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Systemic Infections

Bacterial Infections

1. Brucella
2. Anthrax
3. Yersinia Pestis
4. Lyme disease
5. Tularemia
Viral Infections
1. Yellow Fever
2. Dengue fever
3. Infectious Mononucleosis
4. AIDS
5. Ebola Fever
Protozoal Infections
1. Malaria
2. Sleeping Sickness
Helminthic Infections
1. Filariasis
2. Schistosomiasis




































Brucellosis

Common names
Contagious abortion, Bang's disease, In humans also called Undulant fever and often confused with
malaria or influenza


Brucellosis is a bacterial infection, caused by organisms belonging to the genus
Brucella
. The disease is prevalent in most countries of the world. It primarily affects cattle, buffalo, pigs, sheep,
goats, camels and dogs, and occasionally horses.
The disease in humans, sometimes called Undulant Fever, is a serious public health problem, especially
when caused by Brucella Melitensis.
Brucellosis in cattle is caused almost exclusively by Brucella abortus, although occasionally Brucella
melitensis or Brucella suis may be implicated. Melitensis occurs primarily in sheep and goats; suis in pigs.
Brucella canis is confined to dogs.
Cattle of all ages and sex can be infected with B. abortus,but it is primarily a disease of sexually mature
female cattle, with bulls and immature animals showing little or no clinical disease.


Spread to man
Man becomes infected when in direct contact with cows at abortion, calving or in
the post calving period.
Vets and stockhandlers are particularly at risk from the splashing of infected
droplets into the eye.
Handling of the afterbirth without wearing gloves is very dangerous. Afterbirth of
infected animals should be buried immediately and not handled directly by
anyone.
Infection occurs in people drinking unpasteursied milk or milk products.
Symptoms in humans include recurrent bouts of fever, headache, muscle and
joint pains and and general weakness. Women also abort. Brucellosis is often
confused with malaria and influenza. Diagnosis is done through a blood sample
taken by the doctor, and treatment is usually a very expensive 3 month on
antibiotics


Diagnosis
This is based on the history, serology and bacteriology. Abortions occurring after 6 months of pregnancy
are suggestive. However, blood samples should be taken for detailed laboratory analysis to confirm the
disease.
Serum samples should be taken for agglutination testing.
When abortion occurs, aborted fetuses should be taken intact in a sealed
container to the laboratory for detailed examination. The organisms can be found
in the placenta but more conveniently in pure culture in the stomach and lungs of
an aborted foetus. All foetuses and afterbirths should be handled carefully with
gloves to avoid human infection.

Diseases with similar symptoms Abortion: See Vibriosis, Leptospirosis, Rift Valley Fever


Prevention - Control - Treatment
Prevention and Control
The disease can be controlled through effective sanitary measures in the cattle
environment. Pregnant animals must be closely observed and any which show
signs of aborting must be immediately isolated.
Any animal which has aborted must be kept isolated until all uterine discharges
have stopped. If there is any suspicion of infection, any animal about to calve
should also be isolated.
Under cool conditions the organism may survive for up to 2 months. Exposure to
direct sunlight kills the organisms within a few hours.
The use of plastic gloves and thorough disinfection of the vulva and tail of cattle
helps greatly to reduce the risk of infection when examining pregnant animals.
Because of the danger of human infection, infected fetuses, placenta and cows
should be handled with great care. Proper hygienic precautions should be taken
when handling abortions and where infection is known to occur in certain herds
of cattle. Handlers of such material should always wear gloves for protection.
They should also ensure that they keep their hands away from the mouth, nose
and eyes until after the hands are thoroughly disinfected.
Burn or bury all contaminated materials such as foetuses and foetal membranes
Clean and disinfect all cattle premises which may be contaminated with foetuses
and foetal membranes.
Drinking of raw milk and unpasteurized milk products should be prohibited
Pasteurisation of milk and milk products makes them safe for consumption.


Vaccination
Calves between three and eight months should be vaccinated with live vaccine
(S.19) to prevent infection. Such vaccinations can provide lifelong immunity
against all but the heaviest challenge.
The live vaccine should be used with care in adult animals because it can cause
abortion in in-calf females and inflammation of the testes in adult males. It also
results in persistent antibody titres if used in adults, making differentiation
between antibody levels due to natural infection and vaccination very difficult
Adult cattle should therefore be vaccinated annually with dead B. abortus
vaccine (45/20), or a with a reduced dose - one twentieth - of S19 vaccine.
S19 vaccine should be handled with care. It is a live vaccine and can infect
humans.
Vaccination will reduce the number of infected animals in a herd by by over 90%
if carried out over a period of 5 years. Vaccination cannot eradicate Brucellosis
but it can lay the groundwork for future eradication.
Bulls should not be vaccinated as the vaccine may result in the organism
appearing in the semen.


Recommended treatment
Brucella infections are known to be persistent, so treatment of animals with antibiotic is not
recommended. It is therefore not practical and not useful to make any treatment attempt. Infected animals
should be culled. Meat is safe for consumption if cooked well.

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Anthrax

Anthrax is a serious infectious disease caused by gram-positive, rod-shaped bacteria known as
Bacillus anthracis. Anthrax can be found naturally in soil and commonly affects domestic and
wild animals around the world. Although it is rare, people can get sick with anthrax if they come
in contact with infected animals or contaminated animal products.
Contact with anthrax can cause severe illness in both humans and animals. Anthrax is not
contagious, which means you cant catch it like the cold or flu.
How do animals get infected with anthrax?
Domestic and wild animals such as cattle, sheep, goats, antelope, and deer can become infected
when they breathe in or ingest spores in contaminated soil, plants, or water. In areas where
domestic animals have had anthrax in the past, routine vaccination can help prevent outbreaks.
How do people get infected with anthrax?
People get infected with anthrax when spores get into the body. When anthrax spores get inside
the body, they can be activated. When they become active, the bacteria can multiply, spread
out in the body, produce toxins (poisons), and cause severe illness.
This can happen when people breathe in spores, eat food or drink water that is contaminated with
spores, or get spores in a cut or scrape in the skin. It is very uncommon for people in the United
States to get infected with anthrax.
Where is anthrax found?
Anthrax is most common in agricultural regions of Central and South America, sub-Saharan
Africa, central and southwestern Asia, southern and eastern Europe, and the Caribbean.
Anthrax is rare in the United States, but sporadic outbreaks do occur in wild and domestic
grazing animals such as cattle or deer. Anthrax is more common in developing countries and
countries that do not have veterinary public health programs that routinely vaccinate animals
against anthrax. In the United States, yearly vaccination of livestock is recommended in areas
where animals have had anthrax in the past.
Bioterrorism
A biological attack, or bioterrorism, is the intentional release of viruses, bacteria, or other germs
that can sicken or kill people, livestock, or crops. Bacillus anthracis, the bacteria that causes
anthrax, is one of the most likely agents to be used in a biological attack.
The Threat
We do not know if or when another anthrax attack might occur.
However, federal agencies have worked for years with health departments across the country to
plan and prepare for an anthrax attack. If such an emergency were to occur in the United States,
CDC and other federal agencies would work closely with local and state partners to coordinate a
response.
Why Would Anthrax Be Used as a Weapon?
If a bioterrorist attack were to happen, Bacillus anthracis, the bacteria that causes anthrax, would
be one of the biological agents most likely to be used. Biological agents are germs that can
sicken or kill people, livestock, or crops. Anthrax is one of the most likely agents to be used
because
Anthrax spores are easily found in nature, can be produced in a lab, and can last for a
long time in the environment.
Anthrax makes a good weapon because it can be released quietly and without anyone
knowing. The microscopic spores could be put into powders, sprays, food, and water.
Because they are so small, you may not be able to see, smell, or taste them.
Anthrax has been used as a weapon before.
Anthrax has been used as a weapon around the world for nearly a century. In 2001, powdered
anthrax spores were deliberately put into letters that were mailed through the U.S. postal system.
Twenty-two people, including 12 mail handlers, got anthrax, and five of these 22 people
died.
How Dangerous Is Anthrax?
A subset of select agents and toxins have been designated as Tier 1 because these biological
agents and toxins present the greatest risk of deliberate misuse with significant potential for mass
casualties or devastating effect to the economy, critical infrastructure, or public confidence, and
pose a severe threat to public health and safety. Bacillus anthracis is a Tier 1 agent.
What Might an Anthrax Attack Look Like?
An anthrax attack could take many forms. For example, it could be placed in letters and mailed,
as was done in 2001, or it could be put into food or water. Anthrax also could be released into the
air from a truck, building, or plane. This type of attack would mean the anthrax spores could
easily be blown around by the wind or carried on peoples clothes, shoes, and other objects. It
only takes a small amount of anthrax to infect a large number of people.
If anthrax spores were released into the air, people could breathe them in and get sick with
anthrax. Inhalation anthrax is the most serious form and can kill quickly if not treated
immediately. If the attack were not detected by one of the monitoring systems in place in the
United States, it might go unnoticed until doctors begin to see unusual patterns of illness among
sick people showing up at emergency rooms.

Hopefully, an attack involving anthrax will never happen in the United States. However, there are steps
that you and your family can take to help prepare if an anthrax emergency ever did happen. If such an
emergency were to occur in the United States, CDC and other federal agencies would be ready to
respond.
CDC is working with other federal agencies and health departments across the country to prepare
for an anthrax attack. Activities include
Providing funds and guidance to help health departments strengthen their abilities to
respond to all types of public health incidents and build more resilient communities.
Providing training in emergency response for the public health workforce and healthcare
providers, as well as leaders in the public and private sector.
Coordinating response activities and providing resources to health departments through
the CDC Emergency Operations Center .
Regulating the possession, use, and transfer of biological agents and toxins that could
pose a severe threat to public health and safety through the CDC Select Agent Program .
Promoting science and practices to strengthen preparedness and response activities.
Ensuring that the United States has enough laboratories that can quickly conduct tests
when anthrax is suspected.
Working with hospitals, laboratories, emergency response teams, and health-care
providers to make sure they have the medicine and supplies they would need if an
anthrax attack occurred.
Developing guidance to protect the health and safety of workers who would be
responding during an anthrax emergency.
What You Can Do to Prepare
Get a Kit, Make a Plan, Stay Informed
For details about how to put together an emergency kit, develop a family disaster plan, and stay
informed about all types of emergencies, go to CDCs Emergency Preparedness and You
website. These basic preparedness steps would be essential during an anthrax emergency.
People in areas where anthrax is released would also need to know how to get antibiotics, how to
create a family medical history, and how to recognize the symptoms of anthrax.
Know How You Would Get Antibiotics During an Anthrax
Crisis
If an anthrax emergency happened in your area, your community might need to receive large
amounts of antibiotics and medical supplies from the federal government. The supplies would be
sent to sites that are usually called points of dispensing (PODs). PODs would be located in your
community in safe, familiar places such as schools or convention centers.
In an anthrax emergency, you would be able to find out where the nearest POD is located and
what to bring to the POD by listening to news updates on TV and the radio, visiting your health
departments website, and staying alert for messages from community leaders.
PODs are designed to provide medicine to a large number of people in a short period of time, so
you could expect to stand in line. While at the POD, you would be asked to fill out a form that
includes some basic information about your medical history. Once you complete your form, a
POD staff member would review it and determine which antibiotic is best for you.
Keep a Family Medical History
In some cases, you may be able to pick up antibiotics for others in your household. If you live
with family members, its important to keep a medical history for each person in your family,
including
Medical conditions
Allergies
Any medicines they are taking
Each childs weight
During an emergency, you may be asked to bring this information to a POD to make sure you get
the right antibiotics for everyone in your family.
In an anthrax emergency, many lives would be saved if people started taking antibiotics right
away. It would be very important to start taking antibiotics as soon as you get them, take them as
directed, and keep taking them as for as long as you are told to.

We hope there is never an anthrax emergency that requires PODs to open, but if there is, be
assured the process is in place to get antibiotics to you and your family as quickly as possible.
Be Aware of the Symptoms of Anthrax
During an anthrax emergency, you would need to be able to recognize the symptoms of anthrax,
especially inhalation anthrax, and be prepared to get medical care if you have any of these
symptoms.
Detection & Response
If anthrax were used as a weapon in the United States, the attack could be detected in one of two
ways. Monitoring systems set up nationwide might detect the anthrax after it was released. Or, it
might go unnoticed until doctors begin to see unusual patterns of illness among patients in
emergency rooms. At that point, alert doctors might suspect anthrax and order lab tests to
diagnose anthrax.
It could take days for labs to confirm anthrax in those early samples. But with enough evidence,
CDC and other health agencies would not need to wait for lab confirmation before they took
action.
CDC and partners could respond by
Sending samples through the Laboratory Response Network (LRN)
Continuing to test samples to learn more about the strain of anthrax
Deploying field staff to talk to patients and learn more about how they were exposed
Shipping out medicine and supplies from the Strategic National Stockpile (SNS) to local
Points of Dispensing (PODs)
Providing guidance to clinicians, health departments and other partners on how to
respond
Communicating life-saving information to the public














Lyme Disease



It is caused by Borrelia burgdorferi
It has got 3 clinical stages
The first stage begins 3-32 days after having bitten by the infected tick
Early Localised stage-It is characterized by a circular red rash resembling a bulls eye
surrounding the bite.
Early disseminated stage-The rash disappears and the bacteria spreads to the Lymph node and
blood and other organs including brain,joints,heart,liver,spleen etc.Arthritis is the most common
symptom associated with this disease.
Last stage Lyme disease-After about 6 months the late stage begins. It is expressed as chronic
arthritis which may persist for years.
The Ticks are the vectors which spread this disease.A tick must have 3 blood meals during its 2
year life cycle.The first 2 must be on a small animal. The third one is a deer,In the absence of a
deer the lime disease disappears . Humans become infected when the ticks bite humans instead
of the deer.In all regions ticks reach maturity in summer. So there is high risk of this disease in
summers.











Plague
It is caused by Yersinia pestis
It is a gram negative coccobacillus
It is transmitted from one mammal to another by infected fleas
When an infected flea bites the infected rats the digestive tract of the fleas gets blocked. This
irritates the flea and makes it to bite more aggressively and frequently. It also prevents the flea
from taking a complete meal causes it to regurgitate the infected material into a bite wound.
When the infected flea bites a healthy man it introduces the bacterium subcutaneously
The bacteria causes a swelling in the Lymph nodes called BUBO and hence the name BUBONIC
plague
When the bacteria enters the blood it is called septicemic stage. The blood vessels are ruptured
nd destroyed causing subcutaneous bleeding resulting in black death.
If the lungs become infected then it can spread from one person to another by air and this stage is
called pneumonic plague.
Yersinia Pestis
1. Gram negative
2. Coccobacillus
3. Rod shaped
4. Facultatively anaerobic
5. When stained the microorganism has got a bipolar staining pattern due to the ends
of the bacterium taking up more stain than the centre of the organism.
6. Symptoms of the disease are fever,cough,tightness in the chest
7. Test-Direct fluorescent antibody stain
8. Treatment Antibiotic-streptomycin
9. Precaution Removal of rats from the Household




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Tularemia
Causative agent Francisella tularensis

Gram ve
Coccobacillus
Clinical syndromes-ulceroglandular tularemia,glandular disease,oculoglandular disease
Diagnosis can be made on the basis of a history of hunting or a tick bite. Fluorescent
antibody stain is now available
This disease is most common in the wild animals but it may spread to human beings by
diseased animals through a cut, eyes(conjunctiva),infected meat,inhaled in
laboratory,flies which have been infected by the diseased animal,when a hunter skins or
cleaves a diseased animal.It was one of the 7 standadized biological weapons developed
by US biological warfare program in 1969.












Viral Infections
Yellow Fever


Key facts
Yellow fever is an acute viral haemorrhagic disease transmitted by infected mosquitoes. The
"yellow" in the name refers to the jaundice that affects some patients.
Up to 50% of severely affected persons without treatment will die from yellow fever.
There are an estimated 200 000 cases of yellow fever, causing 30 000 deaths, worldwide each
year, with 90% occurring in Africa.
The virus is endemic in tropical areas of Africa and Latin America, with a combined population of
over 900 million people.
The number of yellow fever cases has increased over the past two decades due to declining
population immunity to infection, deforestation, urbanization, population movements and
climate change.
There is no specific treatment for yellow fever. Treatment is symptomatic, aimed at reducing
the symptoms for the comfort of the patient.
Vaccination is the most important preventive measure against yellow fever. The vaccine is safe,
affordable and highly effective, and a single dose of yellow fever vaccine is sufficient to confer
sustained immunity and life-long protection against yellow fever disease and a booster dose of
yellow fever vaccine is not needed. The vaccine provides effective immunity within 30 days for
99% of persons vaccinated.

Signs and symptoms
Once contracted, the virus incubates in the body for 3 to 6 days, followed by infection that can
occur in one or two phases. The first, "acute", phase usually causes fever, muscle pain with
prominent backache, headache, shivers, loss of appetite, and nausea or vomiting. Most patients
improve and their symptoms disappear after 3 to 4 days.
However, 15% of patients enter a second, more toxic phase within 24 hours of the initial
remission. High fever returns and several body systems are affected. The patient rapidly
develops jaundice and complains of abdominal pain with vomiting. Bleeding can occur from the
mouth, nose, eyes or stomach. Once this happens, blood appears in the vomit and faeces. Kidney
function deteriorates. Half of the patients who enter the toxic phase die within 10 to 14 days, the
rest recover without significant organ damage.
Yellow fever is difficult to diagnose, especially during the early stages. It can be confused with
severe malaria, dengue hemorrhagic fever, leptospirosis, viral hepatitis (especially the
fulminating forms of hepatitis B and D), other hemorrhagic fevers (Bolivian, Argentine,
Venezuelan hemorrhagic fevers and others flavivirus as West Nile, Zika virus etc) and other
diseases, as well as poisoning. Blood tests can detect yellow fever antibodies produced in
response to the infection. Several other techniques are used to identify the virus in blood
specimens or liver tissue collected after death. These tests require highly trained laboratory staff
and specialized equipment and materials.
Populations at risk
Forty-four endemic countries in Africa and Latin America, with a combined population of over
900 million, are at risk. In Africa, an estimated 508 million people live in 31 countries at risk.
The remaining population at risk are in 13 countries in Latin America, with Bolivia, Brazil,
Colombia, Ecuador and Peru at greatest risk.
According to WHO estimates from the early 1990s, 200 000 cases of yellow fever, with 30 000
deaths, are expected globally each year, with 90% occurring in Africa. A recent analysis of
African data sources due to be published later this year, estimates similar figures, but a slightly
lower burden of 84 000170 000 severe cases and
29 00060 000 deaths due to yellow fever in Africa for the year 2013. Without vaccination, the
burden figures would be much higher.
Small numbers of imported cases occur in countries free of yellow fever. Although the disease
has never been reported in Asia, the region is at risk because the conditions required for
transmission are present there. In the past centuries (XVII to XIX), outbreaks of yellow fever
were reported in North America (Charleston, New Orleans, New York, Philadelphia, etc) and
Europe (England, France, Ireland, Italy, Portugal and Spain).
Transmission
The yellow fever virus is an arbovirus of the flavivirus genus, and the mosquito is the primary
vector. It carries the virus from one host to another, primarily between monkeys, from monkeys
to humans, and from person to person.
Several different species of the Aedes and Haemogogus mosquitoes transmit the virus. The
mosquitoes either breed around houses (domestic), in the jungle (wild) or in both habitats (semi-
domestic). There are three types of transmission cycles.
Sylvatic (or jungle) yellow fever: In tropical rainforests, yellow fever occurs in monkeys that are
infected by wild mosquitoes. The infected monkeys then pass the virus to other mosquitoes that
feed on them. The infected mosquitoes bite humans entering the forest, resulting in occasional
cases of yellow fever. The majority of infections occur in young men working in the forest (e.g.
for logging).
Intermediate yellow fever: In humid or semi-humid parts of Africa, small-scale epidemics occur.
Semi-domestic mosquitoes (that breed in the wild and around households) infect both monkeys
and humans. Increased contact between people and infected mosquitoes leads to transmission.
Many separate villages in an area can suffer cases simultaneously. This is the most common type
of outbreak in Africa. An outbreak can become a more severe epidemic if the infection is carried
into an area populated with both domestic mosquitoes and unvaccinated people.
Urban yellow fever: Large epidemics occur when infected people introduce the virus into
densely populated areas with a high number of non-immune people and Aedes mosquitoes.
Infected mosquitoes transmit the virus from person to person.
Treatment
There is no specific treatment for yellow fever, only supportive care to treat dehydration,
respiratory failure and fever. Associated bacterial infections can be treated with antibiotics.
Supportive care may improve outcomes for seriously ill patients, but it is rarely available in
poorer areas.
Prevention
1. Vaccination
Vaccination is the single most important measure for preventing yellow fever. In high risk areas
where vaccination coverage is low, prompt recognition and control of outbreaks through
immunization is critical to prevent epidemics. To prevent outbreaks throughout affected regions,
vaccination coverage must reach at least 60% to 80% of a population at risk. Few endemic
countries that recently benefited from a preventive mass vaccination campaign in Africa
currently have this level of coverage.
Preventive vaccination can be offered through routine infant immunization and one-time mass
campaigns to increase vaccination coverage in countries at risk, as well as for travelers to yellow
fever endemic area. WHO strongly recommends routine yellow fever vaccination for children in
areas at risk for the disease.
The yellow fever vaccine is safe and affordable, providing effective immunity against yellow
fever within 10 days for 80100% of people and 99% immunity within 30 days. A single dose of
yellow fever vaccine is sufficient to confer sustained immunity and life-long protection against
yellow fever disease and a booster dose of yellow fever vaccine is not needed. Serious side
effects are extremely rare. Serious adverse events have been reported rarely following
immunization in a few endemic areas and among vaccinated travelers (e.g. in Australia, Brazil,
Peru, Togo and the United States of America). Scientists are investigating the causes.
In regard to the use of yellow fever vaccine in people over 60 years of age, it is noted that while
the risk of yellow fever vaccine-associated viscerotropic disease in persons 60 years of age is
higher than in younger ages, the overall risk remains low. Vaccination should be administrated
after careful risk-benefit assessment, comparing the risk of acquiring yellow fever disease versus
the risk of a potential serious adverse event following immunization for persons 60 years of age
who have not been previously vaccinated and for whom the vaccine is recommended.
The risk of death from yellow fever disease is far greater than the risks related to the vaccine.
People who should not recommended to be vaccinated include:
children aged less than 9 months (or between 69 months during an epidemic, where the risk of
disease is higher than an adverse event of the vaccine);
pregnant women except during a yellow fever outbreak when the risk of infection is high;
people with severe allergies to egg protein; and
people with severe immunodeficiency due to symptomatic HIV/AIDS or other causes, or in the
presence of a thymus disorder.
Travelers, particularly those arriving to Asia from Africa or Latin America must have a
certificate of yellow fever vaccination. If there are medical grounds for not getting vaccinated,
International Health Regulations state that this must be certified by the appropriate authorities.
2. Mosquito control
In some situations, mosquito control is vital until vaccination takes effect. The risk of yellow
fever transmission in urban areas can be reduced by eliminating potential mosquito breeding
sites and applying insecticides to water where they develop in their earliest stages. Application of
spray insecticides to kill adult mosquitoes during urban epidemics, combined with emergency
vaccination campaigns, can reduce or halt yellow fever transmission, "buying time" for
vaccinated populations to build immunity.
Historically, mosquito control campaigns successfully eliminated Aedes aegypti, the urban
yellow fever vector, from most mainland countries of Central and South America. However, this
mosquito species has re-colonized urban areas in the region and poses a renewed risk of urban
yellow fever.
Mosquito control programmes targeting wild mosquitoes in forested areas are not practical for
preventing jungle (or sylvatic) yellow fever transmission.
3. Epidemic preparedness and response
Prompt detection of yellow fever and rapid response through emergency vaccination campaigns
are essential for controlling outbreaks. However, underreporting is a concern the true number
of cases is estimated to be 10 to 250 times what is now being reported.
WHO recommends that every at-risk country have at least one national laboratory where basic
yellow fever blood tests can be performed. One laboratory confirmed case of yellow fever in an
unvaccinated population could be considered an outbreak, and a confirmed case in any context
must be fully investigated, particularly in any area where most of the population has been
vaccinated. Investigation teams must assess and respond to the outbreak with both emergency
measures and longer-term immunization plans.
WHO response
WHO is the Secretariat for the International Coordinating Group for Yellow Fever Vaccine
Provision (ICG). The ICG maintains an emergency stockpile of yellow fever vaccines to ensure
rapid response to outbreaks in high risk countries.
The Yellow Fever Initiative is a preventive control strategy of vaccination led by WHO and
supported by UNICEF and National Governments, with a particular focus on most high endemic
countries in Africa where the disease is most prominent. The Initiative recommends including
yellow fever vaccines in routine infant immunizations (starting at age 9 months), implementing
mass vaccination campaigns in high-risk areas for people in all age groups aged 9 months and
older, and maintaining surveillance and outbreak response capacity.
Between 2007 and 2012, 12 countries have completed preventive yellow fever vaccination
campaigns: Benin, Burkina Faso, Cameroon, Central African Republic, Cte dIvoire, Ghana,
Guinea, Liberia, Mali, Senegal, Sierra Leone and Togo. The Yellow Fever Initiative is
financially supported by the GAVI Alliance, the European Community Humanitarian Office
(ECHO), the Central Emergency Response Fund (CERF), the Ministries of Health, and the
country-level partners
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Dengue Fever

Figure: Dengue virus structure
The dengue virus has a roughly spherical shape. Inside the virus is the nucleocapsid, which is made of
the viral genome and C proteins. The nucleocapsid is surrounded by a membrane called the viral
envelope, a lipid bilayer that is taken from the host. Embedded in the viral envelope are E and M
proteins that span through the lipid bilayer. These proteins form a protective outer layer that controls
the entry of the virus into human cells.
Dengue Virus Replication and Infectious Cycle
How does the virus behave once it enters the human body? The dengue viral replication process
begins when the virus attaches to a human skin cell (Figure 4). After this attachment, the skin
cell's membrane folds around the virus and forms a pouch that seals around the virus particle.
This pouch is called an endosome. A cell normally uses endosomes to take in large molecules
and particles from outside the cell for nourishment. By hijacking this normal cell process, the
dengue virus is able to enter a host cell. Once the virus has entered a host cell, the virus
penetrates deeper into the cell while still inside the endosome. How does the virus exit the
endosome, and why? Researchers have learned that two conditions are needed for the dengue
virus to exit the endosome:
1. The endosome must be deep inside the cell where the environment is acidic.
2. The endosomal membrane must gain a negative charge.
These two conditions allow the virus envelope to fuse with the endosomal membrane, and that
process releases the dengue nucleocapsid into the cytoplasm of the cell.
Once it is released into the cell cytoplasm, how does the virus replicate itself? In the cytoplasm,
the nucleocapsid opens to uncoat the viral genome. This process releases the viral RNA into the
cytoplasm. The viral RNA then hijacks the host cell's machinery to replicate itself. The virus
uses ribosomes on the host's rough endoplasmic reticulum (ER) to translate the viral RNA and
produce the viral polypeptide. This polypeptide is then cut to form the ten dengue proteins.
The newly synthesized viral RNA is enclosed in the C proteins, forming a nucleocapid. The
nucleocapsid enters the rough ER and is enveloped in the ER membrane and surrounded by the
M and E proteins. This step adds the viral envelope and protective outer layer. The immature
viruses travel through the Golgi apparatus complex, where the viruses mature and convert into
their infectious form. The mature dengue viruses are then released from the cell and can go on to
infect other cells.
Summary
The dengue virus is a tiny structure that can only replicate inside a host organism. The four
closely related dengue viruses DEN-1, DEN-2, DEN-3, and DEN-4 are found in the same
regions of the world. The dengue virus is a roughly spherical structure composed of the viral
genome and capsid proteins surrounded by an envelope and a shell of proteins. After infecting a
host cell, the dengue virus hijacks the host cell's machinery to replicate the viral RNA genome
and viral proteins. After maturing, the newly synthesized dengue viruses are released and go on
to infect other host cells.

/scitable uninitedaudio




Figure 4: Dengue virus replication
The dengue virus attaches to the surface of a host cell and enters the cell by a process called
endocytosis. Once deep inside the cell, the virus fuses with the endosomal membrane and is released
into the cytoplasm. The virus particle comes apart, releasing the viral genome. The viral RNA (vRNA) is
translated into a single polypeptide that is cut into ten proteins, and the viral genome is replicated. Virus
assembly occurs on the surface of the endoplasmic reticulum (ER) when the structural proteins and
newly synthesized RNA bud out from the ER. The immature viral particles are transported through the
trans-Golgi network (TGN), where they mature and convert to their infectious form. The mature viruses
are then released from the cell and can go on to infect other cells.




Dengue fever is a disease caused by viruses that are transmitted to people by mosquitoes. Dengue fever
usually causes fever (high, about 104 F-105 F), skin rash (see Figure 1), and pain (headaches and often
severe muscle and joint pains). The disease has also been termed "breakbone" or "dandy fever" because
the unusually severe muscle and joint pains can make people assume distorted body positions or
exaggerated walking movements in an effort to reduce their pain.
Dengue fever is endemic in tropical and subtropical areas. Dengue fever is estimated by the WHO (World
Health Organization) to cause about 50-100 million infections per year worldwide. The CDC considers
dengue fever to cause the majority of acute febrile illnesses in travelers returning to the U.S. The first
clinical report of dengue fever was in 1789 by B. Rush, although the Chinese may have described the
disease associated with "flying insects" as early as 420 AD. Africans described "ka dinga pepo" as cramp-
like seizure caused by an evil spirit. The Spanish may have changed "dinga" to dengue since it means
fastidious or careful in Spanish, which describes the gait of people trying to reduce the pain of walking.
Unfortunately, the disease incidence seems to be increasing. Researchers suggest the surge in dengue
fever may be due to several factors:
Increased urban crowding with more sites for mosquitoes to develop
International commerce that contains infected mosquitoes, thus introducing the disease to areas
previously free of the disease
Local and world environmental changes that allow mosquitoes to survive the winter months
International travelers who carry the disease to areas where mosquitoes have not been previously
infected.
The symptoms and signs for dengue begin about three to 15 days after a mosquito bite transfers a
virus (dengue virus serotype 1-4) to a person previously unexposed to the viruses. Fever and painful
muscle and joint aches can occur during the first few hours of symptoms when headache, chills, rash,
and swollen lymph nodes first appear. Pain behind the eyes is also a common symptom. These
symptoms usually last about two to four days and then diminish, only to reappear again with a rash
that covers the body and spares the face. The rash also may occur on the palms of the hands and the
bottom of the feet, areas frequently spared in many viral and bacterial infections. The symptoms may
last about one to two weeks with complete recovery, in most cases, in a few weeks. However, some
people can develop more severe symptoms and complications, such as hemorrhagic areas in the skin,
gums, and the gastrointestinal tract. This clinical problem is termed dengue hemorrhagic fever (DHF).
The majority of DHF is seen in children under 15 years of age, but it can occur in adults. Another
clinical variation of dengue fever is termed dengue shock syndrome (DSS); DHF usually precedes
DSS. The patients eventually develop severe abdominal pain, heavy bleeding, and blood pressure
drops; this syndrome, if not treated quickly, may cause death
Four closely related viruses cause dengue fever. The viruses are transmitted from Aedes aegypti and
Aedes albopictus mosquitoes to humans in a viral cycle that requires both humans and these mosquitoes.
There is no human-to-human dengue fever transmission. Once a mosquito is infected, it remains infected
for its life span. A human can infect mosquitoes when the human has a high number of viruses in the
blood (right before symptoms develop). The viruses belong to the Flaviviridae family and have an RNA
strand as its genetic makeup. Virologists term them dengue virus types 1-4 (DENV 1-4). All four serotypes
are closely related. However, there are enough antigenic differences between them that if a person
becomes immune to one serotype, the person can still be infected by the other three serotypes.
Dengue fever is presumptively diagnosed by a medical caregiver by the relatively characteristic sequence
of high fever, rash appearance, and other symptoms in a person who has a history of recent travel to
dengue endemic areas and recalls mosquito bites while in the endemic area. However, if not all of the
symptoms or history is complete, the caregiver is likely to run a number of tests to obtain a definitive
diagnosis. Other diseases may yield similar symptoms (for example, leptospirosis, typhoid fever, yellow
fever, scarlet fever, Rocky Mountain spotted fever, meningococcemia, and several others) if the patient
has severe symptoms; or if the medical caregiver does not have enough information to make a
presumptive diagnosis, the patient is likely to undergo a number of other tests to definitively distinguish
dengue fever from other diseases. In general, the more serious the symptoms such as easy bruising,
fevers at or above 104 F, hemorrhages or shock syndrome, the more tests are likely to be done.
In general, most clinicians will order a complete blood test (CBC), with a metabolic panel, along with
coagulation studies in most patients with high fever and any bleeding problems. In addition, depending on
the symptoms (especially headache) and the clinician, blood and urine cultures plus a spinal tap may be
done to help differentiate between dengue fever and other diseases. A MAC-ELISA assay (an
immunoglobulin M-based test) is the most widely used test for dengue fever virus. However, other tests
are available; they also are based on the person's immunological response to the dengue serovars (for
example, IgG-ELISA, dengue viral plaque reduction tests, and PCR tests). These tests are considered
definitive for exposure to dengue virus; definitive diagnosis of dengue fever is isolation and identification
(usually by immunological tests) of the dengue virus serovar from the patient. Fortunately, this viral
disease is usually self-limited and usually adequate hydration and pain control will help the person
through the infection. However, for dengue fever, a caution is given by most clinicians in home treatment.
Nonsteroidal anti-inflammatory agents (for example, aspirin (Bayer, Ecotrin), ibuprofen (Motrin), and other
NSAIDs) should be avoided because of the tendency of the dengue viruses to cause hemorrhages. The
NSAIDs may add to the hemorrhage symptoms. Other medications such as acetaminophen (Tylenol),
codeine, or other agents that are not NSAIDs may be used.
More severe variations of dengue fever (hemorrhagic and shock syndrome) usually require additional
supportive treatments; these patients often require hospitalization. IV hydration, blood transfusions,
platelet transfusions, blood pressure support, and other intensive-care measures may need to be utilized
in these patients. Consultation with infectious-disease and critical-care specialists is often advised to
optimize patient care.
____________________________________________________________________________________















Infectious mononucleosis

Infectious mononucleosis, peripheral smear, high power showing reactive lymphocytes

Infectious mononucleosis, or "mono", is an infection usually caused by the Epstein-Barr virus.
The virus spreads through saliva, which is why it's sometimes called "kissing disease." Mono
occurs most often in teens and young adults. However, you can get it at any age. Symptoms of
mono include
Fever
Sore throat
Swollen lymph glands
Sometimes you may also have a swollen spleen. Serious problems are rare.
A blood test can show if you have mono. Most people get better in two to four weeks. However,
you may feel tired for a few months afterward. Treatment focuses on helping symptoms and
includes medicines for pain and fever, warm salt water gargles and plenty of rest and fluids.

_________________________________________________________________________________

What is HIV/AIDS?
HIV stands for human immunodeficiency virus, which is the virus that causes HIV infection. The
abbreviation HIV can refer to the virus and or to HIV infection.

AIDS stands for acquired immunodeficiency syndrome. AIDS is the most advanced stage of HIV
infection.

HIV attacks and destroys the infection-fighting CD4 cells of the immune system. Loss of CD4
cells makes it difficult for the body to fight infections and certain cancers. Without treatment,
HIV gradually destroys the immune system and advances to AIDS.
How is HIV spread?
HIV is spread through contact with certain body fluids from a person infected with HIV. These
body fluids include:
Blood
Semen
Pre-seminal fluid
Vaginal fluids
Rectal fluids
Breast milk
The spread of HIV from person to person is called HIV transmission. The spread of HIV from an
HIV-infected woman to her child during pregnancy, childbirth, or breastfeeding is called
mother-to-child transmission of HIV.

In the United States, HIV is spread mainly by having sex with or sharing drug injection
equipment with someone who is infected with HIV. To reduce your risk of HIV infection, use
condoms correctly and consistently during sex, limit your number of sexual partners, and never
share drug injection equipment.

Mother-to-child transmission is the most common way that children become infected with
HIV. HIV medicines, given to HIV-infected women during pregnancy and childbirth and to their
babies after birth, reduce the risk of mother-to-child transmission of HIV.

You cant get HIV by shaking hands or hugging a person infected with HIV. And you cant get
HIV from contact with objects such as dishes, toilet seats, or doorknobs used by a person with
HIV.
What is the treatment for HIV?
The use of HIV medicines to treat HIV infection is called antiretroviral therapy (ART). ART
involves taking a combination of HIV medicines (called an HIV regimen) every day. (HIV
medicines are often called antiretrovirals or ARVs.)

ART prevents HIV from multiplying and reduces the level of HIV in the body. Having less HIV in
the body protects the immune system and prevents HIV infection from advancing to AIDS.

ART cant cure HIV, but it can help people infected with HIV live longer, healthier lives. ART also
reduces the risk of HIV transmission.
What are the symptoms of HIV/AIDS?
Soon after infection with HIV, many people have flu-like symptoms, such as fever, headache, or
rash. The symptoms may come and go for a month or two after infection.

After this earliest stage of HIV infection, HIV continues to multiply but at very low levels. More
severe symptoms of HIV infection, such as chronic diarrhea, rapid weight loss, and other signs
of opportunistic infections, generally dont appear for many years. (Opportunistic infections are
infections and infection-related cancers that occur more frequently or are more severe in
people with weakened immune systems than in people with healthy immune systems.)

Without treatment, HIV can advance to AIDS. The time it takes for HIV to advance to AIDS varies,
but it can take 10 years or more.

HIV transmission is possible at any stage of HIV infectioneven if an HIV-infected person has
no symptoms of HIV.
How is AIDS diagnosed?
The following criteria are used to determine if a person infected with HIV has AIDS:
The persons immune system is severely damaged as indicated by a CD4 count of less
than 200 cells/mm
3
. A CD4 count measures the number of CD4 cells in a sample of
blood. The CD4 count of a healthy person ranges from 500 to 1,600 cells/mm
3
.
AND/OR
The person has one or more opportunistic infections.






Types of HIV/AIDS Antiretroviral Drugs
There are six major types of drugs used to treat HIV/AIDS. Called antiretrovirals because they act against
the retrovirus HIV, these drugs are grouped by how they interfere with steps in HIV replication (PDF).
Entry Inhibitors interfere with the virus' ability to bind to receptors on the outer surface of the cell it tries
to enter. When receptor binding fails, HIV cannot infect the cell.
Fusion Inhibitors interfere with the viruss ability to fuse with a cellular membrane, preventing HIV from
entering a cell.
Reverse Transcriptase Inhibitors prevent the HIV enzyme reverse transcriptase (RT) from converting
single-stranded HIV RNA into double-stranded HIV DNAa process called reverse transcription. There
are two types of RT inhibitors:
1. Nucleoside/nucleotide RT inhibitors (NRTIs) are faulty DNA building blocks. When one of these faulty
building blocks is added to a growing HIV DNA chain, no further correct DNA building blocks can be
added on, halting HIV DNA synthesis.
2. Non-nucleoside RT inhibitors (NNRTIs) bind to RT, interfering with its ability to convert HIV RNA into
HIV DNA
Integrase Inhibitors block the HIV enzyme integrase, which the virus uses to integrate its genetic
material into the DNA of the cell it has infected.
Protease Inhibitors interfere with the HIV enzyme called protease, which normally cuts long chains of
HIV proteins into smaller individual proteins. When protease does not work properly, new virus particles
cannot be assembled.
Multi-class Combination Products combine HIV drugs from two or more classes, or types, into a single
product.
To prevent strains of HIV from becoming resistant to a type of antiretroviral drug, healthcare providers
recommend that people infected with HIV take a combination of antiretroviral drugs in an approach called
highly active antiretroviral therapy (HAART). Developed by NIAID-supported researchers, HAART
combines drugs from at least two different classes.
For a complete listing of Food and Drug Administration (FDA)-approved antiretroviral drugs used to treat
HIV/AIDS, see the FDA website.
Basic Vaccine Discovery
A vaccine works by presenting pieces of the virus or bacteria (also called immunogens or antigens) to the
body's immune system, causing an immune reaction. This primes the immune system so that when it is
exposed to the real pathogen, the bodys immune system can aggressively attack the virus or bacteria
since it will already have seen pieces of it in the vaccine.
While we have been able to make vaccines for some of the worlds deadliest diseases, we have not been
able to find one for HIV due to a number of scientific challenges. One reason is that scientists still do not
know what type of immune response is needed to prevent HIV infection and control HIV
replication. Scientists have, however, begun to shed light on this by analyzing data from an HIV vaccine
trial conducted in Thailand (RV144) that showed modest success in preventing HIV infection. These
analyses are providing some hint as to what type of immune responses may be needed and will help
inform future clinical trial design. Research focused on basic vaccine discovery, particularly the interaction
between HIV and the human immune system, will also help address many of these unanswered
questions and can provide insight for the design and development of new and more effective vaccine
candidates.
Having renewed and expanded its support of innovative basic vaccine discovery research since the
NIAID Summit on Vaccine Research and Development held in 2008, NIAID remains committed to
developing vaccines candidates. NIAID is particularly interested in pursuing four key areas of basic
vaccine discovery:
1. B cell immunology
2. Systems biology analysis of early immune responses to HIV/SIV
3. Immune defense mechanisms at mucosal surfaces
4. Strengthen bridges between non-human primate research and clinical research
In addition, NIAID conducts and supports research to enhance the vaccines immune response. The
areas of investigation include

Addition of adjuvants that enhance the immune response to the vaccine

Route and method of delivery of the vaccine

Dose of the vaccine, the number of immunizations, and the timing between them
In addition to ongoing programs, such as the HIV Vaccine Research and Design (HIVRAD), which
advances concepts further towards the development of a preventive AIDS vaccine, two recently funded
programs that reflect NIAIDs commitment to basic vaccine research: the Centers for HIV/AIDS Vaccine
Immunology and Immunogen Discovery (CHAVI-ID) and the Innovative HIV Vaccine Discovery
(IHVD). CHAVI-ID is a large multi-component research consortia funded to accelerate HIV vaccine
development. These consortia will conduct basic research on how HIV infection might be prevented to
rapidly translate new knowledge into truly novel immunization approaches that will induce broad
protection. They will then conduct proof-of-concept studies in nonhuman primates of their novel vaccine
candidates before preparing them for human clinical trials in collaboration with the NIAID-funded HIV
Vaccine Trials Network and other NIAID-allied groups.
The IHVD supports innovative research that may lead to the discovery, design, and development of an
effective vaccine against HIV. The 14 grantees funded through this program in fiscal year 2012 will
address topics critical for the development of an efficacious vaccine, including methods to induce HIV-
specific mucosal immunity, optimization of immunogens that target HIV envelope, methods to optimize
antiviral T-cell and NK cell activity, and studies to determine the mechanism of protection of an efficacious
vaccine in the nonhuman primate model.
HIV Vaccine Designs and Strategies
Vaccine
Design
How Does this Vaccine Work? Issues for HIV Vaccine
DNA 1. A few HIV genes are inserted into
a backbone of DNA known as
No DNA vaccines have yet been approved for use
in humans by the FDA. FDA guidance on DNA
plasmid
2. The vaccine is injected into
muscle of the recipient where the
HIV genes are expressed into
proteins.
3. The viral proteins are degraded
into small peptide fragments,
which are then presented by
molecules on the cell surface. T
cells recognizing these molecules
generate an immune response.
vaccines can be found on FDA's Considerations
for Plasmid DNA Vaccines for Infectious Disease
Indications
Live
Vectors:
(Viral and
Bacterial)
1. The HIV or SIV genes are inserted
into the genomes of live,
infectious, but non-disease-
causing forms of viruses (e.g.,
adenovirus) or bacteria (e.g.,
Bacille Calmette-Guerin (BCG).
2. These vectors shuttle foreign
genes along with their own into
cells.
3. HIV proteins generated from these
recombinant genes inside the cell
are either secreted or displayed
on the cell surface and presented
to the immune system.
1. The development of viral vectors has been
robust, with a few entering Phase III trials.
2. Only a few bacterial vectors are under
development in small and large animal
models, and some Phase I trials. The
complex nature of bacteria hampers the
development of bacterial vector systems.
Viral
Proteins or
Viral
Peptides
Chemically synthesized pieces of HIV
peptides or proteins that elicit strong T
and B cell responses.
Peptide-based preparations require the addition of
an adjuvant to enhance immunogenicity. At
present, alum is the only adjuvant authorized by
FDA for general medical use, however many
products are being tested, and some are in clinical
trials.
Virus-like
Particles
(VLPs)
1. Empty, non-infectious shells of the
HIV envelope protein; they mimic
the outer coat of the virus but lack
a genome inside and cannot
reproduce.
2. Because VLPs resemble the virus,
they can induce high titers of
neutralizing antibodies to protect
against viral challenge.
VLPs represent an exciting new strategy for HIV
vaccines but it has been difficult to make them
reproducibly

Evaluation of Vaccine Candidates in Animal Models
Before vaccine candidates are tested in humans, they must be first be evaluated in the laboratory for
safety and efficacy. Studies in animal models have been vital in determining disease mechanisms,
predicting disease triggers, and developing treatments and diagnostic tests. It has been difficult to study
HIV because the virus exclusively infects and causes disease in humans. As a result, there is no ideal
animal model that can imitate the natural history and pathogenesis of HIV/AIDS in the human body.
Scientists are using macaque monkeys infected with simian immunodeficiency virus (SIV), a virus closely
related to HIV, as an approximate animal model. This model is useful because SIV in macaques follows a
disease course that is similar to HIV. Macaques are used to evaluate vaccines that closely resemble the
ones being developed for humans. This provides some clues to the safety and potential efficacy of a
vaccine candidate. In addition to nonhuman primates, researchers are making progress in developing
mouse models that may be used in the future for evaluating HIV vaccine candidates.
Data from animal models provides useful information (e.g. safety, potential efficacy) that can help guide
scientists on whether the vaccine candidate should be moved into human clinical trials.
Two grant awards were made through the Consortia for AIDS Vaccine Research in Nonhuman Primates
in 2011 to increase our understanding of the nonhuman primate models. Through this program, Emory
University in Atlanta and Beth Israel Deaconess Medical Center, part of Harvard University in Boston, will
co-lead research designed to understand the events that occur at the earliest stages of mucosal SIV
infection and how those events can be blocked or mediated by vaccine-induced immune responses.
Through a contract mechanism, NIAID supports Simian Vaccine Evaluation Units (SVEUs) to serve as a
resource to evaluate promising SIV and HIV vaccines in nonhuman primates in support of HIV vaccine
development. NIAID accepts proposals from investigators for vaccine studies that if approved, are
conducted at one of the SVEU sites.
Measuring Vaccine Safety and Efficacy in Clinical Trials
Specimens (fluids and cells) collected from clinical trial participants are routinely analyzed in the
laboratory using highly sensitive assays (or tests) in accordance with federal government regulations and
Good Clinical Laboratory Practice guidelines. These assays, which are conducted during all phases of
clinical trials, allow scientists to monitor the safety and well-being of the volunteers and to measure the
immune response induced by the vaccine. Examples of routine safety assays include blood and urine
sample analyses that measure blood cell counts, hemoglobin levels, and kidney and liver function; as well
as screening for infection with syphilis, HIV, and/or hepatitis B and C viruses. In addition, diagnostic
assays are also performed during an HIV vaccine clinical trial to distinguish whether a volunteer tests
positive for HIV due to the vaccine (also known as vaccine-induced seropositivity) or due to natural HIV
infection. The vaccines being tested cannot cause HIV infection because they do not contain the HIV
virus. Vaccine-induced seropositivity, or VISP, occurs because vaccines cause the body to produce
antibodies to components of the vaccine that resemble HIV.
Assays that measure the vaccines potential efficacy are known as endpoint assays. These tests are
important because they provide useful information on whether a vaccine candidate should continue on for
further clinical testing. There are currently four optimized and validated assays that are being used to
evaluate vaccine efficacy, each with different requirements for testing such as type of specimen (whole
blood or peripheral blood mononuclear cells), fresh or cryopreserved (frozen) samples, and length of
incubation time.
History of HIV Vaccine Research
1981 HIV was identified as the cause of AIDS.
1987
The first HIV vaccine clinical trial opened at the National Institutes of Health (NIH)
Clinical Center in Bethesda, Maryland. This Phase I trial enrolled 138 healthy,
uninfected volunteers. The gp160 subunit vaccine showed no serious adverse
effects.
1988
The NIAID AIDS Vaccine Evaluation Group (AVEG), the first U.S. cooperative HIV
vaccine clinical trials group, began enrolling volunteers in its first trial.
1992
NIAID launched the first Phase II HIV vaccine clinical trial. This trial included
uninfected volunteers with a history of high-risk behavior -- injection drug use,
multiple sex partners, or sexually transmitted infections. Participants were
counseled repeatedly to avoid any behaviors that put them at risk of HIV infection.
1998
First annual HIV Vaccine Awareness Day to honor vaccine study
volunteers.
First large scale vaccine trial began: VaxGen initiates Phase III trial of
AIDSVAX in North America and The Netherlands.
1999
NIAID begins first African preventive HIV vaccine trial in Uganda.
First large scale vaccine trial in a developing country began: VaxGen
initiates Phase III trial of AIDSVAX in Thailand.
Dedication of the Dale and Betty Bumpers Vaccine Research Center
(VRC).
2000
NIAID formed the HIV Vaccine Trials Network (HVTN), a network of clinical
sites in the United States and abroad dedicated to developing a preventive
HIV vaccine by testing and evaluating candidate vaccines in all phases of
clinical trials. The network included more than 25 sites in the United
States, Africa, Asia, South America, and the Caribbean
First African vaccine trial completed in Uganda.
2003
U.S. and Royal Thai governments jointly initiated RV144, a Phase III trial
to evaluate a novel HIV vaccine strategy commonly referred to as "prime-
boost."
Formation of Global HIV Vaccine Enterprise proposed in Science
2004 VaxGen candidate failed in Phase III trials.
2007 NIAID halted the Phase II Step and Phambili studies due to safety concerns.
2009
Phase II HVTN 505 study initiated to evaluate a prime-boost vaccine
regimen developed by the VRC.
Results of Phase III Thai Trial (RV144) show vaccine combination is first to
demonstrate modest preventive effect in humans. The trial enrolled more
than 16,000 volunteers.
2010
Two potent antibodies that prevent most strains of HIV identified by the
VRC (VRC01 and VRC02).
Establishment of Pox-Protein Public-Private Partnership (P5)
2011 HVTN 505 expanded to include protection from HIV as primary endpoint.
2012
Additional analyses of samples from RV144 provide insight about what type of
immune response may be needed for an effective vaccine.
2013 HVTN 505 immunizations stopped due to lack of efficacy.

Finding a Cure
Research to find a cure for HIV/AIDS is among NIAID top priorities. NIAID supports a large portfolio of
investigator-initiated grants in HIV cure research to identify where HIV hides, known as the HIV reservoir,
and to determine how these hideouts are established and maintained. In addition, NIAID also funds
research to control and eliminate the viral reservoir.
Goals of NIAID HIV Cure Research

Identify HIV reservoirs throughout the body

Determine the effects of antiretroviral therapy, chemotherapy, and other strategies on the HIV
reservoir

Develop assays and model systems, including a nonhuman primate model, to quantify and study
HIV latency

Characterize viral reservoirs that cause rebounding of viral levels when antiretroviral therapy is
stopped

Determine the role of HIV integration on virus elimination strategies

Determine the role of HIV in hematopoietic progenitor cells regarding cure strategies

Investigate strategies that lead to purging of the latent reservoir and a cure for HIV/AIDS
Funding Opportunities

U.S.-China Program for Research Toward a Cure for HIV/AIDS (R01), (LOI due 10/21/14;
applications due 11/21/14)

Follow That Cell Challenge (for single-cell analysis of latently infected cells in tissues). (Phase 1
applications due 12/16/14; Phase 2 applications due 3/30/15)

Basic Research on HIV Persistence, R01, (Standard Submission dates for AIDS and AIDS-related
Applications)

Basic Research on HIV Persistence, R21, (Standard Submission dates for AIDS and AIDS-related
Applications)

Quantitative Viral Outgrowth Assay (QVOA) Service Resource, RFP-NIAID-DAIDS-NIHAI2013184


(Contract proposals due by 3pm EST on 8/14/2014)

Targeting Latently Infected Cells Without Reactivation (R01), (LOI due 6/15/2014; applications
due 7/15/2014)

Innovative Technologies and Assays in Support of HIV Cure Research (ITAS-Cure), R41/R42,
(Standard Submission dates for AIDS and AIDS-related Applications)

Innovative Technologies and Assays in Support of HIV Cure Research (ITAS-Cure) R43/R44,
(Standard Submission dates for AIDS and AIDS-related Applications)

Improvement of Animal Models for Stem Cell-Based Regenerative Medicine, R24, (Standard Non-
AIDS Submission dates)

Innovative Assays to Quantify the Latent HIV Reservoir (R01), (applications due 11/7/2014)

Ethical Issues in Research in HIV/AIDS and its Co-morbidities, R01 (applications due 1/7/2015)

Ethical Issues in Research in HIV/AIDS and its Co-morbidities, R21 (applications due 1/7/2015)
For updates on potential HIV cure-related funding opportunities, see the latest DAIDS council-approved
concepts
Currently Active Grants (under RFAs and PAs only)

Delivering Therapeutics to Residual Active HIV Reservoirs

Targeting Persistent HIV Reservoirs (TaPHIR)

Basic Research on HIV Persistence

Martin Delaney Collaboratory: Towards an HIV Cure

Beyond HAART: Innovative Therapies to Control HIV-1

Ethical Issues in Research in HIV/AIDS and its Co-morbidities


Scientific Meetings

Antiviral Conference 2014 , September 28 - October 1, 2014, El Jadida, Morocco

Twenty-First West Coast Retrovirus Meeting , October 2-4, 2014, Palm Springs, California

Strategies for an HIV Cure 2014 , October 15-17, 2014, Washington, DC

HIV DART 2014 meeting , December 9-12, 2014, Los Cabos, Mexico

2015 Palm Springs Symposium on HIV/AIDS , March 5-7, 2015 Palm Springs, California

Mechanisms of HIV Persistence: Implications for a Cure , April 26May 1, 2015, Boston,
Massachusetts
External Funding Opportunity Announcements

amfAR

Bill & Melinda Gates Foundation

California Institute for Regenerative Medicine (CIRM)


Resources

Quantitative Viral Outgrowth Assay (QVOA) Resource

NDRI HIV Tissue Procurement Program


What's New

NIH Seeks Input on HIV Cure Research Priorities - March 3, 2014

NIH Expands Focus of Research Funding Opportunity Targeting HIV Reservoirs - February 25,
2014

NIH Seeks Public-Private Proposals for HIV Cure Research - Feb. 5, 2014
All HIV/AIDS News Releases
News From NIAID-Supported Institutions
Ebola Virus
Key facts
Ebola virus disease (EVD), formerly known as Ebola haemorrhagic fever, is a severe, often fatal
illness in humans.
The virus is transmitted to people from wild animals and spreads in the human population
through human-to-human transmission.
The average EVD case fatality rate is around 50%. Case fatality rates have varied from 25% to
90% in past outbreaks.
The first EVD outbreaks occurred in remote villages in Central Africa, near tropical rainforests,
but the most recent outbreak in west Africa has involved major urban as well as rural areas.
Community engagement is key to successfully controlling outbreaks. Good outbreak control
relies on applying a package of interventions, namely case management, surveillance and
contact tracing, a good laboratory service, safe burials and social mobilisation.
Early supportive care with rehydration, symptomatic treatment improves survival. There is as
yet no licensed treatment proven to neutralise the virus but a range of blood, immunological
and drug therapies are under development.
There are currently no licensed Ebola vaccines but 2 potential candidates are undergoing
evaluation.

Background
The Ebola virus causes an acute, serious illness which is often fatal if untreated. Ebola virus
disease (EVD) first appeared in 1976 in 2 simultaneous outbreaks, one in Nzara, Sudan, and the
other in Yambuku, Democratic Republic of Congo. The latter occurred in a village near the
Ebola River, from which the disease takes its name.
The current outbreak in west Africa, (first cases notified in March 2014), is the largest and most
complex Ebola outbreak since the Ebola virus was first discovered in 1976. There have been
more cases and deaths in this outbreak than all others combined. It has also spread between
countries starting in Guinea then spreading across land borders to Sierra Leone and Liberia, by
air (1 traveller only) to Nigeria, and by land (1 traveller) to Senegal.
The most severely affected countries, Guinea, Sierra Leone and Liberia have very weak health
systems, lacking human and infrastructural resources, having only recently emerged from long
periods of conflict and instability. On August 8, the WHO Director-General declared this
outbreak a Public Health Emergency of International Concern.
A separate, unrelated Ebola outbreak began in Boende, Equateur, an isolated part of the
Democratic Republic of Congo.
The virus family Filoviridae includes 3 genera: Cuevavirus, Marburgvirus, and Ebolavirus. There
are 5 species that have been identified: Zaire, Bundibugyo, Sudan, Reston and Ta Forest. The
first 3, Bundibugyo ebolavirus, Zaire ebolavirus, and Sudan ebolavirus have been associated
with large outbreaks in Africa. The virus causing the 2014 west African outbreak belongs to the
Zaire species.
Transmission
It is thought that fruit bats of the Pteropodidae family are natural Ebola virus hosts. Ebola is
introduced into the human population through close contact with the blood, secretions, organs or
other bodily fluids of infected animals such as chimpanzees, gorillas, fruit bats, monkeys, forest
antelope and porcupines found ill or dead or in the rainforest.
Ebola then spreads through human-to-human transmission via direct contact (through broken
skin or mucous membranes) with the blood, secretions, organs or other bodily fluids of infected
people, and with surfaces and materials (e.g. bedding, clothing) contaminated with these fluids.
Health-care workers have frequently been infected while treating patients with suspected or
confirmed EVD. This has occurred through close contact with patients when infection control
precautions are not strictly practiced.
Burial ceremonies in which mourners have direct contact with the body of the deceased person
can also play a role in the transmission of Ebola.
People remain infectious as long as their blood and body fluids, including semen and breast milk,
contain the virus. Men who have recovered from the disease can still transmit the virus through
their semen for up to 7 weeks after recovery from illness.
Symptoms of Ebola virus disease
The incubation period, that is, the time interval from infection with the virus to onset of
symptoms is 2 to 21 days. Humans are not infectious until they develop symptoms. First
symptoms are the sudden onset of fever fatigue, muscle pain, headache and sore throat. This is
followed by vomiting, diarrhoea, rash, symptoms of impaired kidney and liver function, and in
some cases, both internal and external bleeding (e.g. oozing from the gums, blood in the stools).
Laboratory findings include low white blood cell and platelet counts and elevated liver enzymes.
Diagnosis
It can be difficult to distinguish EVD from other infectious diseases such as malaria, typhoid
fever and meningitis. Confirmation that symptoms are caused by Ebola virus infection are made
using the following investigations:
antibody-capture enzyme-linked immunosorbent assay (ELISA)
antigen-capture detection tests
serum neutralization test
reverse transcriptase polymerase chain reaction (RT-PCR) assay
electron microscopy
virus isolation by cell culture.
Samples from patients are an extreme biohazard risk; laboratory testing on non-inactivated
samples should be conducted under maximum biological containment conditions.
Treatment and vaccines
Supportive care-rehydration with oral or intravenous fluids- and treatment of specific symptoms,
improves survival. There is as yet no proven treatment available for EVD. However, a range of
potential treatments including blood products, immune therapies and drug therapies are currently
being evaluated. No licensed vaccines are available yet, but 2 potential vaccines are undergoing
human safety testing.
Prevention and control
Good outbreak control relies on applying a package of interventions, namely case management,
surveillance and contact tracing, a good laboratory service, safe burials and social mobilisation.
Community engagement is key to successfully controlling outbreaks. Raising awareness of risk
factors for Ebola infection and protective measures that individuals can take is an effective way
to reduce human transmission. Risk reduction messaging should focus on several factors:
Reducing the risk of wildlife-to-human transmission from contact with infected fruit bats or
monkeys/apes and the consumption of their raw meat. Animals should be handled with gloves
and other appropriate protective clothing. Animal products (blood and meat) should be
thoroughly cooked before consumption.
Reducing the risk of human-to-human transmission from direct or close contact with people
with Ebola symptoms, particularly with their bodily fluids. Gloves and appropriate personal
protective equipment should be worn when taking care of ill patients at home. Regular hand
washing is required after visiting patients in hospital, as well as after taking care of patients at
home.
Outbreak containment measures including prompt and safe burial of the dead, identifying
people who may have been in contact with someone infected with Ebola, monitoring the health
of contacts for 21 days, the importance of separating the healthy from the sick to prevent
further spread, the importance of good hygiene and maintaining a clean environment.
Controlling infection in health-care settings:
Health-care workers should always take standard precautions when caring for patients, regardless
of their presumed diagnosis. These include basic hand hygiene, respiratory hygiene, use of
personal protective equipment (to block splashes or other contact with infected materials), safe
injection practices and safe burial practices.
Health-care workers caring for patients with suspected or confirmed Ebola virus should apply
extra infection control measures to prevent contact with the patients blood and body fluids and
contaminated surfaces or materials such as clothing and bedding. When in close contact (within
1 metre) of patients with EBV, health-care workers should wear face protection (a face shield or
a medical mask and goggles), a clean, non-sterile long-sleeved gown, and gloves (sterile gloves
for some procedures).
Laboratory workers are also at risk. Samples taken from humans and animals for investigation of
Ebola infection should be handled by trained staff and processed in suitably equipped
laboratories.
WHO response
WHO aims to prevent Ebola outbreaks by maintaining surveillance for Ebola virus disease and
supporting at-risk countries to developed preparedness plans. The document provides overall
guidance for control of Ebola and Marburg virus outbreaks:
Ebola and Marburg virus disease epidemics: preparedness, alert, control, and evaluation
When an outbreak is detected WHO responds by supporting surveillance, community
engagement, case management, laboratory services, contact tracing, infection control, logistical
support and training and assistance with safe burial practices.
WHO has developed detailed advice on Ebola infection prevention and control:
Infection prevention and control guidance for care of patients with suspected or confirmed
Filovirus haemorrhagic fever in health-care settings, with focus on Ebola
Table: Chronology of previous Ebola virus disease outbreaks

Year Country Ebolavirus species Cases Deaths Case fatality

2012 Democratic Republic of Congo Bundibugyo 57 29 51%

2012 Uganda Sudan 7 4 57%

2012 Uganda Sudan 24 17 71%

2011 Uganda Sudan 1 1 100%

2008 Democratic Republic of Congo Zaire 32 14 44%

2007 Uganda Bundibugyo 149 37 25%

Year Country Ebolavirus species Cases Deaths Case fatality

2007 Democratic Republic of Congo Zaire 264 187 71%

2005 Congo Zaire 12 10 83%

2004 Sudan Sudan 17 7 41%

2003 (Nov-Dec) Congo Zaire 35 29 83%

2003 (Jan-Apr) Congo Zaire 143 128 90%

2001-2002 Congo Zaire 59 44 75%

2001-2002 Gabon Zaire 65 53 82%

2000 Uganda Sudan 425 224 53%

1996 South Africa (ex-Gabon) Zaire 1 1 100%

1996 (Jul-Dec) Gabon Zaire 60 45 75%

1996 (Jan-Apr) Gabon Zaire 31 21 68%

1995 Democratic Republic of Congo Zaire 315 254 81%

1994 Cote d'Ivoire Ta Forest 1 0 0%

1994 Gabon Zaire 52 31 60%

1979 Sudan Sudan 34 22 65%

1977 Democratic Republic of Congo Zaire 1 1 100%

1976 Sudan Sudan 284 151 53%

1976 Democratic Republic of Congo Zaire 318 280 88%


Ebola Virus









Life Cycle of the Malaria Parasite
1. A female Anopheles mosquito carrying malaria-causing
parasites feeds on a human and injects the parasites in the
form of sporozoites into the bloodstream. The sporozoites
travel to the liver and invade liver cells.
2. Over 5-16 days*, the sporozoites grow, divide, and produce
tens of thousands of haploid forms, called merozoites, per
liver cell. Some malaria parasite species remain dormant for
extended periods in the liver, causing relapses weeks or
months later.
3. The merozoites exit the liver cells and re-enter the
bloodstream, beginning a cycle of invasion of red blood
cells, asexual replication, and release of newly formed
merozoites from the red blood cells repeatedly over 1-3
days*. This multiplication can result in thousands of
parasite-infected cells in the host bloodstream, leading to
illness and complications of malaria that can last for months
if not treated.
4. Some of the merozoite-infected blood cells leave the cycle
of asexual multiplication. Instead of replicating, the
merozoites in these cells develop into sexual forms of the
parasite, called male and female gametocytes, that circulate
in the bloodstream.
5. When a mosquito bites an infected human, it ingests the
gametocytes. In the mosquito gut, the infected human blood
cells burst, releasing the gametocytes, which develop
further into mature sex cells called gametes. Male and female gametes fuse to form diploid zygotes,
which develop into actively moving ookinetes that burrow into the mosquito midgut wall and form
oocysts.
6. Growth and division of each oocyst produces thousands of active haploid forms called sporozoites.
After 8-15 days*, the oocyst bursts, releasing sporozoites into the body cavity of the mosquito, from
which they travel to and invade the mosquito salivary glands. The cycle of human infection re-starts
when the mosquito takes a blood meal, injecting the sporozoites from its salivary glands into the
human bloodstream .
* Time-frame depends on the malaria parasite species.

More than 40 percent of the worlds population lives in areas where there is a risk of contracting
malaria.

A child dies of malaria every 30 seconds.

Nearly one million people die of malaria every year, mostly infants, young children, and pregnant
women and most of them in Africa.

Approximately 300 to 500 million cases of clinical malaria occur each year.

Malaria accounts for at least $12 billion in economic losses each year in Africa, and a reduction in
annual economic growth estimated at 1.3 percent.
Malaria is caused by a single-celled parasite from the genus Plasmodium. More than 100 different
species of Plasmodium exist. They produce malaria in many types of animals and birds, as well as in
humans.
Glossary
Diploid: Cells containing a full set of
chromosomes.
Gametes: Reproductive elements,
male and female.
Gametocytes: Precursors of the
sexual forms of the malaria parasite,
which release either male or female
gametes within the stomach of the
mosquito.
Haploid: Cells containing a half set of
chromosomes.
Merozoite: The form of the malaria
parasite that invades red blood cells.
Oocyst: A stage of the malaria
parasite within the mosquito which is
produced when male and female
gametes combine.
Ookinete: The actively moving zygote
of the malarial organism that
penetrates the mosquito stomach to
form an oocyst under the outer gut
lining.
Sporozoite: The infectious form of the
malaria parasite, which is injected into
people by mosquitoes.
Zygote: The diploid cell resulting from
union of a male and a female gamete.
Four species of Plasmodium commonly infect humans. Each one has a distinctive appearance under the
microscope, and each one produces a somewhat different pattern of symptoms. Two or more species can
live in the same area and infect a single person at the same time.

Plasmodium falciparum is responsible for most malaria deaths, especially in Africa. The infection
can develop suddenly and produce several life-threatening complications. With prompt, effective
treatment, however, it is almost always curable.

Plasmodium vivax, the most geographically widespread of the species, produces less severe
symptoms. Relapses, however, can occur for up to 3 years, and chronic disease is debilitating.
Once common in temperate climates, P. vivax is now found mostly in the tropics, especially
throughout Asia.

Plasmodium malariae infections not only produce typical malaria symptoms but also can persist
in the blood for very long periods, possibly decades, without ever producing symptoms. A person
with asymptomatic (no symptoms) P. malariae, however, can infect others, either through blood
donation or mosquito bites. P. malariae has been wiped out from temperate climates, but it
persists in Africa.

Plasmodium ovale is rare, can cause relapses, and generally occurs in West Africa.
Transmission
The malaria parasite typically is transmitted to people by mosquitoes belonging to the genus Anopheles.
In rare cases, a person may contract malaria through contaminated blood. Malaria also may be
transmitted from a mother to her fetus before or during delivery ("congenital" malaria).
Because the malaria parasite is found in red blood cells, malaria can also be transmitted through blood
transfusion, organ transplant, or the shared use of needles or syringes contaminated with blood.
Symptoms
Malaria typically produces a string of recurrent attacks, or paroxysms, each of which has three stages
chills, followed by fever, and then sweating. Along with chills, the person is likely to have headache,
malaise, fatigue, muscular pains, occasional nausea, vomiting, and diarrhea. Within an hour or two, the
body temperature rises, and the skin feels hot and dry. Then, as the body temperature falls, a drenching
sweat begins. The person, feeling tired and weak, is likely to fall asleep.
The symptoms first appear some 10 to 16 days after the infectious mosquito bite and coincide with the
bursting of infected red blood cells (RBCs). When many RBCs are infected and break at the same time,
malaria attacks can recur at regular time periodsevery 2 days for Plasmodium vivax malaria and P.
ovale, and every 3 days for P. malariae.
With P. vivax malaria, the person may feel fine between attacks. Even without treatment, the paroxysms
subside in a few weeks. A person with P. falciparum malaria, however, is likely to feel miserable even
between attacks and, without treatment, may die. One reason P. falciparum malaria is so virulent is that
the parasite can infect RBCs in all stages of development, leading to very high parasite levels in the
blood. In contrast, P. vivax parasites infect only young RBCs, which means the number of parasites in the
blood does not reach the same high levels as seen in P. falciparum infection.

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