Vaccine: Unit I Flashcards
Who are disproportionately effected by infectious diseases?
o YOUNG & POOR
o Infectious disease yields among 50% of deaths in low-income countries, in children, and for premature deaths
• About every two seconds someone dies from infectious disease
o Per hour, 1500 people die form an infectious disease; half are under 5
• Of the rest, most will be working age adults—many of them breadwinners and parents (VITAL AGE GROUPS)
How many causes of death in the 20th century can be attributed to infectious disease?
o 30% or around 1.7 BILLION
What is the “case” for having vaccines?
o Past: Vaccination has dramatically reduced the incidence of many of the major historical killers of humankind→dramatically increased quality of life
• Ex: smallpox was eradicated through vaccination, and polio could be next
• Ex: greatly reduced cases of measles, mumps, diphtheria, pertussis, rubella, and tetanus
o Present: if existing vaccines were used to their full potential, millions of additional lives could be saved each year, many of them children
• Reduced cost, expanded access, improved uptake
o Future: BETTER vaccines/NEW vaccines
• Most existing vaccines could be improved by enhancing efficacy, increasing stability, reducing side effects, etc.
• Vaccines for MALARIA, HIV/AIDS, parasitic worms and Ebola would make a huge impact on global health
How does a vaccine work?
o Vaccines induce immune responses (antibodies/cells) that protect against subsequent exposure to a pathogen
o Typically based on NATURAL protective immunity
o Delivered by injection, ingestion, or inhalation
o Like all medical interventions, vaccination carries certain risks that vary depending on vaccine type
In what forms can vaccines come in?
o Live, but WEAKENED organisms (attenuated)
o Inactivated whole pathogen (killed)
o Inactivated toxins (toxoids)
o Purified proteins or carbohydrates (subunit)
o Proteins or carbohydrates linked to carriers (conjugate)
What is smallpox?
o Smallpox was a highly infectious disease caused by the Variola virus
o 30% fatality was typical
• 300-500 million deaths in the 20th century
• Frequently decimated previously naïve populations→was so feared that those who died of smallpox were often buried outside/some distance away from the town cemetery (Ex: Sibel Crane in CT)
o Survivors were left permanently scarred
• Those who survived had immunity
o Blindness and sterility frequently occurred
What is the smallpox cemetery?
- People terrified of smallpox; often buried in separate cemetery
- Smallpox Cemetery, located in Guilford CT, which contains the remains of Captain Ichabod Scranton, a veteran of the French and Indian War
- Town also constructed a pest house nearby for the purpose of quarantining smallpox patients
What is variolation?
- The first widely practiced artificial manipulation of the Immune System
- *A technique by which IMMUNITY to smallpox is artificially induced by administering the material from another person’s healing pustules either by inhalation or via small cuts in the skin
- Concept predicated on observations of naturally acquired immunity
- Lesions on the arm develop after variolation
- When properly employed, practice greatly reduced smallpox mortality upon natural infection from 30% to less than 2%
What are the risks inherent with variolation?
- Variolated person could develop full-blown SMALLPOX
* Variolated person could also SPREAD smallpox to others, starting an epidemic
What is the history of variolation?
- Asian civilizations may have practiced technique over a thousand years ago; technique later spread to Africa and Asia Minor
- Variolation by inhalation was practiced in china
- In the early 1700s, variolation was introduced to Europe and North America
- Lady Mary Wortley Montagu helped to introduce variolation to Europe
Who invented the first TRUE vaccine and what was it?
- In the late 1700s, English physician Edward Jenner decides to test his hypothesis that COWPOX infection would protect against smallpox
- It was common knowledge that milkmaids (who frequently contracted cowpox) rarely developed smallpox
- To test hypothesis, Jenner inoculates an eight-year-old boy with material recovered from a COWPOX LESION and then intentionally infects him with smallpox (TWICE)→found that the boy was immune to smallpox
Why did Jenner’s technique of utilizing cowpox as a vaccine for smallpox work?
- Variola virus (smallpox) and Cowpox virus (cowpox) are closely related, allowing CROSS-PROTECTIVE immune responses
- MAIN ADVANTAGE compared to variolation is that there was NO CHANCE of accidentally causing smallpox
What was initially utilized to administer smallpox vaccination, and what is the modern method?
o 18th century Fleam (bloodletting tool) would have been used for smallpox variolation and vaccination
o 19th century: the automatic vaccinator
o MODERN bifurcated needle for smallpox vaccination
How has smallpox been eradicated?
o In the second half of the 20th century, a concerted global vaccination effort greatly reduces smallpox incidence
o 1972: USA ends routine vaccination
o 1977: LAST naturally acquired smallpox case reported in Somalian hospital worker Ali Maow Maalim
o 1980: smallpox declared dead by WHO; now officially exists only in freezers in research labs in the USA and Russia
o 2014: all humans on planet (even the ones vaccinated prior to eradication) are susceptible to smallpox should it ever be reintroduced by accident or design
What is RINDERPEST? What does it effect and how?
o Rinderpest is cattle-plague
o Highly CONTAGIOUS virus of hoofed mammals (cows, yaks, buffalo, etc.) that is closely related to the human pathogen measles virus
• Evolved from measles sometime between the 5th and 12th centuries
o Rinderpest does not infect humans but caused enormous human suffering for thousands of years by killing livestock
• Kills people indirectly
o Affected animals have a high fever, oral lesions, diarrhea and dehydration
• Fatality rates often exceed 90%
How was Rinderpest eradicated?
o Inoculation was attempted beginning in the 18th century but was largely unsuccessful
o A highly effective and safe vaccine was developed in 1950s by Plowright
o Vaccination was stopped in 2006 with official declaration of eradication in 2011
o The CONTROL and ERADICATION of Rinderpest has led to substantial increases in agricultural productivity in the developing world
Who is Louis Pasteur, and what was his contribution to the development of vaccines?
- In the 1870’s, he ACCIDENTALLY discovered the concept of attenuated (weakened) vaccine while studying fowl cholera
- Chickens that were inoculated with an OLD (and therefore weakened) culture of cholera bacteria became sick, BUT SURVIVED and became immune to a second infection with freshly grown bacteria of cholera thereafter
- In honor of Jenner’s work with cowpox, Pasteur named his attenuated (less virulent) strain of bacteria a vaccine (VACCA=cow in Latin)
Besides Cholera, what other diseases did Pasteur create vaccines for?
*ANTHRAX: demonstrated that sheep vaccinated with heat-treated anthrax bacteria were protected against challenge with live anthrax
*RABIES: Pasteur administered an attenuated rabies virus vaccine to Joseph Meister, a boy who had been bitten by a rapid dog and likely would have developed rabies
• BIG DEAL given that he developed Rabies vaccine in 1885 because viruses had not yet been discovered; viruses were WAY too small to see under microscopes of that time period so amazing that he treated something relatively unknown; rabies is extremely lethal; boy would have died terribly
What effect did Polio, Rubella, Measles, Diptheria, Haemophilus Influenzae Type B, and Pertussis have on children before vaccines were introduced?
o Polio: paralyzed 10,000 children per year
• 1/100 cases were paralytic so HUGE number of people infected
o Rubella: when infected pregnant woman, caused birth defects and mental disability in as many as 20,000 newborns
o Measles: infected about 4 million children, killing 3,000 (death rates rise in underdeveloped countries where malnutrition is rampant)
o Diptheria: one of the most common causes of death in school aged children; airway closes up
o Haemophilus Influenzae type B: caused meningitis in 15,000 children, leaving many with permanent brain damage
o Pertussis: whooping cough that killed thousands of infants
What was the result on morbidity and morality of vaccines during the 20th century?
o Massive decrease in infant mortality, massive increase in life expectancy at birth (gone up by ~30 years)
o Decrease in number of deaths due to common childhood diseases
• By 1940’s, most childhood diseases are tamed if not largely eliminated
o Massive declines in morbidity following introduction of vaccines; reduction % compared to baseline morbidity is often in the 98th-99th percentile (except for pertussis which is at 88.6%)
What two vaccine-preventable diseases have seen a rise in their morbidity (1998 v. 2010)?
o Pertussis
o Mumps
• Outbreaks have been associated with institutional environments (college campuses, Amish groups, hockey players, etc.)
What problems have prevented the complete eradication of Polio?
o Warfare and politics and mistrust of government plays a huge role
o Governments that have had coups or major upsets have difficultly keeping routine vaccine schedules
o Also in dangerous areas, many vaccine workers/hospital workers have been murdered
o Polio virus is still present; found in some sewers; theoretically there are some reservoirs of Polio (could be VACCINE DERIVED)
• Oral polio vaccine occasionally causes Polio
What is HERD immunity?
o Vaccines may provide indirect protection to the unvaccinated via HERD IMMUNITY
o In THEORY, herd immunity protects those who CANNOT be vaccinated for medical reasons
• If enough people are vaccinated, disease will not be transmitted
o In PRACTICE, herd immunity also protects those who WILL NOT be vaccinated for personal reasons
o Problematic because herd immunity WILL break down if the vaccinated population falls below a critical threshold (which varies by disease)
What is chicken pox and what happened after the vaccine was licensed during the 1990’s?
o After vaccine, incidence of mortality dropped, both as a PRIMARY or underlying cause of death
• Reductions in incidence, hospitalizations, and mortality following introduction of vaccine
o Effect of HERD IMMUNITY: see that there is a HUGE decline in incidence of disease in children who have not been vaccinated
o Chicken pox is caused by Varicella Virus
• Yields itchy, blister-like rash on the skin
What would happen if all children were vaccinated and why isn’t that the case?
o If all children received the vaccines recommended for children in the US
What are some issues to consider for vaccine development?
o What is (are) the target population(s)?
• Children may have blocking maternal antibodies
• Elderly adults or immunocompromised persons may not respond well
• Are there potential compliance or accessibility issues?
o Is there an animal reservoir for the pathogen?
• Will the vaccine work in animals?
o Are there side effects or (if live attenuated) risks of reversion?
o Is antigenic variation an issue?
o How will it be made, stored, and delivered? Can enough be made?
o How much will it cost and who will pay for it? Will it divert resources from other efforts?
What are the main features of an IDEAL VACCINE?
o Affordable worldwide (less than 1$ per dose)
o Heat stable (requires no refrigeration)
o Single-dose efficacy
o Efficacy against multiple diseases
o Administered without needles
o Suitable for administration early in life
o No side effects
o **No currently available vaccine has all of these features
Why is it so hard to find a vaccine for HIV? ***
Because there is no natural immunity conveyed by the infection; for chicken pox and measles, the disease itself conveys a natural immunity. But for HIV (and malaria), there is no person who has HAD the disease and survived; no case of an immune system successfully clearing infection; not a disease you get only once. Problem for vaccine creation because usually vaccines based off of natural immunity antibodies
What are antigens?
- Any substance that causes the immune system to produce antibodies
- Each antibody is specifically produced by the immune system to match the antigen; allows precise identification of antigen and tailored response
Immunization
- A procedure designed to induce or convey an IMMUNE RESPONSE to a specific antigen
- designed to increase the concentration of antibodies and/or lymphocytes (B-cells/T-cells) that are reactive against the immunogen
- May be ACTIVE or PASSIVE
Vaccination
- ACTIVE immunization performed for the specific purpose of inducing an immune response that is protective or therapeutic against a given infectious disease
- not all immunizations are technically vaccines (immunization of animals for monoclonal antibody or antitoxin production)
- name derives from vacca (cow) in order to honor Jenner’s use of cowpox (vaccinia) to protect against smallpox
Immunoprophylaxis
- Performed BEFORE (in some cases shortly after) exposure to an infectious agent
- intended to PREVENT infections or disease
- Most current vaccines are of this type
Immunotherapy
- Performed DURING an active infection
- Intended to treat or CURE the infection
- certain passive immunizations are of this type (i.e. antitoxins)
Passive Immunization
- Transfer of performed antibodies to a recipient, conveying INSTANT immunity
- Transient protection; no memory induced
What are natural and artifical sources of passive immunization?
- Natural: maternal antibodies passed on to child; antibodies cross placenta during pregnancy –>antibodies conveyed orally through breast milk after birth
- Artificial: injection of antibodies into recipient; antibodies may be produced by animals or other humans–>may act on WHOLE organism, toxins (antitoxin), or venums (antivenins)
What are indications for passive immuniation use?
- Immunodeficiency affecting antibody production
- Immunoprophylaxis in at-risk populations (ex. RSV, Rh-mom)
- Rapid immunity needed (ex: traveling, have had recent exposure, etc.)
What is Rh?
Four different blood types; each is further classified based on the presence or absence of proteins on the surface of RBCs that indicate the Rh factor; if you have this protein, you are Rh positive.
- most people are Rh positive
- If a woman who is Rh NEGATIVE has a child with a man who is Rh positive, and the baby is Rh positive, could pose risk; for FIRST child, Rh incompatability shouldnt be a problem because the fetuses blood doesn’t enter mothers circulatory system; during DELIVERY however, blood can mingle and mother might create antibodies against Rh proteins
- SECOND CHILD: if 2nd has Rh positive, her Rh antibodies will recognize Rh proteins on surface of babies RBC and will attack those cells–>causes babies blood count to get dangerously low
What are some main sources of passive immunity?
- Maternal (transplacental & via milk)
- blood or blood products (e.g. plasma); have to have compatible blood types to transfer plasma with another person
- pooled human antibody (Human Immune Globulin)
- Human hyperimmune globulin (e.g. human rabies immune globulin; HRIG)
- heterologous hyperimmune serum (animal derived antitoxin/antivenin)
- monoclonal antibodies
Pooled human Antibody
IMMUNE GLOBULIN: produced by combining the IgG antibody fraction from thousands of adult donors in the US; because it comes from many different donors, it contains antibody to many different antigens; human Ig comes from PLASMA
Homologous human hyperimmune globulins
antibody products that contain HIGH titers of specific antibody; these products are made from the donated plasma of humans with high levels of antibody of interest; since hyperimmune globulins are from humans, they will contain other antibodies in lesser quantities
Heterologous hyperimmune serum
ANTITOXIN: product produced in animals (often horses) that contains antibodies against only one antigen; potential problem of SERUM SICKNESS, which is an immune reaction to the horse protein
Monoclonal antibodies
Produced from a single clone of antibody producing B cells, so products contain antibody to only ONE ANTIGEN or closely related groups of ANTIGEN
- mAbs are used for diagnosis and therapy of certain cancers and autoimmune and infectious diseases
- MOST mAbs used in humans are mouse antibodies that have been engineered to be more human in structure; put sequences that code CDRs into human antibody so have human constant region of the antibody
What influences the choice of animal Ig v. normal human Ig v. hyperimmune human Ig?
Is it ethical to create antitoxin/antivenin using people? No. so use animals. Do you need a large quantity of a specific antibody, then use hyperimmune. do you need to protect against various strains, then use normal human Ig.
What is the difference between HIG v. HRIG?
If someone gets bit by a rabid animal, dont just juse pooled human ABs (HIG), use the Abs with HIGH-affinity for the rabies virus (HRIG)
Does passive immunization induce an immune response?
NOT necessarily; it just transfers immunity, hence why you dont form memory and dont recall memory if secondary infection occurs
How is Rh mother-fetus situation treated?
he mother has an intramuscular injection of anti-Rh antibodies (Rho(D) Immune Globulin). This is done so that the fetal Rhesus D positive erythrocytes are destroyed before her immune system can discover them. This is passive immunity and the effect of the immunity will wear off after about 4 to 6 weeks (or longer depending on injected dose) as the anti-Rh antibodies gradually decline to zero in the maternal blood.
What is the danger of animal-derived antisera?
Antisera prepared in animals, while lifesaving, can induce isotypic reactions in human recipients, leading to serum sickness
WHat is esrum sickness?
Immune complexes deposit in blood vessels, joins and organs, activating complement and leading to tissue damage
What is the solution to serum sickness?
DESPECIFICATION: the digestion of antibodies with pepsin to remove MOST of the Fc region, significantly reducing the risk of serum sickness
What are CDRs?
Complementary determining regions: part of the variable chains in Ig (antibodies): where these molecules BIND to their specific antigen
*The most variable parts of the molecule; crucial to the diversity of antigen specificities
What is Palivizumab?
DRUG; brand name is Synagis.
*It is a monoclonal antibody produced by recombinant DNA technology, and used to prevent RSV infections
*Humanized mAb directed against antigenic site of the F protein of respiratory syncytial virus (RSV), a common infection of children
*Delivered by monthly intramuscular injection
*doesnt interfere with response to other vaccines
*indicated for premature infants, children less than 2 years of age with congenital heart or chronic lung disease, and children with compromised immune systems
>1000$ per dose–>biologicals are a LOT more expensive to make
What is active immunization?
INDUCES immune response and/or memory (T-cells & B-cells) that will protect against subsequent exposure to a pathogen
What is natural active immunization?
Infection with certain pathogens (e.g. smallpox) conveys immunity against subsequent infection (if it doesnt kill you the first time)
What is artificial active immunization?
- Injection, ingestion, or inhalation of immunogen to educate the immune system
- vaccines in current use include live attenuated, whole inactivated, toxoid, subunit and conjugate
- next generation vaccines include DNA and recombinant vectors
What are factors affecting active immunization vaccine efficacy?
- pre-existing antibodes (e.g. maternal antibodes)
- poor responders, but “herd” immunity may compensate
- compliance issues (lack of resources or will)
- like all medical interventions, active vaccination carries certain risks that vary depending on vaccine type: BENEFITS OUTWEIGH RISKS
Whhat i the golden rule of active immunization?
the more similar a vaccine is to the disease-causing form of the organism, the better the immune response to the vaccine
Sub-Saharan Africa: Meningitis
*Newly developed meningitis vaccine could save 150,000 lives in Sub-Saharan Africa by 2015; people got together to develop vaccine specifically for aAfrica and with Africas most common strain–>EXTREMELY CHEAP AT .40$$ A DOSE
CD4 Cells
- T Helper Cells
- Lymphocyte (subset of Leukocytes)
- Mature Th cells express the surface protein CD4
- promote innate and adaptive immune responses, especially ADAPTIVE
Leukocytes
WHITE BLOOD CELL: a colorless cell that circulates in the blood and body fluids and is involved in counteracting foreign substances and disease
- All white blood cells are produced and derived from a multipotent cell in the bone marrow known as a hematopoietic stem cell.
- All white blood cells have nuclei, which distinguishes them from the other blood cells, the anucleated red blood cells (RBCs) and platelets.
Granulocytes
*Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm
What are the three principle kinds of Granulocytes?
Basophil granulocytes
Eosinophil granulocytes
Neutrophil granulocytes
Mast Cell
A type of white blood cell.
it is a granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems and contains many granules rich in histamine and heparin.
*Best known for their role in allergy and anaphylaxis
Cytotoxic T cells
- is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways.
- Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. In other words, the epitope is the specific piece of the antigen that an antibody binds to.
Germinal Centers
- where mature B lymphocytes proliferate, differentiate, and mutate their antibody genes (through somatic hypermutation), and switch the class of their antibodies (for example from IgM to IgG) during a normal immune response to an infection.
- Germinal centers are an important part of the B cell humoral immune response, acting as central factories for the generation of affinity matured B cells specialized in producing improved antibodies that effectively recognize infectious agents
Somatic Hypermutation
- Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it
- Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes.
Regulatory T Cells
T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important “self-check” built into the immune system to prevent excessive reactions.
What is the trend in terms of # of microbes along the GI tract from the stomach to the colon?
Increasing numbers of microbes and increasing diversity
Gut Microbiota
Consists of a complex community of microorganisms that live in the digestive tract of the animal. Different people and animals have different types of microorganisms in their guts. The composition of the gut flora also changes over time, when the diet changes.
Microbiome
An aggregate of all the genomes of the microbiota
where do gut microbiota come from?
As infants we (and our guts) come into this world with a blank slate of sorts, awaiting our first contact with the microscopic organisms which surround us. Our first exposure via the birth canal, followed by a gut-nurturing concoction of mother’s milk, is nature’s way of establishing the foundation on which we will build our microbiome. Familial, dietary, and environmental exposure throughout our developing years cultivates an ecosystem which will play a starring role in the determination of our health for a lifetime.
*the vagina
How does our microbiota benefit us?
Starting with our immune system, our microbiome establishes the parameters in which our bodies judge whether or not something is friend or foe. It maintains harmony, balance, and order amongst its own communities, ensuring that opportunistic pathogens are kept to a minimum, while also keeping the host system from attacking itself.
It is our first, second and third line of defense – starting with our skin, then our mucus membranes, and finally our gut, providing a living barrier that is able to be modified and transformed to suit individual needs and unique environments.
How does our microbiota affect our ability to absorb nutrients?
Our gut microbiota is fundamental to the breakdown and absorption of nutrients. Without it, the majority of our food intake would not only be indigestible, but we would not be capable of extracting the critical nutritional compounds needed to function. Our symbiotic cohorts not only provide this service, but also secrete beneficial chemicals as a natural part of their metabolic cycle.
Why are we sick more? (Microbiota)
Antibiotics and an obsession to sterilize our environments have resulted in a significant rise in gut-related illnesses and pressure on the medical community to finally explore this long-ignored aspect of human biology.
Research has uncovered an intricate web connecting our gut flora to virtually every process in our body. As such, imbalances in our microbial communities have been implicated in countless health issues, including immune health, psychological well-being, and some of the deepest chronic health issues of our times.
What are the main infectious agents?
Viruses
Bacteria
Fungi
Parasites
naturally acquired immunity
when the person is exposed to a live pathogen, develops the disease, and becomes immune as a result of the primary immune response. Artificially acquired active immunity can be induced by a vaccine, a substance that contains the antigen.
Smallpox
highly infectious disease caused by the Variola Virus; had a 30% mortality rate.
*survivors were left permanently scarred; blindness and sterility often occurred
Innate Immunity
Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen’s appearance in the body. Individual is BORN with this and requires no prior experience. These mechanisms include physical barriers such as skin, chemicals in the blood, and immune system cells that attack foreign cells in the body. Limits/contains/controls infections and generates signals that activate and enhance the adaptive immune response
Adaptive Immunity
Adaptive immunity refers to antigen-specific immune response. The adaptive immune response is more complex than the innate. The antigen first must be processed and recognized. Once an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen
What are four characteristics of the adaptive immune response?
- specificity
- Diversity: able to react with an almost limitless variety of antigens
- Memory: ability to remember a previous encounter with a pathogen; secondary response is induced more quickly and is more vigorous than original response
- Self/Non-Self
TCRs
T-Cell receptors; produced by helper and cytotoxic T lymphocytes; they are surface bound to a cell and not secreted.
- recognize PROCESSED antigens PRESENTED on specific molecules known as MHC; cannot recognize antigens in the NATIVE FORM
- antigen is presented on MHC complex by an antigen-presenting cell (APC)
- helper T-cells need MHC class II, and cytotoxic T need MHC class I
Lymphocytes
B and T cells; they are a subset of leukocytes which mediate adaptive immune responses; these are generated; generated in the primary lymphoid organs (bone marrow and thymus) and enter the bloodstream
How do babies get microbiota when born? How are some of these reduced?
- Vaginal: passage through birth canal
*babies born via C-section have higher frequency of developing allergies and autoimmune diseases; smaller microbiomes - Cutaneous: contact with skin
- Mammary: through breastfeeding
REDUCTION as more and more babies are being born via Caesarean section, being bottle fed, given early-life antibiotics, and being extensively bathed and cleaned
From birth to one year, and from one year to death, what happens to our microbiome?
From birth to a year, have increasing numbers and increasing diversity of microbiome. Microbial stability is established after one year. After a year, the # of bacteria remains the same, but bacteria diversity greatly increases as the composition of bacteria evolves continuously. Composition is influenced by host genetics, antibiotics, diet, lifestyle, environment, etc. Over time as diversity increases, interindividual variability decreases because we all will have a lot of the same bacteria
How does gut microbiota positively effect our health?
- Increases the metabolic capacity of the HOST; digestion of otherwise UNUSED food components
- completion of the bile-salt cycle
- protect the host from colonization with pathogenic bacteria (colonization resistance)
* If didnt have GOOD bacteria, would be more susceptible to infection by pathogenic bacteria
What are in the genomes of GOOD microbes?
Most microbes have genomes that are full of genes that allow them to metabolize certain carbohydrates; dont code for pathogenic material but have genes that are advantageous to the host
Gnotobiotics
“Known life”–all the forms of life within an organism can be accounted for
*Gnotobiotic animals are born in aseptic conditions, which may include removal from the mother by Caesarean section and immediate transfer of the newborn to an isolator where all incoming air, food and water is sterilized.[2] Such animals are normally reared in a sterile or microbially-controlled laboratory environment, and they are only exposed to those microorganisms that the researchers wish to have present in the animal. These gnotobiotes are used to study the symbiotic relationships between an animal and one or more of the microorganisms that may inhabit its body.
Germ-Free
*MICROBIOLOGICALLY STERILE
*healthy, breed normally
*consume 1/3 more calories than conventionally colonized mice
Germ-free animals are animals that have no microorganisms living in or on it. Such animals are raised within germ-free isolators in order to control their exposure to viral, bacterial or parasitic agents.
*Comparing germ free w/ conventional mice; pinpoint immune differences that exist between mice and illustrates that bacteria and our gut microbiome influence our immune system greatly; germfree mice have fewer of everything, fewer germinal centers, intestinal epithelial cells, T cells, etc.
What are some next generation sequencing technologies?
- rRNA sequencing: group sequences into OTU’s (operational taxonomic unit), compare to database, and identify species and abundance of species within microbiome sample
- Total microbiome DNA sequencing; filter HOST DNA sequences and compare microbial sequences to databases; identification of species, relative abundance within sample, genes, and functional information
How is their microbial regulation of innate immunity?
- Mucosal surfaces such as the intestinal tract are continuously exposed to both potential pathogens and beneficial commensal microorganisms. This creates a requirement for a homeostatic balance between tolerance and immunity that represents a unique regulatory challenge to the mucosal immune system. Recent findings suggest that intestinal epithelial cells, although once considered a simple physical barrier, are a crucial cell lineage for maintaining intestinal immune homeostasis.
- Microbiota regulates intestine immune responses via microbe associated molecular patterns (MAMPS) and bacteria derived metabolic products.
MAMPs
Microbe-associated molecular patterns (MAMPs) are molecular signatures typical of whole classes of microbes, and their recognition plays a key role in innate immunity. TLRs on host cells recognize these, and TLR signaling has been shown to enhance epithelial barrier function. IECs also secrete a broad range of antimicrobial peptides to maintain an immunological barrier.
Intestinal Immune response + Microbiome
- immune cells exist within intestinal tissue; intestinal tissue is MOST immunogenic organ; the whole paradox of situation is that you have so many immune cells and exist SO CLOSE to the bacteria that they potentially could react with
- INTESTINAL are the first cell type that come in contact with commensal bacteria and products derived from commensal bacteria
- *innate immunity functions as a result of receptors that exist on cell surface or within the cells
- receptor are capable of binding to bacterial products; components of the mammalian innate immune system are constantly sampling the dynamic composition of commensal communities.
What are some things that commensal bacteria will produce in intestine?
Bacteria will produce SCFA (short chain fatty acids produced by bacterial metabolism), LPS, Sphingolipids, and Flagellin. Binding of some of these to intestinal cells TLRs can produce proinflammatory cytokine release, or RegIII-gamma that is an antibacterial lectin that is responsible for promoting the spatial segregation of microbiota and host in the intestine.
IECs
the task of differentiating between pathogens and commensal microflora and eliciting the appropriate action is the responsibility of a single layer of intestinal epithelial cells (IECs) that line the intestinal tract and are in direct contact with luminal contents.Under noninflammatory conditions, the intestinal epithelium not only performs its normal functions (i.e., barrier against bacteria, nutrient absorption), but also continuously “prepares” for an unexpected encounter with a pathogen. Even in the absence of pathogens, IECs are known to continually present antigens to T lymphocytes (11) and express Fc receptors on their apical surface.
What is the structure of intestine?
Beneath the intestinal epithelium is a layer of mucosal tissue that has immune cells. in a healthy gut, the intestinal epithelium barrier will prevent penetration of any commensal bacteria, preventing excessive immune response
Why is there a separation of host cells and bacteria in GI tract, and how is this maintained?
studies show that the physical separation of microbiota from the intestinal surface is critical for limiting immune activation and maintaining mutualistic host-bacterial associations
*A plausible mechanism by which intestinal epithelial cells could limit bacterial-mucosal contact is through the production of secreted antibacterial proteins.
How is their microbial regulation of adaptive immunity?
Microbiota stimulation leads to B cell switching and production of IgA, regulatory T cell induction, and T cell differentiation to Th17
- *antigen presenting cell that has seen bacteria and sensed it can signal to a B cell, also specialized dendritic cells; get signaled to B cells and can generate plasma cells or IgA secreting cells
- with B cell help get specific IgA; without, generic IgA—>secreted into GUT LUMEN
IgA
IgA is produced by B cells and plasma cells located on mucosal surfaces. As a result, IgA is produced and secreted in large amounts into the upper respiratory tract, the GI tract, tears, sweat, etc. In these locations, it complements the physical barriers of the body and prevents microbial invasion.
*through a process known as immune exclusion, SIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping them in mucus, and facilitating their remova
Th17
Important part of the adaptive immune response at intestine-bacteria surface. They are a subset of pro-inflammatory cytokine producing T helper cells; serve to help maintain mucosal barriers and contributes to pathogen clearance at mucosal surface
M cells
M cells are specialized epithelial cells that sample and uptake antigens at their apical membrane, encase them in vesicles to transport them to the basolateral membrane of M cells, and from there deliver antigens to the nearby lymphocytes.
*many pathogens exploit the M cells as a conduit to invade the host and establish an infection.
What role do bacterial-derived metabolites play?
KEY COMPONENTS OF CROSS-TALK. immune system is sensing NOT ONLY just the bacterial cell wall but also bacterial metabolites; future therapy of instead of probiotics could take metabolite and have desired effect.
Gut Microbiota in Disease: IBD
Disease considered the result of inappropriate activation of intestinal mucosal immunity in genetically susceptible hosts. However, increasing evidence suggests that the intestinal microbiota play a role in initiating, maintaining, and determining the phenotype of IBD
- Genetic and environmental factors induce IMPAIRED BARRIER function
- translocation of bacteria and bacterial products
- immune activation and proinflammatory cytokine production
- Chronic inflammation leads to tissue desctriction and complications
- proinflammatory responses due to defects in host genetics and microbiota can lead to mucosal damage, which will lead to dysbiosis; this means greater loss of barrier integrity, induction of proinflammatory cytokines, lesions in the intestinal epithelium, and therefore profuse GI bleeding
Why are host genetics & environment important in microbiome?
genetics & environment where you live is regulating microbiome; if have genetics that makes you susceptible to inflammatory diseases (A lot of genes that are defective have to do with anti-microbial protection or section; defective in innate immunity, in phaogcyototic genes, etc).
- if these genes are defective, host is not able to keep bacteria away from barrier and so immune system gets inflated
- If there is abnormal microbiota composition, can lead to Reactive oxygen species development, clastogens, and increased acid, leading to cytotoxicity, and DNA damage, which yields carcinogenesis
Gut Microbiota in Disease: Colon Cancer
many changes in the bacterial composition of the gut microbiota have been reported in colorectal cancer, suggesting a major role of dysbiosis in colorectal carcinogenesis.
What are the three categories of microbiota-induced carcinogenesis?
Certain microbiota can cause:
1. DNA damage leading to increased apoptosis at gastric mucosa
2. abnormal DNA transcription
3. Inflammatory milieu; increased T cells and Th1 cells
All leads to METAPLASIA (conversion in cell type due to change of milieu) and TUMORIGENESIS
H. Pylori: Cancer
- strongly linked to gastric cancer; a bacteria that grows in the mucus layer of the stomach; pylori are so effective because the embed themselves into stomach mucus/lining and attach to gastric mucosa, where they upregulate inflammatory T cells that can feed into making epithelial cells cancerous
- if H. pylori infection was the main cause of stomach ulcers and chronic inflammation, and inflammation a pre-cursor to stomach cancer, then it stood to reason that infection with the bugs could be a leading cause of cancer.
How can H. Pylori be treated?
- Use of antibiotics that will eradicate H pylori itself
- anti-inflammatory drugs that decrease the negative effect that H pylori has, reducing chronic inflammation and therefore reducing the chance of getting cancer
- if have developed cancer, more aggressive treatment, like actual removal of the tumor, may be needed.
Clastogen
A clastogen in biology is a mutagenic agent giving rise to or inducing disruption or breakages of chromosomes, leading to sections of the chromosome being deleted, added, or rearranged.
OBESITY
- misalignment of microbiota linked to metabolic diseases like OBESITY
- microbiota has also an impact on the way calories are absorbed and how fat cells develop
- obesity is being seen as a kind of inflammation (low-grade) in your body that leads to to accumulation of fat
- the composition of the gut microbiota has been shown to differ in lean and obese humans and animals and to change rapidly in response to dietary factors.
- Dietary changes have been shown to have significant effects on the microbiota. Shifting mice to a high-fat, high-sugar “Western” diet, from a low-fat, plant polysaccharide-rich diet, changed the microbiota within 24 h
- the subjects’ ratio of Firmicutes to Bacteroidetes was substantially higher than that of the normal-weight controls. Importantly, in those subjects who had successful and sustained weight loss, the ratio returned to normal.
What are intestinal and extra-intestinal diseases?
There is growing evidence that dysbiosis of the gut microbiota is associated with the pathogenesis of both intestinal and extra-intestinal disorders. Intestinal disorders include inflammatory bowel disease, irritable bowel syndrome (IBS), and coeliac disease, while extra-intestinal disorders include allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity.
Gut Microbiota and disease: obesity and metabolic syndrome
- Gut microbiota (and diet-induced changes in microbiota composition) may contribute to low-grade inflammation, which is associated with obesity & metabolic dysfunction
- The gut microbiota has been identified as a potential contributor to metabolic diseases. It has been shown that obese individuals present different proportions of bacterial phyla compared with lean individuals, with an increase in Firmicutes and a decrease in Bacteroidetes.
- This alteration seems to interfere with intestinal permeability, increasing the absorption of lipopolysaccharide (LPS), dietary lipids, and peptidoglycan, which reaches circulation and initiates activation of Toll-like receptor (TLR) & other immune cells, leading to increased activation of inflammatory pathways. Along with these activations, an impairment of the insulin signaling is observed;The insulin signaling may be impaired by altered secretion of cytokines and chemokines.
- immune cells can start secreting inflammatory cytokines; as a result of this, increase overall inflammatory status of the tissue
- some inflammatory molecules can end up in regions other than the gut (liver, brain, muscles, fat); immune cytokines may show up in organs and cause changes in metabolic pathways in these tissues
LPS
they are found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses in animals; known as endotoxins.
- The presence of endotoxins in the blood is called endotoxemia. It can lead to septic shock
- purified endotoxin from Escherichia coli can induce obesity and insulin-resistance phenotypes when injected into germ-free mouse models; acts through inflammatory pathways
- Weight gain has been associated with a higher gut permeability and subsequent systemic exposure to mildly increased LPS circulating levels. demonstrated that a high-fat diet promotes LPS absorption across the intestinal barrier, increasing its plasma levels by two to three times
- TLR4 is a subclass of TLRs that can be activated by lipopolysaccharide (LPS), a major component of the outer membrane in Gram-negative bacteria, and by nonbacterial agonists, such as saturated fatty acids [73,94]. The activation of TLR4 signaling induces upregulation of inflammatory pathways related to the induction of insulin resistance
Obesity & Endocrine Function
- increased SCFA may increase FAT STORAGE
- Diet induced changes in microbiota suppresses expression of fasting-induced adipose factor (FIAF), which then promotes lipoprotein lipase (Lpl) activity and increases fat storage
- increased LPS levels can stimulate eCB1 receptors, which activates the endocannabinoid pathway and promotes adipogenesis
ALTERED GUT MICROBIOTA
- increased SCFA: increased lipogenesis and fat storage
- Decreased FIAF: increased LPL and fat storage
- Increased Gut permeability: increased LPS; leads to increased proinflammatory cytokines and adipogenesis
- Decreased AMPK: oxidation of fatty acids; increased adipogenesis; AMPK is a master nutrient and energy sensor that maintains homeostasis
What does it mean if the barrier between intestinal cell wall and bacteria is compromised?
Peptidoglycan (PGN) and some of the dietary lipids (LPS) can activate immune cells that underlie the gut activity; they can do that if the barrier is compromised; epithelial cells have mechanisms to keep bacteria away from epithelial cells, but sometimes mechanisms fail
- *microbiotic bacteria can modify junctions between epithelial cells; bacteria can down-regulate proteins that are responsible for tight junctions, allowing bacteria to seep into inner layer where immune cells reside
- immune cells can start secreting inflammatory cytokines; as a result of this, increase overall inflammatory status of the tissue
- some inflammatory molecules can end up in regions other than the gut (liver, brain, muscles, fat)
- changes in gut microbiota can then translate into immune activation and immune cytokines showing up in organs and cause changes in metabolic pathways in these tissues
What is the function of normal gut microbiota?
It is linked to feelings of SATIETY, decreased body weight, and decreased energy intake
Why would it be favorable for inflammation to cause adipogenesis? For SCFA?
Inflammation: good tactic to help conserve energy and fatten up host so if there is sickness, you can live longer
SCFA:good ways to increase fat storage; potentially good in past when food sources were scarce but in more developed societies makes us more prone to obesity
What happened when obese mice microbiota were put in WT mice?
if take microbiota from obese mice and put it in germ free WT mice, see obesity effect take hold, so microbiome itself is likely regulating these hormones
*phenotype of obesity was transferred to mice who had microbiome of obese people
Fecal Transplant
Fecal transplantation (or bacteriotherapy) is the transfer of stool from a healthy donor into the gastrointestinal tract for the purpose of treating recurrent C. difficile colitis. FMT involves restoration of the colonic microflora by introducing healthy bacterial flora through infusion of stool, e.g. by enema, orogastric tube or orally in the form of a capsule containing freeze-dried material, obtained from a healthy donor.
What would a diet largely based off sugars yield for gut microbiota?
*ones diet greatly effects microbiome; if have diet based largely on simple sugars, have simple microbiome, so tend to have more inflammation and a greater likelihood of gut microbiota problems
*malnutrition—>large part of the world suffers from—impairs microbiota
COMPLEX DIET IMPORTANT FOR COMPLEX AND DIVERSE MICROBIOME
*food additives and emulsifiers can change pigments of mucus layer and that can cause low grade inflammation and metabolic diseases
Liver psoriasis gut microbiota
*Gut microbiota is being linked to liver pserosis caused as a result of binge drinking
Whenever mice were fed ethanol, there was a decrease in anti-microbial epithelial secretions, so the host-microbiome interface is not protected that well
—>allows microbes to end up in liver, causing liver problems
LIVER CANCER
Diet or obesity induced changes in the micobiota leads to increased deoxycholic acid (secondary bile acid)
- DCA reaches LIVER via portal vein
- Increased DCA leads to DNA damage, which promotes senescence-associated secretory phenotype (SASP) in HSC (hepatatic stellate cell)
- Combined with activation of oncogenic signaling pathways, promotes HCC development (HCC=hepatocellular carcinoma; liver cancer)
- HSC exhibit proinflammatory phenotype phenotype during senescence
SASP
Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation.
- accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment.
- The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
- A plethora of stresses can provoke cellular senescence, like DNA damage
C-Section Babies
*babies delivered by C-section, tend to have microbitioa that remsebled peoples hands or on the skin; babies delivered naturally had a much greater microbiota diversity; kids born by C section had higher prevalence of developing allergic diseases; model supported by mice; did study of mice that were germ free v. those with microbiome; not having complex microbiota while getting birthed leads to development of stunted immune response that can lead to autoimmune diseases later on
Gut Microbiota and Allergic Disease
Massive increase in prevalence of allergic diseases in westernized countries (>20% over 10 year period)
- Allergic disease is attributed to both genetic predisposition and environmental factors
- Genetic drift over such a short period of time cannot explain increased incidence of disease
- Westernized life style has introduced several environmental risk factors that disturb the homeostatic balance of GUT microbiota
What are some major factors of westernized life style that disturb gut microbiota homeostasis?
- excessive antibiotic use, especially during early life and pregnancy
- shift towards more formula-fed babies
- shift towards more C-section babies
- western diet; food emulsifiers and additives causing low-grade inflammation
Dietary antigens
Dietary antigens are normally rendered nonimmunogenic through a poorly understood “oral tolerance” mechanism that involves immunosuppressive regulatory T (Treg) cells; constantly being sampled by the IEC
*tolerance built into immune system so unselect T and B cells that are selective for food antigens so we can eat stuff
How can gut microbiota positively effect immune response to food antigens?
- Certain types of bacteria produce SCFAs, which can drive induction of regulatory T cells, which reduce cytokine production by down-regulating T cells activity
- Certain types of bacteria promote IL-22 production by CD4+ and ILC, which promotes barrier protection–>Il-22 strengthens the barrier and makes it impermeable to some food antigens that might cause food allergies
Gut Microbiota in Disease: Type I Diabetes
Patients with T1D exhibit a less diverse and less stable gut microbiome compared to healthy controls and changes of the ratio of Firmicutes to Bacteroidetes have been observed in the patients. Prediabetic children harbor more Bacteriodetes compared to controls
- these alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes.
- Generally beleived that the altered microbiota and subsequent leaky gut have led to increased permeability to dietary antigens, yielding greater cytokine release and therefore abnormal epithelial activation, as well as ALTERED mucosal immunity, leading to an autoimmune process (induction of T cells and antibodies), generating pancreatic islet inflammation, beta cell destruction, and Type I diabetes
Type I Diabetes
Type 1 Diabetes (T1D) is one of the most common metabolic disorders in children and young adults. This autoimmune-mediated disease results in a progressive loss of insulin-producing beta cells in the islets of Langerhans in the pancreas.
Coeliac Disease & Gut
Associated with intestinal micriobiota dysbiosis
Rheumatoid Arthritis & Gut
altered micriobiota linked to arthritis *A chronic inflammatory disorder affecting many joints, including those in the hands and feet. body turns on itself to attack the joints Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. It is triggered by a faulty immune system (the body’s defense system) and affects the wrist and small joints of the hand, including the knuckles and the middle joints of the fingers. *potentially a missing microbe species that upregulates Treg and decreases immune system activity and attack so the immune system attacks too much at joints *animal models of arthritis were exacerbated or rescued depending on gut microbiota
How is the microbiome kept away from IEC?
physicochemical barrier composed of a thick mucus layer, antimicrobial proteins, and secretory IgA antibodies51 coalesces to minimize the contact between the commensal microbes in the gut lumen and intestinal epithelial cells that line the gut wall. Bacteria escaping this initial ‘buffer zone’ encounter a second defense strategy, a physical boundary provided by the tight junctions formed between the intestinal epithelial cells. These cells are not only an anatomical boundary, but also exhibit active antibacterial properties
*epithelial cells present Toll-like receptors (TLRs) in their cellular membrane, which allow for the recognition of PAMPs and induction of downstream inflammatory responses. The lamina propria innate immune cells, constantly surveying the contents of the gut lumen in search of undesirable antigens, constitute another defense mechanism
Gut Microbiota in Disease: GUT-BRAIN AXIS
Bi-directional communication between microbiome, gut, and brain
- bacterial waste products can also influence the brain–for example, at least two types of intestinal bacterium produce the NT gamma-aminobutyric acid (GABA)
- mice born by C-section, which hosted different and less diverse microbes from mice born vaginally, were significantly more anxious and had symptoms of depression–>animals inability to pick up mothers vaginal microbes during birth, the first bacteria they would normally encounter, may cause lifelong changes in mental health
What are three main ways the Gut may interact with the brain?
- Peripheral serotonin: cells in the gut produce large quantities of serotonin which may effect brain signaling
- Immune system: intestinal microbiome can prompt immune cells to produce cytokines that can influence neurophysiology
- Bacterial molecules: microbes produce metabolites such as butyrate that can alter the activity of cells in the blood-brain barrier
* *neural communication by vagal and sympathetic nerve
* *systemic communication by HPA axis, NT, bacterial metabolites and cytokines
What are future questions and directions regarding the microbiome?
- can the microbiota be altered to improve vaccine responses?
- can microbiota be used to deliver vaccine antigens?
- Can specific vaccines be designed to target particular microbiota strains?
How has our conception of vaccine and vaccine safety shifted?
Because of vaccination, relatively FEW PEOPLE have had personal experience with the diseases they prevent; so there is lower risk tolerance by the public because are less aware of alternative (disease)
*public confidence in vaccines is also lower because new communication technologies have allowed the dissemination of INCORRECT information that is difficult to retract; increased attention on vaccine RISK
Measles Disney Outbreak
141 people infected in Disneyland with measles; this is NOT a problem of the measles vaccine not working but rather it NOT BEING USED
- the majority of people who got measles were unvaccinated
- herd immunity is compromised because not enough people with measles vaccine
- measles has a basic reproductive number of 18; so on average, each person infected with measles will infect 18 other people before they recover
Herd Immunity
Vaccines may provide INDIRECT immunity to unvaccinated through herd immunity by protecting those for whom vaccines are contraindicated or for those who have religious objections; having most of the population get vaccine allows some to NOT get vaccine because disease cannot spread if most people cannot get it
❁Relationship between how contagious disease I is and what % of people needs to be vaccinated for herd immunity
Pre-Licensure Vaccine Safety
- in vitro and in silico (computer-based) studies
- animal studies
- Phase I, II and III clinical trials on HUMANS
- Pre-licensure studies will detect COMMON side effects, but not rare or late side effects
- Only after a vaccine is shown to be safe and efficacious may a manufacturer apply for licensing
What are the two kinds of licenses required?
- product license: the vaccine itself and procedure for how it is to be made and administered
- establishment license: where it is made; Physical building where it is made; make sure facilities are really secure and are protecting people and public from deadly things getting OUT
What are the three phases for human clinical trials?
- Phase I: 20-100 volunteers; initial safety studies–looking for adverse side-effects & undesirable toxicity
- Phase II: hundreds of volunteers; optimization of dosage and schedule
- Phase III: hundreds to thousands of volunteers; determines efficacy; may last several years
Post-Licensure surveillance?
- Post-licensure surveillance is CRITICAL to ensure that rare events are identified and quantified
- monitor increases in known reactions
- identify risk factors or conditions associated with reactions
- identify vaccine batches with unusual rates or types of adverse events
- identify adverse reactions that require further study
What are some post-licensure safety activities?
- passive reporting by healthcare providers
- ad hoc studies of adverse reactions/events
- Phase IV trials
- Large Linked Databases (LLDBs)
- CISA Network
Phase IV Trials
- More than 10,000 participants
- better than phase III trials; larger scope and greater understanding of more rare side effects and what subgroups of people are more likely to have adverse reactions/events
Large-Linked Databases (LLDBs)
- Link immunization and medical records from defined populations (done by large companies with computerized medical records like HMOs and Medicare)
- Aimed at addressing limitations to passive reporting systems which are: inability to determine causality, lack of timelines, underreporting, and recall bias
- ACA includes incentives to increase the usage of electronic medical records which will increase denominator of LLDBs
- Helpful in finding adverse reactions that people might not remember or associate with the vaccine
- Helps with timeliness question; reports are well documented because see DATES of things so allow connections between certain things, like when you got the vaccine and when you got onset of symptoms
- Because have verified record, can do better epidemiological studies and make a case for causality
Clinical Immunization Safety Assessment (CISA) Network
- Established in 2001 to improve understanding of vaccine safety issues at the individual level
- Evaluates person who experienced adverse health events following vaccination
- major goal is to study the pathophysiological basis of adverse events, study the risk factors associated with adverse events, and develop evidence-based guidelines for healthcare providers.
- Group of researchers from CDC go and check VAERS claims; academically focused; fly to where adverse events are reported and investigate you
- Concerned with finding NEW biologically plausible causational adverse reactions that we didn’t know before
Advisory Committee on Immunization Practices (ACIP)
- Advisory body consisting of medical and public health experts across many disciplines that develops recommendations about vaccines
- role is to provide ADVICE that will lead to a reduction of vaccine preventable diseases in the USA
- ACIP develops RECOMMENDATIONS for routine administration of vaccines (age, dosing intervals, precautions & contraindications)
- insurance companies tend to follow & abide by ACIP decisions, often forcing doctors to do the same because going against ACIP means going out of insurance bubble meaning cost is out of pocket
What are some issues considered by ACIP?
- The safety and effectiveness of the vaccine when given at specific ages (immune responses can vary depending on age)
- the NUMBER of children who get the disease if there is no vaccine; vaccines that dont provide benefits to MANY children may not be recommended for ALL children
- the severity of the disease
- only vaccines LICENSED by the FDA are recommended; thus vaccine manufactureres must conduct studies to show that a vaccine is SAFE and EFFECTIVE at specific ages
What are ACIP conflict of interest policies?
- ACIP members CANNOT have a conflict of interest; researchers and clinicians who lead vaccine studies at their respective institutions may become ACIP members but NOT comment or vote on their own vaccines or vaccines associated with the company they work for; must excuse themselves
- Those who serve on a board of directions of a vaccine manufacturer, those who hold patents on vaccines or related products, and those who are directly employed by a vaccine manufacturer or have immediate family members so employed are EXCLUDED from membership
Adverse Reaction
*inappropriate effect caused by a vaccine that is unrelated to its primary purpose of producing immunity; a SIDE EFFECT
Adverse Event
- any medical event following vaccination
* may be true adverse reaction and may be coincidental (fell down stairs after vaccination)
Vaccine-induced Adverse Reaction
- Due to intrinsic characteristics of the vaccine and the individuals response
- event would NOT have occurred without the vaccine
Vaccine -potentiated adverse reaction
- event would have occurred anyway but was precipitated by the disease
- ex: vaccine may cause slight fever which may induce febrile seizures that would have occurred anyway but now occur earlier because of fever
Programmatic error adverse reaction
*event due to errors in vaccine storage, preparation, handling or administration
Coincidental Adverse EVENT
*event was not caused by vaccination but occurred by change or as the result of underlying illness
How do you determine causality v. adverse events?
- BRADFORD-HILL CRITERIA developed as a checklist for causality
- TIMELINE: did the adverse event occur within a plausible time frame?
- BIOLOGICALLY PLAUSIBLE
- POSITIVE RECHALLENGE: does event recur upon administration of the vaccine
- have there been any laboratory evidence, clinical trials, or epidemiological studies indiciating a h`igher level of adverse events among vaccinated v. unvaccinated
What are the three classifications of adverse reactions?
- Local
- Systemic
- Allergic
Local Adverse Reactions
Pain, swelling, redness at SITE of injection
- common with inactivated vaccines
- usually mild and self-limited
Systemic Adverse Reactions
- fever, malaise, headache, muscle pain, loss of appetite, etc.
- some LIVE vaccines may cause a mild form of the illness as a result of replication
Allergic Adverse Reactions
Rare allergic reaction to the vaccine antigen, or to some other component of the vaccine itself (some allergic to egg-based vaccines)
- may be life-threatening if not immediately treated
- classified differently from systemic response because it’s a different mechanism; more of a known quantity rather than an issue with a vaccine itself (like systemic)
VAERS
- Vaccine Adverse Event Reporting System
- System created in 1990s to collect reports of adverse events
- passive system that ACCEPTS reports from healthcare providers, vaccine manufacturers, and the general public (does not solicit)
- Receives 15,000 reports per year
- collects data on patient, vaccine administered, and suspected adverse event, and WHO is reporting; if doctor is reporting, given greater weight
- VAERS detects new or rare events, increases in rates of known side effects, patient risk factors, etc.
- additional studies REQUIRED to confirm VAERs signals; cannot get causality from these, especially given subjectivity of patient reports
What “active” role does VAERS play?
Follows up on all reports of SERIOUS adverse events
*serious adverse events defined as an event involving or prolonging hospitalization, life threatening illness, permanent disability, or death
What are the six main limitations to VAERS data?
- Underreporting: common to all surveillance systems which require voluntary reporting; occurs more frequently with LESS serious adverse events
- Differential reporting: reporting is increased in the first few years after vaccine licensure; increased reporting of events occurring soon after vaccination
- Stimulated reporting: reporting increases after a KNOWN or alleged type of adverse event is brought to public; like if SOMETHING happens or celebrity speaks out or somethings is in the news
- Reporting of coincidental events
- Data quality; data not always complete or accurate
- No denominator data: VAERS does not collect data on # of vaccine doses administered so don’t know exact RATES of adverse events
Vaccines: Benefits & Risk Communication
- Parent, Guardians, and patients should be informed of the risks and benefits of vaccines in understandable language
- Vaccine concerns should be anticipated and discussed in empathetic manner using clear and factual language
- importance of VACCINE INFORMATION STATEMENTS (VISs)–>per federal law, MUST be provided before each dose of vaccine; available in multiple languages
Contraindication
Contraindication is a condition in a recipient that greatly increases the change of a SERIOUS adverse reaction
*Vaccine should NOT be given
Precaution (vaccines)
A precaution is a condition that MIGHT increase the chance of a severe reaction or that might compromise efficacy
- vaccine should NOT be given
- in SOME cases the benefit may outweigh the risk sufficiently so as to indicate vaccination in case of precaution
Invalid Contraindications to Vaccinations
- mild acute illness
- Mild/moderate local reaction
- antimicrobial therapy
- breastfeeding
- multiple vaccines, etc.
Valid Contraindications to Vaccines
- Moderate to severe illness (fever, respiratory issues, cardiac problems)
- pregnant
- severe allergy to vaccine component or an allergic reaction following a prior dose of vaccine
- immune disorder like autoimmune disease of immunosuppression
Salk Vaccine
Salk inactivated polio vaccine (IPV) was declared SAFE and effective following a trial conducted in 1.8 million children (POLIO pioneers)
- within HOURS, five pharmaceutical companies were granted licenses to manufacture IPV
- millions of doses were quickly produced and administered, mostly to children
The Cutter Incidence
- Reports began to surface of children becoming paralyzed after receiving IPV manufactured by Cutter Laboratories
- Vaccine was immediately recalled
- Later determiend that 120,000 doses of vaccine produced by Cutter contained LIVE POLIO VIRUS due to a manufactoring error
- Of the children vaccinated, 40,000 developed abortive polio, 51 were permanently paralyzed, and 5 died
- vaccine started a polio epidemic that paralyzed 113 and killed 5 more
What went wrong in cutter laboratories?
Cell debris in the vaccine prevented adequate exposure of the virus to formaldehyde
- they miscalculated the extrapolation; expected that for a given increase in temperature, the amount of live polio virus in the vaccine would decrease logarithmically, but at very high temperatures, begins to taper off and so the same temperature increment has smaller effect, so they did not heat it enough because based on extrapolation of what graph SHOULD look like, the heat they used should be sufficient
- now they WAY overdo it to ensure that virus is KILLED
What was the fallout from the Cutter incident?
- manufacturing requirements for IPV were revised
- cutter laboratories was sued by many of the affected families; the company was found to be financially liable but NOT NEGLIGENT–legal precedent of liability without fault made it easier for courts to rule against pharmacuetical companies in other cases
- by the 1980s, liability issues caused increases in the price and a dwindling number of manufacturers, threatening the supply; tension caused establishment of VICP
VICP
Vaccine Injury Compensation Program
- major goals: to provide JUST compensation to those injured by rare adverse events and provide liability protection for VACCINE manufacturers, helping to ensure adequate vaccine supply
- no fault program: no need to prove negligence on part of provider or manufacturer
- Settlements are based on a vaccine injury table; if event not listed on table, must PROVE vaccine caused it
The Wakefield Paper
- in 1998, British Gastroenterologist Wakefield published article in the Lancet saying that MMR vaccine caused INTESTINAL INFLAMMATION, which allowed the movement of otherwise nonabsorbed peptides into the bloodstream and subsequently to the brain where they affected development
- studied only 12 children; believed that MMR vaccine led to children developing autism
- Hypothesized neurological mechanism for immunological event; he studied 12 children; hypothesized that there was intestinal inflammation in stomach called leaky gut allowing absorption of proteins into bloodstream, crossing BBB and in the brain, causing autism in the baby
What effects did the Wakefield paper have?
- Following media reports on the wakefield paper, MMR immunization rates dropped and reached a low of 80% (way below what is necessary for herd immunity)
- measles cases dramatically increased during this period
- immunization rates have subsequently increased but are STILL below the 95% threshold needed to prevent outbreaks
- the Wakefield paper was FORMALLY retracted in 2010 after Wakefield was found to have engaged in multiple ethics violations while conducting study
What are some major ISSUES with the Wakefield paper?
- 12 people is not enough people to draw a conclusion; no statistical significance or power
- 3 of children reported with regressive autism did NOT have diagnosed autism
- 5 of the children had DOCUMENTED pre-existing developmental concerns
- in 9 cases, unremarkable colonic histopathology results were changed to NON-specific colitis
- patients were recruited through anti-MMR vaccine campaigners, and the study was commissioned and funded for planned litigation
What are the 3 incorrect hypothesis linking vaccines to autism?
- MMR Hypothesis
- Thimerosal Hypothesis
- “Too Many Vaccines” Hypothesis
MMR hypothesis for Vaccine=Autism
MMR vaccine causes inflammation that damages the intestinal lining, allowing the entrance of encephalopathic peptides
**DEBUNKED: the MMR vaccine has NOT been shown to cause intestinal inflammation or loss of barrier function & the putative autism-inducing encephalopathic peptides have NOT been identified
THIMEROSAL hypothesis for Vaccine=Autism
The MERCURY containing preservative thimerosal found in some vaccines is toxic to the CNS
*DEBUNKED: well described signs and symptoms of mercury poisoning are DISTINCT from those of autism; furthermore a tuna can has more mercury in it than vaccine
Too Many Vaccines hypothesis
The simultaneous administration of multiple vaccines OVERWHELMS or weakens the immune system and creates a pathological interaction with the nervous system
- debunked because number of proteins and ANTIGENS in vaccines has decreased drastically over the years while autism has increased; know it is antigens that activates immune system so fewer antigens=less activation
- DEBUNKED: the immune system can and DOES respond to many more antigenic challenges than vaccines represent; multiple vaccinations do NOT weaken the immune system and even as the # of childhood vaccines has increased, the # of antigens in them has declined
Why do vaccine mytths exist?
scientific community is poor at speaking colloquially and understandably about situation while the anti-vaccine campaign tends to speak using colloquial language and famous personalities and preys on fears people already have
What factors contribute to public distrust of vaccines?
- many vaccine preventable disease are unfamiliar to parents and increasingly clinicians (so less risk aversion driving use of vaccines)
- # of recommended vaccines has increased considerably
- Vaccine mandates can fuel distrust; American individualism is strong and resists this impetus
- misinformation about vaccines has equal access to the internet and popular media, and greatly exceeds the volume of reputable information; misplaced trust in celebrities expressing scientifically UNFOUNDED POSITIONS
Are all immunizations vaccines?
Although the terms are often used interchangeably, not all immunizations are technically vaccines; immunization of animals for monoclonal antibody or antitoxin production is not to treat the animal and provide a protective or therapeutic response, but just to get antibodies that can be used to treat OTHERS
What are some ways to optimize and make DNA vaccines BETTER?
Can make plasmid better, the specific gene better, use adjuvants, and deliver to the right part of the body where it will be most efficacious. Can make gene easier to express and more stable when it gets into a cell. P
What are same DNA vaccine CONCERNS?
- Integration: DNA vaccines integrate into cellular DNA owing to optimized expression plasmids, which could result in chromosomal instability or inactivation of tumor suppressor genes.
- Autoimmunity: development of autoimmune disorders against patient DNA or immune adjuvants
- Antibiotic Resistance: potential risk that antibiotic resistance could be transferred to patients receiving vaccines through the unintentional transfer of bacteria.
- Low immunogenicity: first generation DNA plasmids elicit low levels of T and B cell memory
How are the potential concerns regarding DNA vaccines resolved?
- Integration studies are done for DNA vaccines before human trials are done
- Autoimmunity is unlikely
- Antibiotic resistance; antibiotics used are those not commonly used to treat human infections/ have a bacterial, not mammalian origin of replication
- Increasing immunogenicity using plasmid adjuvants
What are some advantages of DNA vaccines over conventional vaccines?
- Design: simple engineering; easy to manufacture and modify; antigen genes could be combined with genes for cytokines, TLR ligands, etc.
- Time: rapid production & large-scale production
- Safety: cant revert into virulent forms and no significant adverse events to date
- Stability: long shelf life
- Mobility: ease of storage and transport; doesnt require cold chain & can be administered without needles
- Immunogenicity; similar to live attenuated; induce humoral and cell-mediated immunity
- Antigens expressed in natural form in myocytes and DCs (myocytes are muscle cells); DNA is typically injected into muscle cell; some muscle cells will take up DNA and express it, which then allows immune system to respond to it
* could theoretically express antigen right in antigen presenting cell
What is the West-Nile innovator?
- the first DNA vaccine was the for West-Nile virus for HORSES
- if horses get west nile it can be really bad for them so there is a DNA vaccine that works really well (94% efficacy)
