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            Enteric fever is
one of the leading causes of illness and death globally. Typhoid fever, which
falls under the category of enteric fever, is an important cause of illness and
death around the world. Typhoid fever is common in most parts of the world
except in industrialized regions such as the United States, Canada, Japan, and
other countries. It is endemic in Africa and Asia. It is also very common in
the Middle East, a few Southern and Eastern European countries, and Central and
South America (WHO…2015). The Centers for Disease Control and Prevention
estimates that typhoid fever affects 21.5 million people globally each year
(CDC…cc2013-2016). Typhoid fever accounted for 225,000 deaths in 2015. About
5,700 cases occur in the United States annually, and most cases are acquired
from international travel (CDC…cc2013-2016). Typhoid fever accounts for about
1% of mortality in both men and women around the world, with the heaviest
burden in developing countries where there is poorer sanitation and hygiene
(Loranzo et al. 2012). Developing nations share the highest burden of typhoid
fever also due to rapid population growth and increased urbanization. Children
in particular are more vulnerable, as severe typhoid is very common below 2
years of age in developing countries (Loranzo et al. 2012). The case–fatality
rate in children under 5 years is higher than school aged children and
adolescents, and is highest in Sub-Saharan Africa and North Africa/Middle East

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As such, addressing
typhoid fever on a public health level should focus on improving sanitation,
mitigating the effects of population growth, and preventing infection in young
children. While this paper will mainly discuss public health approaches to
prevention and control of typhoid, vaccination against the pathogen is an
interesting facet of the efforts to treat the susceptible. This is one of the
more promising areas of research for preventing typhoid infection in children
in developing countries. Currently there are only two licensed vaccines, but
many more are being developed, especially with concurrent discoveries that
answer some of the oldest questions about typhoid. Typhoid being similar to
other illnesses is also helpful in research and development. Typhoid is an area
of abundant research, and as such cutting edge research surrounding vaccination
against typhoid is an important innovation in regards to prevention and control
of the disease.

Cause of the disease and Biology

The agent in typhoid
fever is Salmonella enterica typhi, an obligate, rod-shaped, aerobic,
Gram-negative bacterium (Sabbagh et al. 2012). Typhoid is a problem mainly due
to poor sanitation and unsafe food and water sources. S. typhi uses
humans as hosts and is able to survive in water and food for long periods of
time. Specifically, S. typhi invades macrophages to cause systemic
infection. When it enters the human body by ingestion, secretes an endotoxin
typical of Gram-negative bacteria, as well as the Vi capsular antigen once the
pathogen enters the small intestine, increasing the pathogen’s virulence (Tran
et al. 2009). The etiology of this virulence increase is currently unknown. In
addition, S. typhi produces and secretes a protein called invasin, which
promotes the entry of the pathogen into the cell it is going to survive in.

Invasin from S. typhi is also able to inhibit the oxidative burst of
leukocytes, inactivating the innate immune response (Winter et al. 2014). These
characteristics make the agent itself very effective at infecting the host and
causing disease.

Once ingested, S.

typhi multiply in the small intestine over a period of 1-3 weeks,
infiltrate the intestinal wall, and then spread to other organ systems and
tissues via the blood. As mentioned before, the innate host defenses do little
to prevent infection due to the inhibition of oxidative lysis and the
pathogen’s ability to grow intracellularly after uptake (Winter et al. 2014).

Typhoid fever is part of a range of enteric fevers. It is difficult to
differentiate between typhoid fever and other febrile illnesses from clinical
manifestations alone. Typhoid is characterized by broad, nonspecific symptoms
in the gastrointestinal system. Symptoms include lasting high fevers, weakness,
stomach pains, headache, and loss of appetite. Some less common symptoms are
constipation and rash. Internal bleeding and death can occur (Kovalenko et al.

2011). As a result, people who contract the disease take antibiotics such as
azithromycin, fluoroquinolones, or third generation cephalosporins (SOURCE).

The most common source
of infection is drinking water contaminated with urine and feces of infected
individuals. Poor hygiene of patients shedding the organism can lead to
secondary infection, as well as consumption of shellfish from polluted bodies
of water. Transmission of S. typhi has only been shown to occur by
fecal-oral route, often from asymptomatic individuals. A small percentage of
previously infected individuals become chronic carriers who show no signs of
disease, but are highly capable of infecting others (Eisele et al. 2013). One
of the most famous examples is Mary Mallon (known as “Typhoid Mary”), who was a
cook in the 1900s responsible for infecting at least 25 people and killing 3
(Marineli et al. 2013). These highly infectious carriers pose a great public
health hazard due to their lack of disease manifestation, and as such more
research is needed on these individuals to truly understand the etiology of
typhoid fever.

Approaches to prevention and control

The key to avoiding
infection by S. typhi is prevention of fecal contamination in drinking
water and food supplies. There is less incidence of typhoid fever in industrial
nations due to better sanitation, and places that have improved sanitation have
shown a sharp decrease in typhoid mortality (Clasen et al. 2014).  After
the introduction of treatment to municipality waste water, pasteurization of
milk and other products, and safe handling of human feces, the rate of
occurrence of enteric fever has dropped severely in these communities. Since the
only source of this agent is infected humans, it is possible to control
transmission by proper hygiene, waste management, water purification, and
treatment of the sick. Therefore, sanitation is still the hallmark of
preventing typhoid fever.

Antibiotics are very
important for treating infected individuals. The introduction of
chloramphenicol (in 1948), ampicillin (1961), co-trimoxazole (1970s), and
third-generation cephalosporins and fluoroquinolones (1980s) reduced the
mortality of typhoid fever considerably. Cephalosporin resistance has been
slower to develop, but it is on the rise. Azithromycin is increasingly given
for enteric fever, but is mainly used to treat children and patients with
multidrug-resistant enteric fever because of its cost (Kaurthe 2013).

Antibiotic resistance has made treatment of typhoid fever more difficult, and
if cephalosporin resistance is finally incurred then it is a large detriment to
how typhoid fever is currently controlled and poses a large risk of mortality.

This further reiterates the importance of prevention.

Vaccination is then an
important and rapidly developing control of typhoid fever. There are currently
only two licensed vaccines are available, one orally administered
live-attenuated Ty21a (galE mutant, licensed in 56 countries of Asia, Africa,
USA and Europe) and the other parenterally administered Vi-polysaccharide
subunit (Vi-PS) vaccine. Ty21a is the most cost-effective option of the two and
provides long-term protection, but since it is a live-attenuated vaccine there
is always the chance of it reverting back to its wild-type highly virulent
form. Vi-PS provides moderate to long-term protection and is very effective due
to its injection intramuscularly. However, both licensed vaccines are not
recommended for young children, alienating the population most susceptible to
typhoid fever. The WHO recommends the currently licensed typhoid vaccines for
those at high risk or people traveling to areas where the disease is common.

Proposed Solutions

            Typhoid is unique
in that it can be spread at devastating levels by asymptomatic carriers. These
carriers have the pathogen but are not in a diseased state; this has remained
mystery in epidemiology since the time of Mary Mallon. It was only in 2013 that
researchers elucidated a molecular path to long-term intracellular bacterial
survival in M2 macrophages (Eisele et al. 2013). In addition, identification
for chronic carriage in individuals is challenging and inefficient (Gilman et
al. 1979). This implies that there is a need for continued research into the
etiology of the disease in order to develop vaccination and other medication
for treatment. Understanding the molecular mechanism of the pathogen itself
will better help scientists develop vaccines to aid high risk individuals.

The currently licensed
vaccines are not effective enough to meet the needs of high risk individuals.

Thus, novel nonliving vaccines should be developed and encouraged. One example
of the research for typhoid vaccination is with bacterial Outer Membrane Vesicles
(OMVs), which can theoretically work at higher immunogenicity and protective
efficacy. Scientists have been working on OMVs for the past few decades. OMVs
are nano-spherical non-living compounds containing TLR2 and TLR4 agonists,
proteins and LPS, respectively among others. Because they act as an adjuvant
and an immunogen as well, no other adjuvants need to be added to increase their
effectiveness. This technique has already been used in developing vaccines for
other waterborne disease such as cholera (Chatterjee and Chaudhuri 2013).

Public health should pay attention to innovative vaccine research such as this
in order to assess cost, policy, and distribution.

            Overall, basic
science and public health researchers should work together to address typhoid
fever. There are copious amounts of research being conducted around typhoid
fever prevention and treatment. There should be a combination of prevention by
improved sanitation and hygiene, research, and developed therapies such as
antibiotics and vaccination. Typhoid fever rates have decreased in recent years
and can continue to decrease.