So, what is a vaccine?

A vaccine is defined as a biological preparation that resembles a particular disease-forming

microorganism, which when administered provides acquired immunity to the disease caused
by that microorganism. “On a global scale, vaccines represent one of the most successful and
cost-effective health, medical and veterinary, interventions ever” commented Professor of
Veterinary Clinical Microbiology, Anders Mikki Bojesen, of the Department of Veterinary
and Animal Sciences at the University of Copenhagen in Denmark. “Appropriate concerns
about antimicrobial resistance has sparked new life and funding into sciences aiming at
preventing infections rather than dealing with them when they appear using antibiotics”.

But when looking to tackle a pathogen with a vaccination strategy, where does one begin? It
may seem obvious but the key facilitator in developing an effective vaccine is having a
comprehensive understanding of the pathogen, how it interacts with and evades the hosts
immune system and then goes on to cause the disease. Whilst this sounds simple in principal
it can be, and usually is, a far more complex undertaking. “Whilst some toxin associated
diseases like tetanus and viruses like smallpox have been successfully controlled for decades
by vaccines, larger organisms like bacteria and parasites are antigenically much more
complex and hence have been much more difficult to handle by vaccination. Due to a deeper
insight into the pathogenesis of these organisms combined with novel ways of identifying
universal antigens (vaccine targets) and new knowledge about efficient immune responses,
we are now at the brim of a new era where also bacterial infections may be prevented in a
cost-effective manner” continued Professor Bojesen.

Choosing a type of vaccine

Once you understand your pathogen of choice (or at least think you have a vague idea) you
will have to decide on the type of vaccine best suited to confer the highest levels of
protection. There are a number of ways that you can modify a virulent microorganism to
make it both safe for use as a vaccine and still retain the ability to induce a protective immune
response to challenge. None of the methods are necessarily “better” than others and different
ones may well work as efficiently for the same pathogen. However the ease of design and
manufacture will ultimately determine the cost and how much the vaccine is used in reality.
So, what are some of the options in this constantly developing field of science?

1. Killed/inactivated - virulent organisms that have been deactivated in some way, such
as chemical or heat treatment. Examples include polio and hepatitis A.

2. Toxoid – a purified toxic component that causes the disease that has been inactivated,
often chemically or via the use of heat. Tetanus and botulism vaccines are good examples.

3. Live attenuated – live organisms that have been disabled in some manor (via gene
mutation or deletion – be it naturally through passaging or by genetic/chemical engineering)
that makes them none pathogenic, for example yellow fever, tuberculosis (TB), MMR and
Salmonella typhi.
4. Protein subunit – purified proteins of a microorganism are used to generate a
productive immune response, for example some influenza vaccines. New vaccines using
recombinant expression of components in Escherichia coli are currently in development.

5. DNA – insertion of DNA into vaccinated individuals that is capable of expressing a

component of the infectious microorganism and inducing a productive immune response.

6. Conjugate carbohydrate – normally contains a carbohydrate expressed on the

surface of a microorganism that is used to produce immunity, linked to an adjuvant like
cholera toxin. Examples are the vaccines to prevent infection with Streptococcus
pneumoniae.

Please be aware that transient adverse reactions like pyrexia and injection site discomfort are
not necessarily bad. Indeed they are suggesting that the immune system of the vaccinated
individual is responding to the vaccine and may well be generating a protective response that
could prevent disease in the future. Does anyone remember the TB vaccine at school? What
do you want, a pusy painful arm that your best mate decides to punch for fun or a slow,
lingering death from a virtually untreatable infection with multi-drug resistant
Mycobacterium tuberculosis? I know which I would choose without any hesitation.

In addition to the actual protective components, an adjuvant may be added to a vaccine

formulation which helps to stimulate the appropriate immune response in the individual being
vaccinated. One example of a simple adjuvant is aluminum hydroxide which can be applied
to most vaccine types. However, the science behind adjuvant technology is as fast developing
as vaccine design and there is a plethora of adjuvants available that stimulate the immune
system in different ways to generate a productive immune response.

Whichever you chose, one of the most important current considerations in vaccinology is the
ability to differentiate a vaccinated individual from a naturally infected one - so called DIVA
capability. The concept was first developed by J.T. van Oirschot et al. in Holland for the
prevention of pseudorabies in pigs. Generally, the concept is that the diagnostic tests that are
available to diagnose the disease are not compromised by the vaccines available so that
vaccines can be used in the presence of virulent pathogens without hindering their
eradication.

What should you look for in a vaccine target?

When selecting a vaccine target, there are multiple aspects that must be considered in
choosing a candidate, or candidates, including coverage, efficacy, feasibility and the type of
vaccine being developed. It needs to be conserved across the majority of strains in order to
cover as much of the pathogen’s population (or at least the strains that cause issues) as
possible, be immunogenic so you mount a response to it, stable in the population so the bugs
don’t just lose it in response to immunity in the host population and seen by the immune
system when it’s in its native form in the pathogen.
One final consideration is choosing the route of vaccination, i.e. intra-nasal vs subcutaneous
vs intramuscular vs oral. Where a mucosal immune response is found to improve protection,
vaccination may be given into a mucous membrane, such as the lip. However, it is worth
bearing in mind not only which route is most effective, but also the age group or species to
which the vaccine is being designed for as to what is a viable route of administration.

Is that the end?

So you have a vaccine, champagne corks pop and you save thousands of lives. In the case of
some biological agents this seems to be true. One such example is the 17D vaccine developed
to prevent infection with the yellow fever virus which seems to afford protection against all
of the known circulating strains of virus and may provide lifelong protection. This is however
not the case for influenza in many host species. “Although vaccines exist for equine influenza
they need to be updated regularly because influenza viruses undergo antigenic drift
[hyperlink to drift vs shift article]. This is caused by a gradual accumulation of mutations in
the hemagglutinin (HA) protein which alters its appearance and so helps the virus avoid
immunity acquired from previous infection or vaccination. Surveillance is needed to monitor
these changes, and their effects, so that vaccine strain recommendations can be updated in a
timely manner. The same is also true for human influenza vaccines” states Dr. Adam Rash,
Post-doctoral Scientist in the equine influenza surveillance team based at the Animal Health
Trust in Newmarket, England.

Concluding thoughts

It is an expensive an often-time-consuming process but someone has to put the work in.
“Governments should fuel prevention against infections to a much larger extend as a market
driven approach is likely superseded by the increasing presence of resistant bacteria with
devastating potentials” concludes Professor Bojesen.
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How are vaccines
developed?
What are the ingredients in a vaccine?
Vaccines contain tiny fragments of the disease-causing organism or the blueprints
for making the tiny fragments. They also contain other ingredients to keep the
vaccine safe and effective. These latter ingredients are included in most vaccines
and have been used for decades in billions of doses of vaccine.

Each vaccine component serves a specific purpose, and each ingredient is tested in
the manufacturing process. All ingredients are tested for safety.

Antigen

All vaccines contain an active component (the antigen) which generates an immune
response, or the blueprint for making the active component. The antigen may be a
small part of the disease-causing organism, like a protein or sugar, or it may be the
whole organism in a weakened or inactive form.

Preservatives
Preservatives prevent the vaccine from becoming contaminated once the vial has
been opened, if it will be used for vaccinating more than one person. Some vaccines
don’t have preservatives because they are stored in one-dose vials and are
discarded after the single dose is administered. The most commonly used
preservative is 2-phenoxyethanol. It has been used for many years in a number of
vaccines, is used in a range of baby care products and is safe for use in vaccines, as
it has little toxicity in humans.

Stabilizers

Stabilizers prevent chemical reactions from occurring within the vaccine and keep
the vaccine components from sticking to the vaccine vial.

Stabilizers can be sugars (lactose, sucrose), amino acids (glycine), gelatin, and
proteins (recombinant human albumin, derived from yeast).

Surfactants

Surfactants keep all the ingredients in the vaccine blended together. They prevent
settling and clumping of elements that are in the liquid form of the vaccine. They are
also often used in foods like ice cream.

Residuals

Residuals are tiny amounts of various substances used during manufacturing or

production of vaccines that are not active ingredients in the completed vaccine.
Substances will vary depending on the manufacturing process used and may include
egg proteins, yeast or antibiotics. Residual traces of these substances which may be
present in a vaccine are in such small quantities that they need to be measured as
parts per million or parts per billion.

Diluent

A diluent is a liquid used to dilute a vaccine to the correct concentration immediately

prior to use. The most commonly used diluent is sterile water.

Adjuvant

Some vaccines also contain adjuvants. An adjuvant improves the immune response
to the vaccine, sometimes by keeping the vaccine at the injection site for a little
longer or by stimulating local immune cells.

The adjuvant may be a tiny amount of aluminium salts (like aluminium phosphate,
aluminium hydroxide or potassium aluminium sulphate). Aluminium has been shown
not to cause any long-term health problems, and humans ingest aluminium regularly
through eating and drinking.

How are vaccines developed?

Most vaccines have been in use for decades, with millions of people receiving them
safely every year. As with all medicines, every vaccine must go through extensive
and rigorous testing to ensure it is safe before it can be introduced in a country’s
vaccine programme.

Each vaccine under development must first undergo screenings and evaluations to
determine which antigen should be used to invoke an immune response. This
preclinical phase is done without testing on humans. An experimental vaccine is first
tested in animals to evaluate its safety and potential to prevent disease.

If the vaccine triggers an immune response, it is then tested in human clinical trials in
three phases.

Phase 1

The vaccine is given to a small number of volunteers to assess its safety, confirm it
generates an immune response, and determine the right dosage. Generally in this
phase vaccines are tested in young, healthy adult volunteers.
Phase 2

The vaccine is then given to several hundred volunteers to further assess its safety
and ability to generate an immune response. Participants in this phase have the
same characteristics (such as age, sex) as the people for whom the vaccine is
intended. There are usually multiple trials in this phase to evaluate various age
groups and different formulations of the vaccine. A group that did not get the vaccine
is usually included in phase as a comparator group to determine whether the
changes in the vaccinated group are attributed to the vaccine, or have happened by
chance.

Phase 3

The vaccine is next given to thousands of volunteers – and compared to a similar

group of people who didn’t get the vaccine, but received a comparator product – to
determine if the vaccine is effective against the disease it is designed to protect
against and to study its safety in a mu,ch larger group of people. Most of the time
phase three trials are conducted across multiple countries and multiple sites within a
country to assure the findings of the vaccine performance apply to many different
populations.

During phase two and phase three trials, the volunteers and the scientists
conducting the study are shielded from knowing which volunteers had received the
vaccine being tested or the comparator product. This is called “blinding” and is
necessary to assure that neither the volunteers nor the scientists are influenced in
their assessment of safety or effectiveness by knowing who got which product. After
the trial is over and all the results are finalized, the volunteers and the trial scientists
are informed who received the vaccine and who received the comparator.
When the results of all these clinical trials are available, a series of steps is required,
including reviews of efficacy and safety for regulatory and public health policy
approvals. Officials in each country closely review the study data and decide whether
to authorize the vaccine for use. A vaccine must be proven to be safe and effective
across a broad population before it will be approved and introduced into a national
immunization programme. The bar for vaccine safety and efficacy is extremely high,
recognizing that vaccines are given to people who are otherwise healthy and
specifically free from the illness.

Further monitoring takes place in an ongoing way after the vaccine is introduced.
There are systems to monitor the safety and effectiveness of all vaccines. This
enables scientists to keep track of vaccine impact and safety even as they are used
in a large number of people, over a long time frame. These data are used to adjust
the policies for vaccine use to optimize their impact, and they also allow the vaccine
to be safely tracked throughout its use.

**Vaccine Design:**

1. **Identification of Antigen:**
 - The first step in vaccine design is identifying the antigen, a substance that
triggers an immune response. This could be a weakened or inactivated form of the
pathogen, a protein, or genetic material.

2. **Antigen Characterization:**

- The selected antigen undergoes detailed characterization to ensure its safety and
efficacy. Scientists analyze its structure, function, and how it interacts with the
immune system.

3. **Selection of Adjuvants:**

- Adjuvants are substances added to vaccines to enhance the immune response.

They help stimulate a stronger and longer-lasting immune reaction to the antigen.

4. **Vaccine Platform:**

- Choosing the right vaccine platform is crucial. This could be live attenuated
vaccines, inactivated vaccines, subunit, conjugate, or mRNA vaccines, each with its
own advantages and limitations.

5. **Preclinical Testing:**

- In the preclinical phase, the vaccine is tested in the laboratory and on animals to
assess its safety, immunogenicity, and efficacy before advancing to clinical trials.

**Vaccine Production:**

1. **Cultivation of the Pathogen or Antigen Production:**

 - Depending on the type of vaccine, the pathogen is cultured and then inactivated
or weakened, or the antigen is produced through genetic engineering or other
methods.

2. **Purification:**

- The obtained material goes through purification processes to remove impurities

and ensure a highly concentrated and pure antigen.

3. **Formulation:**

- The purified antigen is combined with adjuvants and other components to create
the final vaccine formulation. This step aims to enhance the stability and
effectiveness of the vaccine.

4. **Fill and Finish:**

- The formulated vaccine is filled into vials or syringes in a controlled environment

to maintain sterility. This process is crucial to prevent contamination.

5. **Quality Control:**

- Rigorous quality control tests are conducted at various stages to ensure the
vaccine meets safety and potency standards. This includes testing for purity,
potency, and absence of contaminants.

6. **Batch Release:**

- Before distribution, each batch of the vaccine undergoes final testing and
approval by regulatory authorities.
**Vaccine Administration:**

1. **Vaccination Schedule:**

- Vaccines are administered according to a specific schedule, often involving

multiple doses to prime the immune system and provide long-lasting protection.

2. **Route of Administration:**

- Vaccines can be administered through different routes, such as intramuscular,

subcutaneous, or oral, depending on the type of vaccine and the targeted immune
response.

3. **Cold Chain Management:**

- Maintaining the cold chain is crucial to preserving vaccine potency. Vaccines are
stored and transported at controlled temperatures to prevent degradation.

4. **Monitoring and Surveillance:**

- Post-vaccination, monitoring and surveillance systems are in place to track

adverse events, assess vaccine effectiveness, and ensure the ongoing safety of the
population.

5. **Record Keeping:**

- Accurate record-keeping is essential to track the vaccination status of individuals

and populations, ensuring timely booster doses and managing potential outbreaks.
In summary, vaccine design, production, and administration involve a
comprehensive and systematic approach, encompassing scientific research,
rigorous testing, and stringent quality control measures to ensure the safety and
efficacy of vaccines in preventing infectious diseases.