Since human plague is rare in most parts of the world, routine vaccination is not needed other than for those at particularly high risk of exposure, nor for people living in areas with enzootic plague, meaning it occurs at regular, predictable rates in populations and specific areas, such as the western United States. It is not even indicated for most travellers to countries with known recent reported cases, particularly if their travel is limited to urban areas with modern hotels. The CDC thus only recommends vaccination for: (1) all laboratory and field personnel who are working with "Y. pestis" organisms resistant to antimicrobials; (2) people engaged in aerosol experiments with "Y. pestis"; and (3) people engaged in field operations in areas with enzootic plague where preventing exposure is not possible (such as some disaster areas).

A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine.

Transmission of "Y. pestis" to an uninfected individual is possible by any of the following means.

- droplet contact – coughing or sneezing on another person

- direct physical contact – touching an infected person, including sexual contact

- indirect contact – usually by touching soil contamination or a contaminated surface

- airborne transmission – if the microorganism can remain in the air for long periods

- fecal-oral transmission – usually from contaminated food or water sources

- vector borne transmission – carried by insects or other animals.

"Yersinia pestis" circulates in animal reservoirs, particularly in rodents, in the natural foci of infection found on all continents except Australia. The natural foci of plague are situated in a broad belt in the tropical and sub-tropical latitudes and the warmer parts of the temperate latitudes around the globe, between the parallels 55 degrees North and 40 degrees South.

Contrary to popular belief, rats did not directly start the spread of the bubonic plague. It is mainly a disease in the fleas ("Xenopsylla cheopis") that infested the rats, making the rats themselves the first victims of the plague. Infection in a human occurs when a person is bitten by a flea that has been infected by biting a rodent that itself has been infected by the bite of a flea carrying the disease. The bacteria multiply inside the flea, sticking together to form a plug that blocks its stomach and causes it to starve. The flea then bites a host and continues to feed, even though it cannot quell its hunger, and consequently the flea vomits blood tainted with the bacteria back into the bite wound. The bubonic plague bacterium then infects a new person and the flea eventually dies from starvation. Serious outbreaks of plague are usually started by other disease outbreaks in rodents, or a rise in the rodent population.

Bubonic plague is an infection of the lymphatic system, usually resulting from the bite of an infected flea, "Xenopsylla cheopis" (the rat flea). In very rare circumstances, as in the septicemic plague, the disease can be transmitted by direct contact with infected tissue or exposure to the cough of another human. The flea is parasitic on house and field rats, and seeks out other prey when its rodent hosts die. The bacteria remain harmless to the flea, allowing the new host to spread the bacteria. The bacteria form aggregates in the gut of infected fleas and this results in the flea regurgitating ingested blood, which is now infected, into the bite site of a rodent or human host. Once established, bacteria rapidly spread to the lymph nodes and multiply.

"Y. pestis" bacilli can resist phagocytosis and even reproduce inside phagocytes and kill them. As the disease progresses, the lymph nodes can haemorrhage and become swollen and necrotic. Bubonic plague can progress to lethal septicemic plague in some cases. The plague is also known to spread to the lungs and become the disease known as the pneumonic plague.

Human "Yersinia" infections most commonly result from the bite of an infected flea or occasionally an infected mammal, but like most bacterial systemic diseases, the disease may be transmitted through an opening in the skin or by inhaling infectious droplets of moisture from sneezes or coughs. In both cases septicemic plague need not be the result, and in particular, not the initial result, but it occasionally happens that bubonic plague for example leads to infection of the blood, and septicemic plague results. If the bacteria happen to enter the bloodstream rather than the lymph or lungs, they multiply in the blood, causing bacteremia and severe sepsis. In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), where tiny blood clots form throughout the body, commonly resulting in localised ischemic necrosis, tissue death from lack of circulation and perfusion.

DIC results in depletion of the body's clotting resources, so that it can no longer control bleeding. Consequently, the unclotted blood bleeds into the skin and other organs, leading to red or black patchy rash and to hematemesis (vomiting blood) or hemoptysis (spitting blood). The rash may cause bumps on the skin that look somewhat like insect bites, usually red, sometimes white in the center.

Untreated septicemic plague is almost always fatal. Early treatment with antibiotics reduces the mortality rate to between 4 and 15 percent. Death is almost inevitable if treatment is delayed more than about 24 hours, and some people may even die on the same day they with the disease.

Septicemic plague is caused by horizontal and direct transmission. Horizontal transmission is the transmitting of a disease from one individual to another regardless of blood relation. Direct transmission occurs from close physical contact with individuals, through common air usage, from direct bite from a flea or an infected rodent. Most common rodents may carry the bacteria and so may Leporidae such as rabbits:

Significant carriers of the bacteria in the United States include:

- Rats

- Prairie dogs

- Squirrels

- Chipmunks

- Rabbits

The bacteria are cosmopolitan, mainly in rodents in all continents except Australia and Antarctica. The greatest frequency of human plague infections occur in Africa. The bacteria most commonly appear in rural areas and wherever there is poor sanitation, overcrowding, and high rodent populations in urban areas. Outdoor activities such as hiking, camping, or hunting where plague-infected animals may be found, increase the risk of contracting septicemic plague, and so do certain occupations such as veterinary or other animal-related work.

Pneumonic plague can be caused in two ways: primary, which results from the inhalation of aerosolised plague bacteria, or secondary, when septicaemic plague spreads into lung tissue from the bloodstream. Pneumonic plague is "not" exclusively vector-borne like bubonic plague; instead it can be spread from person to person. There have been cases of pneumonic plague resulting from the dissection or handling of contaminated animal tissue. This is one type of the plague formerly known as the Black Death.

Bubonic plague is one of three types of plague caused by bacterium "Yersinia pestis". One to seven days after exposure to the bacteria, flu like symptoms develop. These include fever, headaches, and vomiting. Swollen and painful lymph nodes occur in the area closest to where the bacteria entered the skin. Occasionally the swollen lymph nodes may break open.

The three types of plague are the result of the route of infection: bubonic plague, septicemic plague, and pneumonic plague. Bubonic plague is mainly spread by infected fleas from small animals. It may also result from exposure to the body fluids from a dead plague infected animal. In the bubonic form of plague, the bacteria enter through the skin through a flea bite and travel via the lymphatic vessels to a lymph node, causing it to swell. Diagnosis is made by finding the bacteria in the blood, sputum, or fluid from lymph nodes.

Prevention is through public health measures such as not handling dead animals in areas where plague is common. Vaccines have not been found to be very useful for plague prevention. Several antibiotics are effective for treatment including streptomycin, gentamicin, and doxycycline. Without treatment it results in the death of 30% to 90% of those infected. Death, if it occurs, is typically within ten days. With treatment the risk of death is around 10%. Globally there are about 650 documented cases a year which result in ~120 deaths. The disease is most common in Africa.

The plague is believed to be the cause of the Black Death that swept through Asia, Europe, and Africa in the 14th century and killed an estimated 50 million people. This was about 25% to 60% of the European population. Because the plague killed so many of the working population, wages rose due to the demand for labor. Some historians see this as a turning point in European economic development. The term "bubonic" is derived from the Greek word , meaning "groin". The term "buboes" is also used to refer to the swollen lymph nodes.

The following steps and precautions should be used to avoid infection of the septicemic plague:

- Caregivers of infected patients should wear masks, gloves, goggles and gowns

- Take antibiotics if close contact with infected patient has occurred

- Use insecticides throughout house

- Avoid contact with dead rodents or sick cats

- Set traps if mice or rats are present around the house

- Do not allow family pets to roam in areas where plague is common

- Flea control and treatment for animals (especially rodents)

Since 2002, the World Health Organization (WHO) has reported seven plague outbreaks, though some may go unreported because they often happen in remote areas. Between 1998 and 2009, nearly 24,000 cases have been reported, including about 2,000 deaths, in Africa, Asia, the Americas, and Eastern Europe. Ninety-eight percent of the world's cases occur in Africa.

Since the invention of antibiotics, the rate of death associated with tularemia has decreased from 60% to less than 4%.

There are no safe, available, approved vaccines against tularemia. However, vaccination research and development continues, with live attenuated vaccines being the most thoroughly researched and most likely candidate for approval. Sub-unit vaccine candidates, such as killed-whole cell vaccines, are also under investigation, however research has not reached a state of public use.

Optimal preventative practices include limiting direct exposure when handling potentially infected animals, such as wearing gloves and face masks while handling potentially infected animals (importantly when skinning deceased animals).

The overall case-fatality rate for ordinary-type smallpox is about 30 percent, but varies by pock distribution: ordinary type-confluent is fatal about 50–75 percent of the time, ordinary-type semi-confluent about 25–50 percent of the time, in cases where the rash is discrete the case-fatality rate is less than 10 percent. The overall fatality rate for children younger than 1 year of age is 40–50 percent. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat-type is 90 percent or greater and nearly 100 percent is observed in cases of hemorrhagic smallpox. The case-fatality rate for variola minor is 1 percent or less. There is no evidence of chronic or recurrent infection with variola virus.

In fatal cases of ordinary smallpox, death usually occurs between the tenth and sixteenth days of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating immune complexes, overwhelming viremia, or an uncontrolled immune response may be contributing factors. In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. Cause of death in hemorrhagic cases involved heart failure, sometimes accompanied by pulmonary edema. In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death. In flat smallpox modes of death are similar to those in burns, with loss of fluid, protein and electrolytes beyond the capacity of the body to replace or acquire, and fulminating sepsis.

Feeding on a human who carries the bacterium infects the louse. "R. prowazekii" grows in the louse's gut and is excreted in its feces. The disease is then transmitted to an uninfected human who scratches the louse bite (which itches) and rubs the feces into the wound. The incubation period is one to two weeks. "R. prowazekii" can remain viable and virulent in the dried louse feces for many days. Typhus will eventually kill the louse, though the disease will remain viable for many weeks in the dead louse.

Epidemic typhus has historically occurred during times of war and deprivation. For example, typhus killed hundreds of thousands of prisoners in Nazi concentration camps during World War II. The deteriorating quality of hygiene in camps such as Auschwitz, Theresienstadt, and Bergen-Belsen created conditions where diseases such as typhus flourished. Situations in the twenty-first century with potential for a typhus epidemic would include refugee camps during a major famine or natural disaster. In the periods between outbreaks, when human to human transmission occurs less often, the flying squirrel serves as a zoonotic reservoir for the "Rickettsia prowazekii" bacterium.

Henrique da Rocha Lima in 1916 then proved that the bacterium "Rickettsia prowazekii" was the agent responsible for typhus; he named it after H. T. Ricketts and Stanislaus von Prowazek, two zoologists who had died from typhus while investigating epidemics. Once these crucial facts were recognized, Rudolf Weigl in 1930 was able to fashion a practical and effective vaccine production method by grinding up the insides of infected lice that had been drinking blood. It was, however, very dangerous to produce, and carried a high likelihood of infection to those who were working on it.

A safer mass-production-ready method using egg yolks was developed by Herald R. Cox in 1938. This vaccine was widely available and used extensively by 1943.

Sylvatic plague is primarily transmitted among wildlife through flea bites and contact with contaminated fluids or tissue, through predation or scavenging. Humans can contract plague from wildlife through flea bites and handling animal carcasses.

Sylvatic plague is most commonly found in prairie dog colonies; the flea that feeds on prairie dogs (and other mammals) serves as the vector for transmission to the new host.

Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia. Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated.

Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2 percent of all cases). Pustules can form on the eyelid, conjunctiva, and cornea, leading to complications such as conjunctivitis, keratitis, corneal ulcer, iritis, iridocyclitis, and optic atrophy. Blindness results in approximately 35 percent to 40 percent of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2 to 5 percent of young children with smallpox, virions reach the joints and bone, causing "osteomyelitis variolosa". Lesions are symmetrical, most common in the elbows, tibia, and fibula, and characteristically cause separation of an epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis, malformed bones, flail joints, and stubby fingers.

Symptoms include severe headache, a sustained high fever, cough, rash, severe muscle pain, chills, falling blood pressure, stupor, sensitivity to light, delirium and death. A rash begins on the chest about five days after the fever appears, and spreads to the trunk and extremities. A symptom common to all forms of typhus is a fever which may reach 39 °C (102 °F).

Brill-Zinsser disease, first described by Nathan Brill in 1913 at Mount Sinai Hospital in New York City, is a mild form of epidemic typhus which recurs in someone after a long period of latency (similar to the relationship between chickenpox and shingles). This recurrence often occurs in times of relative immunosuppression, which is often in the context of malnutrition and other illnesses. In combination with poor sanitation and hygiene which leads to a greater density of lice, this reactivation is why typhus forms epidemics in times of social chaos and upheaval.

Common vectors for urban plague are house mice, black rats, and Norway rats.

The bacterium that causes typhoid fever may be spread through poor hygiene habits and public sanitation conditions, and sometimes also by flying insects feeding on feces. Public education campaigns encouraging people to wash their hands after defecating and before handling food are an important component in controlling spread of the disease. According to statistics from the United States Centers for Disease Control and Prevention (CDC), the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever in the United States.

Urban plague is an infectious disease among rodent species that live in close association with humans in urban areas. It is caused by the bacterium Yersinia pestis which is the same bacterium that causes bubonic and pneumonic plague in humans. Plague was first introduced into the United States in 1900 by rat–infested steamships that had sailed from affected areas, mostly from Asia. Urban plague spread from urban rats to rural rodent species, especially among prairie dogs in the western United States.

As resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and streptomycin is now common, these agents have not been used as first–line treatment of typhoid fever for almost 20 years. Typhoid resistant to these agents is known as multidrug-resistant typhoid (MDR typhoid).

Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia. Many centres are shifting from using ciprofloxacin as the first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand, or Vietnam. For these people, the recommended first-line treatment is ceftriaxone. Also, azithromycin has been suggested to be better at treating typhoid in resistant populations than both fluoroquinolone drugs and ceftriaxone. Azithromycin significantly reduces relapse rates compared with ceftriaxone.

A separate problem exists with laboratory testing for reduced susceptibility to ciprofloxacin: current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), and that isolates that are sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", but that isolates testing sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". However, an analysis of 271 isolates showed that around 18% of isolates with a reduced susceptibility to ciprofloxacin (MIC 0.125–1.0 mg/l) would not be picked up by this method. How this problem can be solved is not certain, because most laboratories around the world (including the West) are dependent on disk testing and cannot test for MICs.

Currently, no vaccine against relapsing fever is available, but research continues. Developing a vaccine is very difficult because the spirochetes avoid the immune response of the infected person (or animal) through antigenic variation. Essentially, the pathogen stays one step ahead of antibodies by changing its surface proteins. These surface proteins, lipoproteins called variable major proteins, have only 30–70% of their amino acid sequences in common, which is sufficient to create a new antigenic "identity" for the organism. Antibodies in the blood that are binding to and clearing spirochetes expressing the old proteins do not recognize spirochetes expressing the new ones. Antigenic variation is common among pathogenic organisms. These include the agents of malaria, gonorrhea, and sleeping sickness. Important questions about antigenic variation are also relevant for such research areas as developing a vaccine against HIV and predicting the next influenza pandemic.

A spotted fever is a type of tick-borne disease which presents on the skin. They are all caused by bacteria of the genus "Rickettsia". Typhus is a group of similar diseases also caused by "Rickettsia" bacteria, but spotted fevers and typhus are different clinical entities.

The phrase apparently originated in Spain in the seventeenth century and was ‘loosely applied in England to typhus or any fever involving petechial eruptions.’ During the seventeenth and eighteenth centuries, it was thought to be ‘“cousin-germane” to and herald of the bubonic plague’, a disease which periodically afflicted the city of London and its environs during the sixteenth and seventeenth centuries, most notably during the Great Plague of 1665.

Types of spotted fevers include:

- Mediterranean spotted fever

- Rocky Mountain spotted fever

- Queensland tick typhus

- Helvetica Spotted fever

In 2012, the World Health Organization estimated that vaccination prevents 2.5 million deaths each year. If there is 100% immunization, and 100% efficacy of the vaccines, one out of seven deaths among young children could be prevented, mostly in developing countries, making this an important global health issue. Four diseases were responsible for 98% of vaccine-preventable deaths: measles, "Haemophilus influenzae" serotype b, pertussis, and neonatal tetanus.

The Immunization Surveillance, Assessment and Monitoring program of the WHO monitors and assesses the safety and effectiveness of programs and vaccines at reducing illness and deaths from diseases that could be prevented by vaccines.

Vaccine-preventable deaths are usually caused by a failure to obtain the vaccine in a timely manner. This may be due to financial constraints or to lack of access to the vaccine. A vaccine that is generally recommended may be medically inappropriate for a small number of people due to severe allergies or a damaged immune system. In addition, a vaccine against a given disease may not be recommended for general use in a given country, or may be recommended only to certain populations, such as young children or older adults. Every country makes its own vaccination recommendations, based on the diseases that are common in its area and its healthcare priorities. If a vaccine-preventable disease is uncommon in a country, then residents of that country are unlikely to receive a vaccine against it. For example, residents of Canada and the United States do not routinely receive vaccines against yellow fever, which leaves them vulnerable to infection if travelling to areas where risk of yellow fever is highest (endemic or transitional regions).

Along with "Rickettsia prowazekii" and "Bartonella quintana", "Borrelia recurrentis" is one of three pathogens of which the body louse ("Pediculus humanus humanus") is a vector. Louse-borne relapsing fever is more severe than the tick-borne variety.

Louse-borne relapsing fever occurs in epidemics amid poor living conditions, famine and war in the developing world. It is currently prevalent in Ethiopia and Sudan.

Mortality rate is 1% with treatment and 30–70% without treatment. Poor prognostic signs include severe jaundice, severe change in mental status, severe bleeding and a prolonged QT interval on ECG.

Lice that feed on infected humans acquire the "Borrelia" organisms that then multiply in the gut of the louse. When an infected louse feeds on an uninfected human, the organism gains access when the victim crushes the louse or scratches the area where the louse is feeding. "B. recurrentis" infects the person via mucous membranes and then invades the bloodstream. No non-human, animal reservoir exists.

Measures to reduce contact between the vesper mouse and humans may have contributed to limiting the number of outbreaks, with no cases identified between 1973 and 1994. Although there are no cures or vaccine for the disease, a vaccine developed for the genetically related Junín virus which causes Argentine hemorrhagic fever has shown evidence of cross-reactivity to Machupo virus, and may therefore be an effective prophylactic measure for people at high risk of infection. Post infection (and providing that the person survives the infection), those that have contracted BHF are usually immune to further infection of the disease.