smallpox

• Smallpox


  • The scourge of humanity
  • it first impacted humans 3,000 to 12,000 years ago
  • How the virus evolved to infect humans is unknown
  • Today, NOT zoonotic pathogen and does NOT impact animals
• In the 20th century alone, smallpox caused around 300 million deaths worldwide

  • Almost everybody contracted disease
  • The last natural OUTBREAK in US was in 1949
  • The last natural CASE in world was in Somalia in 1977
  • WHO declared endemic smallpox eradicated in 1980 after world vaccine campaign
• Poxviruses


  • Large DNA viruses
  • Stable in environment
  • Among the largest and most complex of all viruses
  • Characteristically a "brick-shaped" structure with a diameter of ~200 nm
• Representative poxviruses

  • Variola virus (smallpox)
  • Cowpox virus (broad host range)
  • Vaccinia virus (broad host range)
  • Horsepox virus
  • Fowlpox virus
  • Canarypox virus
  • Sheeppox virus
  • Mpox virus (zoonotic infection)
• Human-to-human transmission of smallpox


  • Primarily, inhalation of large, virus-containing airborne droplets of saliva from an infected person
  • Direct contact with infected bodily fluids (skin lesions)
  • Contaminated objects like bedding or clothing
• There are no known animal or insect reservoirs or vectors for smallpox
• Smallpox: disease manifestation

  • Incubation period: 7-17 days (average 12 days)
  • Illness begins with fever, headache, backache (prodrome)
  • Patients are considered infectious from the earliest onset of small painful ulcerations on the tongue and oropharynx that extend to a skin rash on the face, hands, forearms, and trunk
  • The rash progresses through stages of papules, vesicles, pustules, and scabs
  • Patients remain infectious until the separation of scabs

  
• Pathogenesis and clinical presentation

  • Initial clinical symptoms consist of fever, malaise, rigors, vomiting, headache, backache, and prostration
  • The eruptive phase consists of a disfiguring rash with scar formation
  • Scabs start to fall off around 14 days after rash onset
  • By 3 weeks, most scabs will have fallen off
  • Possible sequelae –blindness, encephalitis (inflammation of the brain), osteomyelitis (bone infection), stillbirths and miscarriage, infertility

  
• Pathogenesis and clinical presentation (continued)

  • Painful ulcerations and rash begin on the tongue and mouth that progresses to face, extremities, and trunk
  • Rash begins as small red rash (2-3 mm)
  • Macules progress to vesicles (3-5 mm)
  • Vesicles become pustules (4-6 mm)
  • Pustules form scabs 8–14 days after onset that leaves depressed, depigmented scars after healing
  • "Centrifugal" distribution – lesions more abundant on extremities and face -> a clinical diagnostic feature
• Two distinct forms of smallpox

  • Variola major (most common): ~30% case fatality rate in unvaccinated individuals. Higher in some popu. like natives, older etc. Two major forms:
  • Hemorrhagic-type: occurred in 2-3% of all cases with ~95% case fatality rate in unvaccinated individuals
  • Flat-type: occurred in 2-5% of all cases with ~95% case fatality rate in unvaccinated individuals
  • Variola minor: milder disease recognized in the 20th century: <1% fatality rate in unvaccinated individuals

  
• Medical management of smallpox

  • Symptomatic care
  • Patients require isolation using both droplet and airborne precautions
  • Asymptomatic contacts should be quarantined for 17 days after exposure to a confirmed case
  • Each case is estimated to be able to infect up to 10 additional people (conservative estimate)
  • The vaccine is effective in preventing smallpox when given before exposure and was essential to smallpox eradication
  • Vaccines can be effective as a post-exposure prophylaxis if administered before symptoms manifest
  • An antiviral is now available, but it is unknown how effective it will be clinically

  
• The global spread of smallpox correlates with the growth of civilizations and exploration
• Highlights from history of smallpox spread

  • 6th century –Increased trade with China and Korea brings smallpox to Japan
  • 7th century –Arab expansion brings smallpox to northern Africa, Spain, and Portugal
  • 11th century –Crusaders spread smallpox in Europe
  • 16th century –European settlers and African slave trade import smallpox into the Caribbean, Central, and South America
  • 17th century –European settlers bring smallpox to North America
  • 18th century –Explores from Great Britain bring smallpox to Australia
• Today, an emerging novel viral outbreak anywhere is only a plane ride away from spreading to your community
• Effect of smallpox on Native Americans and civilizations

  • Native Americans were very healthy and brought few infections with them, but were physically strong and immunologically weak
  • 1492 - Columbus sailed to America, his crew carried European diseases which they transmitted to the native islanders
  • Over many generations, Europeans had encountered diverse infections such as measles, influenza, and smallpox, and the weak died while the survivors passed on their genes, making Europeans have stronger immunity
• Smallpox in Native Americans

  • Pox lesions went deeper into the skin
  • Bleeding occurred into the lesions
  • Skin peeled off
  • Massive loss of fluid and blood
  • Death by fluid loss
  • Mortality – over 50% and up to 90%
• Smallpox made it easy for Spaniards the conquest of Central America, caused the demise of Aztec Empire in Mexico, and led to the collapse of the Inca Empire in Peru
• Smallpox caused the collapse of Mississippian civilization, and French pirates brought smallpox to Massachusetts – wiping out coastal tribes, allowing the Pilgrims to settle a territory empty of native inhabitants
• During the French and Indian Wars, the British deliberately gave smallpox blankets to native tribes (biological warfare?)
• Variolation


  • An obsolete method of immunizing people against smallpox by infecting them with substance from the pustules of patients with a mild form of the disease (variola minor)
  • Inhaling dried scab material
  • Scratching pustule material into the skin with a lancet
  • The disease then usually occurred in a less dangerous form than when contracted naturally
  • The recovered individuals were immune to smallpox infection for life
  • Not risk-free (up to 1% mortality following variolation)
• Variolation in Europe

  • Letter to the Royal Society of London by Emanuel Timonius in 1713 about the practice of variolation in Constantinople (Ottoman Empire)
  • Conservative English physicians were skeptical and did not approve of its use
• Lady Mary Montagu 1689-1762


  • She survived smallpox and was largely responsible for turning public opinion in favor of variolation in Britain
  • She inoculated her daughter in 1721 and convinced the College of Physicians to demonstrate variolation in prisoners and orphans
  • Variolation was adopted by the Royal Society and gained general acceptance
• Variolation in USA


  • An African slave, Onesimus, informed Cotton Mather about the practice in 1707
  • In 1721, with Zabdiel Boylston, a physician, Cotton Mather conducted a variolation trial in Boston during a smallpox outbreak
  • Variolation was opposed and outlawed in many colonies for several years
• Lady Mary Montagu


  An English aristocrat who was largely responsible for turning public opinion in favor of variolation in Britain
• The death rate was 1 in 40 in the variolation groups, compared to 1 in 7 in the naturally infected groups
• Cotton Mather


  A Minister in Boston
• Variolation and the American Revolution

  • Smallpox was brought to Boston by British troops who came to stamp out the rebellion during the American Revolution (1775-1778)
  • Most Americans were not immune
  • George Washington's Continental Army
  • Strict control measures to protect soldiers
  • Continental Congress was opposed to variolation
  • 1777-78; Washington boldly used variolation to protect his
  • army
• Variolation was the first massive state-funded immunization campaign in American history

  • Washington realized smallpox could cripple his army ending the war before it began
  • Smallpox variolation was a massive logistical undertaken conducted in secrecy
  • It was not the deciding factor, but it was a bold move that prevented early defeat
• The Continental Army faced dual enemies: British soldiers (protected by herd immunity) and smallpox (revolutionary soldiers unprotected)
• Vaccination replaces variolation


  1796
• Edward Jenner


  • The Latin word for cow is vacca
  • Cowpox is also called vaccinia.
  • Jenner described the new procedure, vaccination,
  • Was not the first to observe that cowpox exposure and its lesions protected against smallpox
  • He was the first to apply scientific rigor to understanding the observation
  • credited with discovering vaccination
• In 1855, Massachusetts was the first state to require that children have a smallpox vaccine before going to school to prevent the spread of smallpox in schools
• The WHO smallpox eradication campaign was initiated in 1958 but did not take much traction initially

  • Became a diplomatic priority
  • Vaccinia virus was used as a vaccine
  • A virus derived from horsepox virus and propagated in cows
• On May 8, 1980, the WHO officially declared that smallpox had been eradicated, making it the first and only human infectious disease to be eradicated
• The last smallpox death was in 1978 of Janet Parker, a laboratory worker in the UK who was accidentally infected
• The smallpox eradication program cost approximately $300 million from 1967-1980, compared to $24 billion to put a man on the moon
• In 1967, there were 10 million smallpox cases and 2 million deaths, but by 1972 the last U.S. vaccination was given
• Reasons for the success of smallpox eradication


  • High quality, freeze dried, affordable vaccine available
  • Bifurcated needle
  • Case surveillance system
  • Diseased patients easily identifiable (contact tracing)
  • Mass vaccination campaigns, ring vaccination strategy
  • Vaccinees easily identifiable (scar afterwards)
  • No animal reservoir
• Today, the global population is immunologically naïve should smallpox return
• The only remaining official live variola virus stocks are kept at the CDC in Atlanta, Georgia, US and the Russian State Centre for Research on Virology and Biotechnology in Koltsovo, Russian Federation