach to cilia (tiny, hair-like extensions) that line portions of the upper respiratory tract. The bacteria then produce toxins that paralyze and damage the cilia (and causes inflammation), and it leads to the host being unable to properly clear the lungs. The damage causes the symptoms to linger for a long time after the bacteria are cleared

What are some reasons for "vaccine hesitancy"?

- Physicians aren't able to spend adequate amounts of time with patients - and some people (particularly some parents) feel like they should be able to share in medical decisions of all types - Information (and misinformation) is spread so rapidly due to social media, news, etc. - Some people have a general distrust in "big pharma" - Some people have an increased interest in things that are "natural" - Some people have a general distrust in science and the scientific community L - Concerns about safety - Oddly enough, vaccines are "victims of their own success" - people don't recognize the vaccine preventable diseases as substantial dangers (because most people haven't seen smallpox, or measles, or polio, for example) ~ Combine this with the fact that people tend to overestimate the risk from vaccines and some seem to prefer the more well-known risks from actual diseases...and you have a mess

How is Whooping cough prevented? Why is maternal vaccination important? What is cocooning?

- Prevention: vaccines (DTaP and Tdap) - Maternal vaccination: give a vaccine to the mother in her 3rd trimester to allow the passage of antibodies to the infant; since infants cannot be vaccinated, this is important so that they do not develop the whooping cough ~ Infants have a high mortality rate and severe complications - Cocooning: vaccinate all close contacts of the unvaccinated infant to surround babies with protected individuals didn't work because people still come into contact with other people

Why are influenza A viruses prone to reassortment?

- Reassortment - the mechanism through which antigenic shift happens - When more than one influenza virus infects a single cell - Remember that the viral genome is in 8 segments. After the virus pieces have been made, they have to be assembled. Mistakes can happen during assembly that allow for pieces from more than one virus to be put together - Pigs are particularly problematic here because they are susceptible to avian, swine, and human viruses....so they can serve as effective mixing vessels - You could end up with a human virus and a pig virus in a pig cell...reassortment could occur...and you could end up with a virus that is capable of infecting humans, but that has surface proteins from a pig virus (that humans have never "seen" before) - no one would have immunity

Briefly describe the 2001 anthrax attacks.

- September to October 2001 - The letters were filled with Bacillus anthracis spores - "At least five envelopes" - possible 6th envelope mailed to another news outlet in Boca Raton - outbreak in the building, postal facilities were contaminated - but no letter was ever recovered (report that it was thrown away). - Of the 11 inhalational anthrax victims, 5 of them died - Impact: ~ The 10,000 "at risk" people ended up on prophylactic antibiotics ~ Two of the postal facilities were heavily contaminated and took 2 and 4 years to reopen (during this time, over 1.8 million pieces of mail were "quarantined") ~ The cost of this attack was enormous. I haven't seen a total estimate, but the cost to just clean up the buildings on Capitol Hill was $27 million

Explain the controversy surrounding the H5N1 mortality rate.

- Since 2003, H5N1 has infected around 860 people and killed about 450 of them - about a 60% mortality rate (remember that 1918 influenza had just over 2.5%...and seasonal influenza has less than 0.1%) ~ There are some studies that suggest that there might be large number of subclinical or even asymptomatic cases. If that is correct, then the mortality rate is significantly lower - There are three things that an infectious agent needs to do/have in order to cause a pandemic ~ Have little or no human immunity ~ Cause human illness ~Spread easily between humans *So far, H5N1 and many other avian influenzas have the first two characteristics, but do NOT spread easily between people. Most individuals with H5N1 has close contact with chickens.

Why are vaccination rates for the MMR vaccine low? What role has Andrew Wakefield's paper played in this? What were some of the problems with his paper?

- Some concern about a potential connection between the two comes from the coincidental timing of when the first dose of the MMR vaccine is given (12-15 months) and when most parents first begin to notice lower skills or developmental delays (around 18 months) - The argued connection here is primarily due to a paper published by Dr. Andrew Wakefield and others in 1998 in The Lancet. ~ The study was found to be highly flawed (with major ethical problems and other issues), and it was retracted in 2010. Just a few of the problems: *A very small study (12 kids) *Children were carefully selected to "fit" the study (not randomly selected, like they should have been) *Research was funded by lawyers who were actively defending parents in lawsuits against vaccine manufacturers *Authors did not have proper approval for human experimentation *Discrepancies with the published findings and the children's medical records and/or parental recall *Wakefield was working on developing a "new" measles vaccine at the time

Explain the concerns regarding autism and vaccines.

- The cause of autism is unknown - There appeared to be an increase in cases of autism at the same time that the number of people getting vaccinated increased worried there was a connection - People were also concerned that thimerosal (preservative to keep vaccines from being contaminated) was linked to it ~ However, it is not in any childhood vaccines - Parents were also concerned because they would start noticing the developmental delays around 18 months, which was a couple months after the kids were vaccinated

What is herd immunity? How does it work?

- The concept that a large number of vaccinated individuals would prevent non-vaccinated individuals from becoming sick is herd immunity. - It is based on the idea that if enough people are immune to a disease (through vaccination or natural infection), then it should shut down transmission between susceptible individuals

Why can it be difficult to identify rare risks from vaccines ahead of release to the public?

- The problem with detecting the rare risks before release is the sheer number of people that the vaccine needs to be tested on in order to find the really rare potential problems - For example, if a vaccine is tested on 60,000 people, that is a huge clinical trial that takes a lot of time and funding. BUT, if a severe side effect occurs in 1 out of every 100,000 vaccine doses, it is entirely possible the clinical trial would miss it!

Explain the controversy surrounding the H5N1 dual purpose research. Do you think the research should have been published?

- They caused mutations in the viruses that caused transmission through the air, not just close contact - Debate whether they should have been published or conducted because even if they were done to help, they could also be used to hurt (i.e. be used for biological warfare); also, the danger that any breach in protocol could lead to accidental release - Do not publish ~ This work could lead to other labs performing these experiments - could lead to accidental or intentional (bioterrorism) release - Publish ~ Could lead to an understanding of transmissibility ~ Could lead to better vaccine production ~ The techniques these investigators used are not new; anyone with an understanding in influenza genetics could perform these experiments ~ The necessary open-nature of science

From an immunology standpoint, what is the point of immunization?

- With immunization, we are targeting the adaptive portion of the immune system. The idea is that the vaccination provides the FIRST exposure to an antigen (or antigens) - This way, your body can mount the slower and weaker immune response without the danger of becoming sick from the infectious agent.That way, the second time you are exposed to the antigen or antigens (the first time you are actually exposed to the virulent infectious agent), your body quickly mounts the second strong