Control of Infectious Diseases

Research Project Dylan Adlard

The Oxford Dictionary of Biology states that a vaccine is a liquid preparation of treated
disease-producing microorganisms or their products used to stimulate an immune response
in the body and so confer resistance to the disease 1. Vaccination is artificial active immunity,
which confers resistance to that disease over a long-term period. Artificial passive immunity
on the other hand occurs when a person is injected with antitoxin, a preparation of foreign
human antibodies against the toxin. Immediate protection is provided, but it is often
temporary as the antibodies are not produced by the bodys own B cells and are eventually
removed from circulation 2. Natural immunity is always achieved through normal life
processes inside the hosts body. Passive natural immunity is provided to a baby through the
mothers placenta and breast milk, thus giving the baby time to fully develop its immune
system 5.

In both artificial and natural

active immunity, the
antibody concentrations in
the blood follow similar
patterns to those shown in
figure 1 2. Once the immune
system has been activated by
the antigens, antibodies and
memory cells are
manufactured. The antigenic
material in vaccines can be
either live microorganisms
with very similar antigens to
those of the disease causing
agent, a dead pathogen
(often a bacterium such as in
Figure 1: Changes in antibody concentration in blood during
primary and secondary response to the same antigen 3
the cholera vaccine 4), an
attenuated pathogenic
organism, a preparation of antigens from the disease causing pathogen, or a harmless version
of a toxin known as a toxoid 5. Live attenuated vaccines, however, usually induce a longer
lasting immunity than killed preparation, as they briefly grow in the body. Yet, there are
certain problems with this method and pregnant women cannot be vaccinated in this way 6.

The first vaccine was created by Edward Jenner against the smallpox virus, variola. A young
boy was given cowpox (a relatively harmless virus) from a milkmaid who had been infected
by a cow. The boy then conferred resistance against smallpox as the two viruses genetic
material is 95% identical to one another6. In 1967, the WHO stated its intentions to rid the
world of the disease within ten years. When a case of smallpox was reported, everyone in the
household, as well as the 30 surrounding households, were vaccinated. This method is known
as ring vaccination, and is also used to control the spread of livestock disease2.
Similarly, to ring vaccination, herd vaccination also provides vaccines to a large number of
people, however this method vaccinates the entire population at risk 5. Herd immunity
interrupts transmission in a population, so that those who are susceptible never encounter
the infectious agents concerned. Roughly 95% of a population, for example, would need to
be immunized to prevent the transmission of measles in that population. The basic
reproduction number (R0) of an infection is the average number of further cases one infection
in one victim by a pathogen causes 4. If R0 < 1, the infection will die out due to unsustainable
transmission between hosts. Therefore, in the example of measles, a 95% immunized
population is required to reduce R0 below one.

However, once a disease has been eradicated, the routine vaccination program is calmed 5.
Problems arise when the pathogen was not fully eradicated, and at a later stage bounces back
with mutations that render the bodys memory cells helpless as they do not recognize the
pathogens new antigens. This can cause an increase in the incidence and transmission of the
disease. An epidemic is defined as an outbreak of a disease (especially an infectious disease)
that affects a large number of individuals within a population at the same time 1. Pathogens
such as the influenza virus regularly undergo antigenic changes. When these changes are
minor, they are known as antigenic drift, and memory cells will still recognize them and start
a secondary response. Problems arise when antigenic shift occurs, and the viral antigens
mutate considerably and the protective immunity given by vaccination against a previous
strain is ineffective against the new one 2. This can lead to an epidemic. However, vaccination
programs continue in the UK, specifically directed to those above the age of 65. Furthermore,
rhinoviruses that cause the common cold have huge antigenic variation, with over 100
different strains, making it almost impossible to develop a vaccine that protects against all
strains.

Diseases caused by protoctists, such as malaria (the parasite being plasmodium), currently
have no effective vaccines. These pathogens are eukaryotes, therefore having significantly
more genes than bacteria and viruses. This allows them to have thousands of antigens on
their cell surfaces, and plasmodium for example, passes through three stages in its lifecycle
whilst in a human host, each with its own specific antigens 2. Another problem with vaccines
comes with the ability some pathogens have to evade either recognition or attack by the
immune system. Vibrio cholerae, for example, remains in the intestine walls where it is
beyond reach of many antibodies, whilst certain flaviviruses disrupt signal transduction
pathways within macrophages and dendritic cells.

Vaccinations are not, however, the only form of treatment or prevention used against a
disease. Whilst vaccines are given to the patient to prevent them contracting a disease,
medicines are generally administered whilst the patient is already sick, to help flush out the
pathogen. The first antibiotic to be discovered was penicillin from the fungus penicillium
notatum by Alexander Fleming in 1928, which was purified by Howard Florey ten years later.
Fleming was working on Staphylococcus, and after a period of leave from his lab, he returned
to find one of the agar plates covered in fungus. In the areas surrounding the mould, there
was a distinct lack of bacteria growth. After further research, it became apparent that
penicillin killed bacteria, whilst leaving human cells alive. Mass production of penicillin
commenced in 1944, saving the lives of many Second World War victims with infected
wounds 6.

Antibiotics interfere with either the synthesis of the bacterial cell wall, the plasma
membranes proteins, enzyme action, DNA synthesis or protein synthesis. Penicillin inhibits
an enzyme in the cell wall of the bacteria, preventing the synthesis of the cross-links between
peptidoglycan polymers. As bacteria grows, autolysins (a type of enzyme) are secreted to
make small holes in the cell wall in order for it to stretch and allow peptidoglycan chains to
link. However, as penicillin prevents the linking, and autolysins keep making new holes, water
diffuses into the cell. The weakened cell wall cannot withstand the pressure exerted on it by
the cell contents, and the bacterium cytolyses 2.

Certain bacteria are only susceptible to specific antibiotics, however, bacteria have the
potential to develop resistance if a genetic mutation occurs, and for example, a new protein
is coded that protects the cell from the antibiotic 5, or if they acquire the genes from other
bacteria via plasmids (horizontal transmission). Furthermore, bacteria can double their
numbers every twenty minutes, allowing a great chance of resistant mutants to appear, thus
giving the bacteria a selective advantage 6. This is especially true when the patient does not
follow the correct dosage prescribed to them and stops the treatment early because they feel
cured. The few resistant bacteria now have the opportunity to explode in numbers 2. With the
widespread use (and abuse) of antibiotics, pathogens such as M. tuberculosis, salmonella, and
staphylococcus now show multidrug resistance. Many pathogenic bacteria that have become
resistant to penicillin have acquired genes that code for an enzyme called beta-lactamase,
which has the ability to break down the structure of the antibiotic 7. Additionally, bacteria
have a single of loop of DNA, therefore having only one copy of each gene, thus allowing a
mutant gene to have an immediate effect on the bacterium holding it. The bacterium will
reproduce via vertical transmission 2 and quickly confer resistance to the majority of the
bacteria population. As the misuse of antibiotics continue, and the scarcity of new
antimicrobial drugs remains constant, the use of remaining effective antibiotics increase,
ultimately too reducing their efficacy 8.

An even greater problem arises when bacteria living where there is widespread use of
antibiotics, have plasmids carrying resistance genes against several different antibiotics, thus
leading to multiple resistance. Methicillin-resistant Staphylococcus aureus (MRSA), for
example, has become a major problem in both hospitals around the world and prisons in the
USA. The infection usually ascends after a surgery, which were controlled by the antibiotic
vancomycin when all other treatments against infection failed. However, Enterococcus
faecalis, another bacterium common in hospitals, developed resistance to the antibiotic and
passed this resistance to S. aureus. Currently, carbapens are used as a last resort against
bacteria with multiple resistance, however certain bacteria, such as Klebsiella pneumoniae,
have lately developed resistance to this as well. Another bacterium, Clostridium difficile, also
has multiple resistance against antibiotics. The patient suffers from severe diarrhea, and like
MRSA, often infects those who have been recently hospitalized. The pathogen has not yet
developed resistance to antibiotics used to directly treat the disease, but it is resistant to
many other antibiotics that are used to treat other infections, such as fluoroquinolone
antibiotics 9. Presently, it is crucial antibiotics are chosen carefully, following thorough testing
of resistance the bacterial strain may have towards certain antibiotics. Although bacteria
seem to develop resistance to antibiotics as quickly as new ones are developed, antibiotics
with slightly altered chemical structures may be effective against a bacterial strain the original
antibiotic is not 2, 5.

Although penicillin was the first antibiotic to be discovered, traditional medicine derived from
plants and trees have been used for thousands of years. Neem tree leaves, for example,
secrete an oil that inhibits the growth of numerous species of fungi, preventing several
diseases in humans and crops 10. The plant Artemisia annua, or sweet wormwood, contains a
compound known as artemisinin, which rapidly reduces the number of plasmodium parasites
in the blood of uncomplicated malaria patients. The drug is usually taken with five other ATC
drugs, which altogether rid the body of the parasites. However, as of July 2016, five countries
of the Greater Mekong sub region have reported cases of artemisinin resistance, which
provides a major risk to other malaria endemic countries 11. Artemisinin is not the only
antimalarial derived from plants though, and quinine, an alkaloid isolated from the bark of
the cinchona tree, was used by the Quechua people in Peru before being discovered by the
Spanish in the 1600s. The drug works by preventing crystallization of heme (toxic to
plasmodium) in haemoglobin, meaning the parasites die before inflicting too much damage
to the body. Unfortunately, plasmodium has developed resistance to quinine, and it is no
longer in use 12.

Furthermore, opium is extracted from unripe poppy plants and has been used for hundreds
of years as an anaesthetic. By the early 19th Century, morphine was discovered to be the
active ingredient in opium, and both drugs were taken to reduce nervous action in the central
nervous system 10, 5. Both aspirin and ibuprofen had their origins in willow-bark, which
contained an extract that relieved pain and fever, and once an acetyl group is added to its
active ingredient, the effects of stomach bleeding can be reduced 5. Many of the traditional
medicines that have now been enhanced into successful 21 st Century drugs, were found or
extracted from tropical plants due to their great diversity. One must therefore realise the
importance of maintaining a high level of biodiversity throughout the world, if not for simply
conservation, then for human and livestock health.

Pharmaceutical and biomedical companies are currently conducting research into the
methods microorganisms use to cause disease. The Nuffield Department Medicines Jan
Rehwinkel, for example, has been investigating the cell signalling transduction pathways used
to detect viruses, and the way in which both viruses block these signals and sometimes use
them to cause cell pathology. Furthermore, HIV binds to CCR5 and CD4 receptors on T helper
cell surfaces. Sequencing the glycoprotein receptor molecules allows a molecular model to
be determined. Then, a drug must be found or synthesised with a very similar shape of the
receptor and ultimately bind to and inhibit the action of the virus from entering the cell 5.

As sequencing technology improves, medical institutions will be able to cost effectively and
quickly sequence the genes from patients with certain conditions. Everyones genetic makeup
is slightly different from one another, but these differences are enough to make an impact on
the effectiveness of specific drugs administered to different patients 13. Personalised
medicine is the development of designer medicines for individuals 5, and will enable doctors
to provide better disease prevention, more accurate diagnoses, safer drug prescriptions and
more effective treatments.
Briefly mentioned earlier, synthetic biology too can have, and is having, a major impact on
novel medicine production. Synthetic biology is the design and synthesis of biological
components and systems that do not already exist in the natural world, as well as the
redesign, and in some cases improvement in one way or another, of existing biological
components 14. The premise behind synthetic biology is to solve problems by creating new
models, rather than simply analysis and observation of what already exists. Originally,
synthetic biology referred to the genetic engineering of bacteria, and now also refers to the
development of new and artificial molecules that mimic natural molecules, such as enzymes.
For example, tomatoes are being developed that contain a pigment known as anthocyanin,
which is an antioxidant that also helps protect against coronary heart disease 5. With the
gradual improvements and research that surround synthetic biology and personalised
medicine, in the future we could hope for a complementary relationship between the two
that will overcome world health problems such as antibiotic resistance. All this is leading to
better control of infectious diseases.
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