Vaccsbook

Infectious Diseases . . . and How to Avoid Them

Vaccines

This information is for entertainment purposes only. It has not been verified by a third party. Last updated: a while ago.

Antigens, Epitopes, and Antibodies

Antigens
are anything (but commonly a microbe) which can provoke an immune response.
Epitopes
are the specific parts of an antigen, e.g. "bumps" or "spikes" on the outer surface of the microbe, that uniquely identify that particular microbe.
Microbes often contain multiple epitopes; but the word "Antigen" is commonly used to refer to one or more epitopes.
Antibodies
are complex molecules produced by the immune system to exactly match epitopes and latch on to them, which then allows other parts of the immune system to recognize and destroy the microbe.
All vaccines either contain epitopes, contain molecules which "look like" epitopes, or cause a microbe's epitopes to be produced on host (human) cells.
Vaccines, such as mRNA, target a single epitope; if that epitope mutates the vaccine loses its effectiveness.
Inactivated and Live Attenuated vaccines, also known as "Whole Virus" vaccines, contain all the epitopes of a microbe, and maintain their effectiveness if any epitope mutates.

How Vaccines Work

The goal of all vaccines is to get antigens of the the microbe to be destroyed - the "target" microbe - into the human body to cause the immune system to produce and remember the right antibodies . . . without the person getting sick.

When an infectious microbe enters a person's body, several events occur.
1. The immune system immediately responds to limit the microbe from multiplying and damaging the body's tissues.
2. The initial immune response causes symptoms: fever, headache, cough etc.
3. If antibiotics are given, they can start to destroy the microbe.
4. If this initial immune response is inadequate, the person may die.
5. The immune system detects the antigen(s) of the microbe.
After a few days, the immune system produces antibodies which are highly specific for that microbe's antigens, and allow the microbe to be destroyed.
6. The immune system "remembers" which antibodies are needed to fight this microbe, so the next time it enters the body, it can immediately be destroyed.

Vaccines allow steps 1 through 5 to be skipped (particularly step 4 !).

Vaccine Development

The World Health Organization (WHO) states that out of 100 vaccines that start laboratory tests, only 7 are approved for further human trials. Of those vaccines that enter human trials, only 1 in 5 become approved for use in the general population.

The average time from inital proposal to approval for human use is 10 to 15 years; until recently the shortest was 4 years for the Mumps vaccine.

Creation of a vaccine typically follows several stages:

Laboratory experiment to identify possible antigens; this can take many years particularly for a newly discovered microbe.
Laboratory culture of the antigen(s) and animal testing to establish basic safety and efficacy.
Regulatory approval of the results of stages 1 & 2, with a plan for phased human trials.
Phase 1 Trials:
1. involve a small (less than 100) human adult test subjects
2. evaluate the vaccine for basic safety (no obvious adverse effects)
3. evaluate the vaccine for basic efficacy (the production of antibodies)
4. may involve deliberately exposing test subjects to the disease to see if it prevents infection
Phase 2 Trials (if phase 1 is successful)
1. involve several hundred human adult test subjects
2. may include some test subjects at high risk for the disease.
3. usually involves giving half the test subjects the vaccine, and half a placebo
4. usually involve comparison of different dosages, and number and timing of doses
5. continue to evaluate safety and efficacy
Phase 3 Trials (if phase 2 is successful),
1. involve many thousand human adult test subjects
2. look for rare (1 in 10,000) adverse effects
3. continue to evaluate safety and efficacy
Creation and approval of the manufacturing process.

Percentage Efficacy . . . and Effectiveness

Following clinical trials, a vaccine manufacturer will state the vaccine's Percentage Efficacy; if 100 people are vaccinated and then exposed to the disease, 90 stay healthy and 10 get sick, the efficacy is 90%.

However, this measure only relates to clinical trials, before a vaccine is released for general use.

Vaccine manufacturers may also state different efficacy percentages for reductions in deaths, reductions in hospitalizations, prevention of severe symptoms, and even for different dosing schedules.

Effectiveness is a measure of how well a vaccine protects people in the general population, and how long that protection lasts.

Real world Effectiveness is almost always lower than Efficacy).
Unfortunately, and this is particularly the case with recently authorized COVID-19 vaccines, media reports often use Effectiveness when referring to Efficacy.
Most common vaccines given in childhood are at least 90% effective, but only if the vaccination schedule is followed and a full course of boosters is received. Influenza vaccines (are a special case because of the high number of strains which vary from year to year) but are between 20% to 60% effective.

Types of Vaccine

There are many technologies used in the creation of vaccines, some well established but some still experimental and not well understood.
Some vaccines use a blend of technologies making precise, consistent classification difficult.

Live Attenuated
Live Attenuated vaccines are made by taking whole live microbes and then weakening them, usually by repeated culture, so they can no longer replicate in the body and no longer cause disease.

When injected, the attenuated microbe provokes an immune (antibody) response, but without causing any symptoms or tissue damage.
These vaccines can occasionally cause a mild form of the disease, which may be more severe in a person with an immunodeficiency (poorly functioning immune system)

Live Attenuated vaccines usually require only a single dose and give long lasting protection.
Examples are vaccines for Measles, Mumps, Rubella, Chickenpox, Shingles, and Rotavirus.

Inactivated

Inactivated vaccines are made by treating the microbe with chemicals or heat to prevent it from multiplying, so it can never cause disease but still cause the immune system to produce antbodies.
In some cases, additional purification is done to leave just that part of the microbe which comprises the antigen (the part which is recognized by the immune system).

Inactivated vaccines often need multiple (booster) doses to create enough antibodies, and then may still need to be repeated throughout life.
Examples are vaccines for Polio, Hepatitis A, Influenza (some) and Rabies.

Most vaccines are manufactured using chickens' eggs. A sample of the virus is injected into an egg, then incubated for several days allowing the virus to replicate. Fluid inside the egg is then extracted and purified into an injectable vaccine.
Some vaccines are also manufactured by growing the virus inside animal cells instead of chickens' eggs.

Toxoid
Some microbes cause disease by producing a Toxin (poisonous proteins), rather than by multiplying and directly damaging the body's tissues.
Toxoid vaccines are protein molecules which look like the toxin, and cause the immune system to create antibodies to the toxin rather than to the microbe's antigens.
Examples are vaccines for Tetanus, Diptheria, and Pertussis (whooping cough).

Subunit
Subunit vaccines (sometimes called Acellular) do not use the whole microbe, but just those specific parts of it known to provoke the immune system.
These can be a protein or a "polysaccharide" molecule (poly=many, saccharide=sugar) forming part of the microbe's outer coating.
There are several approaches to producing subunit vaccines.

Conjugate vaccines use both polysaccharides and ("conjugated with") proteins,
These vaccines may also include an "adjuvant" most commonly toxoid proteins described above; this conjugation improves the immune response and the production of antibodies.
Examples are vaccines for Haemophilus Influenza (Hib), Meningitis types C & ACWY, Pneumococcus(PCV-13) given in infancy and more recently in adults, and some Influenza.

Recombinant vaccines use genetic engineering to take the DNA of the microbe and insert it into a "producer" or "carrier" cell, usually a yeast cell.
The microbe antigen DNA is re-"combined" with the yeast DNA, so when the yeast cell multiplies it produces antigens in sufficent quantity to create the vaccine. The yeast cells are then processed/purified to extract the antigen which can then be injected as the vaccine.

Some newer recombinant vaccines use Nanoparticles, tiny (1 millionth of a millimetre) molecules with special chemical properties, to "carry" the antigen to the cells of the body, while protecting it from normal degrading/elimination processes in the circulation.

Some recombinant vaccines also include Virus-Like Particles (VLPs), molecules similar to those found in or on a virus, but without viral DNA.
These are often antigenic molecules, or combinations of antigens, and can be processed to provide high density/concentration of antigens.
VLP vaccines prompt an immune response similar to that elicited by the natural virus.

Examples of recombinant vaccines for Hepatitis B, Shingles, Human Papilloma Virus, Meningitis type B, Influenza (some), and Pneumococcus (PPSV-23).

Viral-Vector
Viral-vector vaccines use a separate virus (the vector) to create the necessary immune response.
Unlike many conventional vaccines they do not contain the target antigen.
Instead, DNA of the target virus antigen is combined with the DNA of the vector.
Some vectors are otherwise unmodified, some are modified to prevent them from replicating, some have their own vector antigen DNA removed.

When injected, the vector (like all viruses) "infects" the cells of the body and the immune system makes antibodies against the target antigen.

For example, the DNA of the COVID-19 virus which makes its "spike" is inserted into a vector, which when injected, provokes the immune system to produce antibodies against the spike.

Adenoviruses (common cold virus) which are relatively harmless to humans, are the most commonly used vectors. They have been used in gene therapy for many years, but only recently to create a vaccine.
Potential limitations are that populations previously exposed to the vector are possibly immune to the vector and won't respond to the vaccine. In some parts of the world, up to 80% of the population already has immunity to commonly used adenovirus vectors.
Additionally, some patients may develop immunity to the vector as soon as it is injected, making booster doses ineffective.

DNA and RNA
DNA and RNA vaccines, are not based on live or inactivated microbes themselves, nor on parts of the microbe containing the antigens.
DNA vaccines contain that part of a microbe's DNA which "codes" (is used to produce), its antigens.
When a DNA vaccine is injected, and taken up by human cells, the antigens are reproduced by normal cellular synthetic processes and appear on the surface of the cell, causing the immune system to produce antibodies.
DNA vaccines are different from Recombinant (described above); the target viral DNA is injected directly, and it is human cells (not Producer or Carrier cells) which create the antigen.

Similarly, RNA vaccines (specifically Messenger RNA, abbreviated to mRNA) consist of mRNA molecules created from the DNA of the target microbe.
Some mRNA vaccines use nanoparticle technology to preserve the mRNA in the circulation and allow it to enter the body's cells.
Click DNA and RNA for more details.

DNA vaccines are relatively stable when stored at room temperature; mRNA vaccines must be stored and transported close to the freezing point, and in some cases far below the freezing point.
(Failure to store and transport any vaccine correctly, (e.g. preserve the "cold-chain") could lead to an ineffective vaccine being administered and people acquiring a false sense of protection.)

As of mid-2019, the U.S. National Institute of Allergy and Infectious Diseases (Dr. A. Fauci, director) considered DNA & RNA vaccines to be "investigational".
In mid-2021, there were no DNA vaccines approved for human use, but trials were ongoing for HIV, West Nile, and Zika viruses.
However, Zydus Cadila, India, received approval for phase III trials for a DNA COVID-19 vaccine, ZyCOV-D.

COVID-19 Vaccines

As of November 2021, there are over 20 COVID-19 vaccines in use around the world, with over 100 more under development and in various stages of clinical trials.

Very few have been "Approved" for use unconditionally, and only then by specific health authorities. The majority are being used under an "Emergency Use Athorization" (EUA), i.e. lack full approval usually required for vaccine use.
Some have been authorized on the basis of "real world data", in distinction to data from controlled human trials.

All but a handful of the W.H.O.'s 194 member countries have at least one authorized COVID-19 vaccine.

The extent to which these vaccines were evaluated in laboratory or animal studies is difficult (for this author) to establish. Human clinical trials are stll in progress.
The dosing schedules and real world effectiveness of these vaccines is being updated frequently. Also, trials are under may to "mix and match" the different vaccines for 1st and 2nd doses.
Adverse events including deaths have been reported following injection of all COVID-19 vaccines but causality has yet to be established.

Since the genetic identification of the SARS-CoV-2 virus in early 2020, mutations to the gene sequence of the spike protein are creating variants .
The effectiveness of each COVID-19 vaccine against each variant is still under intense investigation.

BNT162b2 also known as Comirnaty by Pfizer & BioNTech is a mRNA vaccine. It was initially claimed to be over 90% effective in preventing serious illness; however one limited study in the U.K. found effectiveness dropped to 48% 6 months after the second dose.
It requires storage and transportation at sub-zero temperatures.
It received full approval for use in the USA in August 2021, and in Canada as of mid-September 2021. It requires two doses 21 days apart (although some jurisdictions, in the absence of trial data, have extended this to 4 months).

Pfizer is a multinational pharmaceutical company based in the USA.
BioNTech is a biotechnology company based in Germany; it was founded in 2008, primarily to develop anti-cancer vaccines and partnered with Pfizer in 2018.
BioNtech began development of its COVID-19 vaccine in January 2020.

"No one should take this vaccine if they are allergic to any of its ingredients", which are: lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-Distearoyl-sn-glycero-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose. (Seriously!)

mRNA-1273 also known as SpikeVax by Moderna, Mass., USA is a mRNA vaccine which is claimed to be 95% efficacious.
It requires storage and transportation at normal fridge temperatures.
As of November 2021, it is operating under EUA status in most countries where available. In the USA, full approval is pending further assessment of the risk of cardiac side effects.
It requires two doses 4 weeks apart (although some jurisdictions, in the absence of trial data, have extended this to 4 months).

Moderna is reportedly working on an "Omicron-specific booster", mRNA-1273.529. Whether this is different enough to warrant separate authorization is unclear.

Moderna is a biotechnology company based in Massachusettes; it was founded in 2010 to create mRNA-based treatment for non-infectious diseases.

No one should take the Moderna vaccine(s) if they are allergic to any of its ingredients, which are: lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose.

AZD1222 , also known as ChAdOx1-S , by AstraZeneca/Vaccitech/Oxford University(U.K.) is a viral-vector vaccine which is claimed to be 62% to 90% efficacious; uncertainty remains about the best dosing protocol, but is generally recommended as two doses 8 to 12 weeks apart.
It's first real-world use (i.e. following trials) was in January 2021.
The vector is an adenovirus isolated from chimpanzees, which (hopefully) few humans have previously been exposed to. However, early trials showed better efficacy when the first dose was only half strength, possibly due to the vector creating immunity against itself on the first dose.

AstraZeneca is based in the U.K., with facilities worldwide. The vaccine is manufactured by AstraZeneca (under the brand name Vaxzevria) and the Serum Institute of India (under the brand name Covishield).

On pre-vaccination screening, you will likely be asked if you are allergic to any of its ingredients, which are: disodium edetate dihydrate (EDTA), ethanol, L-histidine, L-histidine hydrochloride monohydrate, magnesium chloride hexahydrate, polysorbate 80, sodium chloride, and sucrose.

Nuvaxoid NVX-CoV2373 (previously known as NVX-CoV2373 and COVOVAX), by Novovax, Maryland, USA, is described as a recombinant vaccine using virus-like particle and nanoparticle technology.
It has also been referred to as a "protein-based" and "sub-unit" vaccine; essentially the same, familiar, technology as existing vaccines for Hepatitis B, Shingles, Human Papilloma Virus, Meningitis B, Influenza, and Pneumococcus (PPSV-23).
As of August 2021, phase III trials were in progress, using two doses six months apart.
Earlier trials showed high levels of antibodies against the alpha, beta, and delta variants.
NVX-CoV2373 is expected to require normal cold chain storage of 2 to 8 degrees celcius.

It has been authorized for use in USA, Canada (as of February 2022) and several countries in western Europe.
The vaccine was initially manufactured in India; as of early 2022 it is being manufactured in the USA, with a facility under construction in Montreal, Canada.

Novovax has also begun trials on a combined COVID-19/Influenza vaccine.

JNJ-78436735 also known as Ad26.COV2.S by Jannsen, is a viral-vector vaccine which is claimed to be 65% to 80% efficacious after the single recommended dose.
The vector is a human adenovirus; the vaccine can be stored at normal fridge temperatures.

Janssen is a pharmaceutical company founded in 1953, and acquired by of Johnson & Johnson in the early 1960s.

No one should take this vaccine if they are allergic to any of its ingredients, which are: citric acid monohydrate, trisodium citrate dihydrate, ethanol, 2-hydroxypropyl-β-cyclodextrin (HBCD), polysorbate-80, sodium chloride, and hydrochloric acid.

SputnikV by Gamaleya Research Institute in Moscow, is a viral-vector vaccine which is claimed to be 95% effective.
It requires two doses 3 weeks apart.
This vaccine uses a human adenovirus as the vector(s), but different "serotypes" for the 1st and 2nd dose to overcome possible immunity to the serotype of the first dose.
It has been authorized for use in Russia, and several other countries in eastern Europe and Asia.
Sputnik Light is an alternate name for the 1st dose of SputnikV; it is easier and cheaper to produce, facilitating distribution to developing ountries.

ZyCoV-D by Zyduz Cadila, India is a DNA vaccine which is claimed to have 100% efficacy in preventing moderate disease and death.
It requires three doses, but the dosing schedule is still to be established. ZyCov-D is stable at room temperature.
This vaccine is based on "plasmid" DNA, which is DNA in the shape of a circle vs. the traditional helix. (Plasmids are most commonly found in bacteria and have a variety of uses.)
An initial description of ZyCoV-D states that after injection, it is taken up by various human cells where it enters the nucleus, but without combining with the human cell DNA.
As of November 2021, ZyCoV-D was being administered under an EUA from the Indian government.

AKS-452 by Massachusetts-based Akston Biosciences Corporation is a protein subunit vaccine, i.e. using a more established technology than the mRNA and viral vector vaccines first used during the COVID-19 pandemic.
Initial trials showed extremely high antibody levels.
As of November 2021, phase II trials were ongoing, with both one-dose and two-dose schedules being evaluated.
AKS-452 is stable at room temperature for many months; it is easy and cheap to produce in high quantities .
Most significant, AKS-452 targets a part of the CoV-2 spike protein which remains essentially the same across all known variants.

VLA2001 by Valneva SE of France is a whole virus Inactivated vaccine, i.e. uses a more established technology than the mRNA and viral vector vaccines first used during the COVID-19 pandemic.
In November 2021, phase III trials had reported favourable immune response compared to AstraZeneca's AZD1222 vaccine; in June 2022, it was authorized for use throughout the EU for ages 18 to 50..
VLA2001 is expected to require normal cold chain storage of 2 to 8 degrees celcius.

Other vaccines in various stages of trials and authorization include:

UB-612 by Vaxxinity Inc, Texas, USA is a multi-epitope protein subunit vaccine.
Ad5-nCoV by CanSino Biologics, Wuhan,China, is a viral-vector vaccine,
CoronaVac by Sinovac, China is an Inactivated vaccine,
BBIBP-CorV by Sinopharm , China is an Inactivated vaccine,
Covaxin by Bharat Biotech, India is an Inactivated vaccine,
bacTRL-Spike by Symvivo, Canada, is a DNA vaccine, taken orally.
Covifenz(previously CoVLP) by Medicago, Canada, is a "recombinant Coronavirus Virus-Like Particle vaccine", described as using "proven plant based technology".
Medicago is a private Quebec-based company in business since 1997; it has a single investor, the Government of Canada. In Februrary 2022, it was authorized for use in Canada.

Mix and Match Strategies
Some jurisdictions (for a variety of health, logistical, or political considerations) are allowing the use of different COVID-19 vaccines for the first and subsequent booster doses.
It should be noted that different vaccines elicit different immune reponses in terms of antibody levels, antibody structure, antibody longevity, and probably overall adaptive immunity. Even the mRNA vaccines are different from each other, as illustrated by the different adverse effects.
Whether these different responses are additive, or alternatively fall short of the response when the same vaccine is used for both/all doses, is still to be determined.

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