Lecture 18

Vaccination vs. Natural Immunity

"A systematic review and meta-analysis including data from three vaccine efficacy trials and four observational studies from the US, Israel, and the United Kingdom, found no significant difference in the overall level of protection provided by infection as compared with protection provided by vaccination." "The randomized controlled trials appeared to show higher protection from mRNA vaccines whereas the observational studies appeared to show protection to be higher following infection." Both natural immunity and immunity via the vaccine appear to last 6 months to a year

What is herd immunity? How is it defined? How is it determined?

"[Herd immunity] is achieved when persons with protective immunity in a population have crossed a threshold preventing a further propagation of the pathogen even in the presence of non-immune subjects." The threshold for herd immunity varies from disease to disease but depends on the 'infectious force' or the (R0), the number of secondary infections caused by an index case. For perspective, SARS-CoV-2 has a higher infectious force than the flu, but lower than chicken pox or measles

What is Herd Immunity?

"[Herd immunity] is achieved when persons with protective immunity in a population have crossed a threshold preventing a further propagation of the pathogen even in the presence of non-immune subjects."The threshold for herd immunity varies from disease to disease, but depends on the 'infectious force' or the (R0),the number of secondary infections caused by an index case.For perspective, SARS-CoV-2 has a higher infectious force than the flu, but lower than chicken pox or measles

Dysfunctional immune response

-excessive infiltration of monocytes, macrophages, and T cells -systemic cytokine storm -pulmonary edema and pneumonia -widespread inflammation and multiorgan damage

healthy immune response

-infected cells rapidly cleared -virus inactivated by neutralizing antibodies -minimal inflammation and lung damage

How Does it Infect Us?

1. An infected individual expels virus-laden droplets which are then inhaled by a second (third, fourth...) individual 2. The inhaled virus finds its way to the upper respiratory tract (the nose and throat) where it utilizes a receptor known as angiotensin-converting enzyme 2 (ACE2) to enter into the host cell. The S protein of the virus attaches to ACE2 on the host, and the virus is endocytosed into the cell. 3. One inside the host cell, it does what viruses do: It hijacks the cell's machinery to make more of itself and then is shed (to infect other cells) 4. Further infection results in movement down the respiratory tract. As noted, lower respiratory tract barriers are thinner, with fewer cells. These cells are also very rich in ACE2, making them targets for the virus. 5. As the lower respiratory tract is infected, inflammatory molecules are recruited (cytokine storm?), but often at the expense of oxygen transfer, which is a highly sensitive and delicate process. (Pneumonia)

What are the four types of potential treatment options for COVID-19?

1. Antibodies to spike resulting from vaccination or adoptive transfer block virus binding to ACE2 2. Protease inhibitor blocks and prevents TMPRSS2 from activating the spike protein through protease cleavage 3. Virus-specific effector CD8+ T cells arising from vaccinations recognize infected cells, secreting cytotoxic granules to kill infected cells 4. Proinflammatory cytokines

The antiviral response is really about two things:

1. Eliminating the infected cell(s) TH1 cells, CD8+ T cells, NK cells, macrophages, etc. 2. Stopping the spread to uninfected cells Type I interferons; antiviral proteins; flu like symptoms

What are the goals of the antiviral response?

1. Eliminating the infected cell(s) TH1 cells, CD8+ T cells, NK cells, macrophages, etc. 2. Stopping the spread to uninfected cells Type I interferons; antiviral proteins; flu like symptoms

What About the Immunology?

1. The virus infects the host cell and takes over, doing what viruses do 2. The host cell undergoes pyroptosis, releasing several DAMPs, such as ATP, host DNA, and apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC) 3. DAMPs are recognized by adjacent cells (endothelial cells, epithelial cells, and alveolar macrophages) expressing PRRs 4. Those adjacent cells release pro-inflammatory cytokines (e.g. IL-6), recruiting other cells to the spot of inflection 5. The adaptive immune system is programmed towards a TH1 response

How Many People Report?

2,684,287,568 vaccines given 3806 compensable settlements 5006 cases dismissed 0.000019%

Pyroptosis:

A highly inflammatory form of programmed cell death; common in cytopathic viruses

What is the spike (S) protein?

A protein sticking out from the surface of the virus. Usually interacts with host cells.

Sepsis:

A systemic response to infection that includes fever, elevated heartbeat and breathing rate, low blood pressure, and compromised organ function due to circulatory defects

Vaccine Schedules

Booster vaccination is required to achieve protective immunity to many pathogens

What is a vaccine schedule? What is a booster?

Booster vaccination is required to achieve protective immunity to many pathogens

Septic Shock:

Circulatory and respiratory collapse (90% mortality)

Can you distinguish between the terms coronavirus, SARS-CoV-2, and COVID19?

Coronavirus: Type of virus SARS-CoV-2: The specific virus COVID19: The named disease caused by infection of the virus

What is the Coronavirus?

Coronavirus: Type of virus SARS-CoV-2: The specific virus COVID19: The named disease caused by infection of the virus Ring around it is the spike protein

What does the term endemic mean? Can you distinguish between an outbreak? An epidemic? A pandemic?

ENDEMIC is something that belongs to a particular people or country. AN OUTBREAK is a greater-than-anticipated increase in the number of endemic cases. It can also be a single case in a new area. If it's not quickly controlled, an outbreak can become an epidemic AN EPIDEMIC is a disease that affects a large number of people within a community, population, or region. A PANDEMIC is an epidemic that's spread over multiple countries or continents.

What is gain of function research? What are the three potential outcomes of GoF research?

Gain-of-function (GOF) research involves experimentation that aims or is expected to (and/or, perhaps, actually does) increase the transmissibility and/or virulence of pathogens. Increased transmissibility and virulence, chance of infecting humans, more knowledge

COVID-19 What Is It, Exactly?

Hcov-strains that cause the human cold SARS-coronavirus A contagious viral respiratory disease that may cause serious complications, especially in people who are more than 60 years old and/or who already have serious health concerns.

The Immune System Gone Bad

In most cases, the immune response is capable of resolving the infection, but in certain cases the immune system can contribute to and worsen the pathology, both in the lung and systemically. Pyroptosis can/will trigger an immune response and—again—most of the time that's a good thing. However, patients requiring intensive care exhibit higher levels of IL-2, IL-7, IL-10, G-CSF, TNFα, etc. atients who don't survive have significantly higher IL-6 than those who do

Septicemia:

Infections in the blood (e.g. gram negative bacteria such as E.coli or Salmonella)

Other Side Effects:

Inflammation of the heart (54 cases/1 million; .0054%) Blood clotting issues (7 cases/1 million; .0007%) Guillian-Barre syndrome (8 cases/1 million; .008%)

mRNA vaccine

Inject a machine-made mRNA molecule that will be used by your own body cells to make a viral protein, like the Spike Protein of Covid-19. Once your cells use those mRNA molecules to make the Spike Proteins, your own immune system cells will develop the antibodies and memory B cells to quickly identify and fight those Spike Proteins. Then, if you actually get the Covid-19 virus, your body has already made the antibodies and the memory cells to identify and destroy those Spike Protein and destroy Covid-19. In this way, you gain protection from a virus without ever having the actual virus injected into your body.

WHY?

Is it possible that the virus' ability to subvert the immune response causes them immune system to kick into high(er) gear? What if that higher gear isn't helpful, but harmful? Some evidence demonstrates that the virus can diminish levels of IFNs (crucial to the viral response), causing pyroptosis to continue and leading to a more sustained systemic inflammatory response

How Does COVID19 Compare?

Look at graph. It's in there.

Distribution of Cases Worldwide and in the US

March 11, 2020 COVID19 is declared a pandemic

What is Long-COVID? MIS-C and MIS-A?

Multisystem Inflammatory Syndrome in Children (MIS-C) Multisystem Inflammatory Syndrome in Adults (MIS-A) Pulmonary, Cardiovascular, and Neurological -> Exercise Intolerance Autonomic Dysfunction Cognitive Impairment

Do Vaccines Cause Autism?

NOPE

But What if They're Not Safe?

National Vaccine Injury Compensation Program (VICP or NVICP) was established by the 1986 National Childhood Vaccine Injury Act (NCVIA), created in response to the DPT scare The court is 'no fault' meaning that it doesn't require criminal intent or even fault Requires a 'preponderance of evidence' (more likely to be true than not true) Each case is heard by a panel of nine people: Three individuals with a medical/scientific background Three individuals with a legal background Three 'lay' individuals If the decision is not to the liking of the injured party, they may sue the manufacturer in civil court, but the burden of proof is higher

Common Side Effects:

Pain and soreness at the site of injection Fever/Chills Fatigue Nausea/Vomiting Malaise Swollen lymph nodes

How Do These Vaccines Work?

Pfizer and Moderna are mRNA Vaccines What does that mean? Johnson and Johnson is a viral vector vaccine. What does that mean?

How Were Vaccines Developed So Quickly?

Rapid availability of COVID19 sequence Pre-existing technology (mRNA Vaccines) Pre-existing knowledge (Spike protein) Removal of regulatory 'red tape' mRNA Increased funding ($$$$$$$$)

Where Did it Come From?

SARs-CoV-2 is almost certainly zoonotic, meaning that it has crossed species It most likely came from a bat, though it could have jumped to another species (pangolin) before crossing over to humans The 'jump' likely happened at a wet-farm in Wuhan, China This is very similar to what (we think) happened in the 1918 H1N1 flu pandemic Death Toll: 1918: 50,000,000 deaths worldwide WWI: 40,000,000 deaths worldwide

In general, what happens when the immune system goes bad (in terms of the COVID-19 response?)

Some evidence demonstrates that the virus can diminish levels of IFNs (crucial to the viral response), causing pyroptosis to continue and leading to a more sustained systemic inflammatory response

PAMP -> PRR ->

TNFa, IL-6, IL-1B -> Amplified immune response positive feedback mechanism

Are vaccines effective against the delta variant?

The Pfizer vaccine is 88% effective against protecting against symptomatic disease and 96% effective against severe disease The Moderna vaccine is 72% effective at preventing symptomatic disease and 96% effective against severe disease The J&J vaccine is 85% effective at preventing severe disease

How does coronavirus infect us? What is the ACE2? What is the relationship between the spike protein and ACE2?

The S protein of the virus attaches to ACE2 on the host, and the virus is endocytosed into the cell.

What are therapeutic vaccines? What are some examples?

Therapeutic vaccines are given after illness has occurred Tumor therapy, chronic infection, indirect effects of infections, autoimmune disease, allergy, chronic inflammation, hypertension, neurodegenerative disease

The Future: Potential Therapeutic Vaccine

Tumor therapy, chronic infection, indirect effects of infections, autoimmune disease, allergy, chronic inflammation, hypertension, neurodegenerative disease

What is VAERS? How does it work?

Vaccine Adverse Event Reporting System VAERS is designed to rapidly detect unusual or unexpected patterns of adverse events, also referred to as "safety signals."

Rapid Timeline for Vaccine Development

Vaccine innovation: most vaccines take years to develop, but scientists created multiple vaccines for SARS-CoV-2 within a year. A vaccine in a year: the drug firms pfizer and biontech got their joint SARS-Cov2 vaccine approved less than eight months after trials started. The rapid turnaround was achieved by overlapping trials and because they did not encounter safety concerns

Potential Treatment Options?

Vaccines and Therapeutics

How Do We Know?

We don't

The Benefits aren't Just Health-Related

What is the economic impact of COVID-19?(Trillions?) What is the investment into a Sar-CoV-2 vaccine? (Billions?) Risk(Cost) to Benefit Ratio?

Are Vaccines Safe?

Yes

Can Vaccinated People Spread the Disease?

Yes, there can be shedding

Is too much inflammation a bad thing?

collateral damage

What are the Consequences of Non-Vaccination?

ex. measles can kill immune memory cells so there is a benefit to getting vaccinated against it.

What are the consequences of non-vaccination?

example: measles can destroy immune memory cells if not vaccinated against

Regarding infectious disease, what is the relationship between infectivity and mortality (in general)? What is the relationship between infectivity and mode of transmission (in general)?

infectivity: ability of a biological agent to enter and grow in the host more infectivity more chance of mortality mode of transmission determines infectivity chances

AN EPIDEMIC

is a disease that affects a large number of people within a community, population, or region.

AN OUTBREAK

is a greater-than-anticipated increase in the number of endemic cases. It can also be a single case in a new area. If it's not quickly controlled, an outbreak can become an epidemic

A PANDEMIC

is an epidemic that's spread over multiple countries or continents.

ENDEMIC

is something that belongs to a particular people or country.

Do vaccines cause autism?

nope

How Do mRNA Vaccines Work?

synthetic mRNA is manufactured and modified to make it more stable and less immunogenic. lipid nanoparticles (LNP) to protect the mRNA and deliver it into cells. RNA is negatively charged and cannot enter cells. positively charged lipids neutralize this, mediate entry into cells and protect the mNRA from nucleases

Viral vector vaccines

use a modified version of a different virus as a vector to deliver protection