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WHO
Fact Sheet on Smallpox
October 2001
Smallpox is an acute contagious disease
caused by variola virus, a member of the orthopoxvirus family.
Smallpox, which is believed to have
originated over 3,000 years ago in India or Egypt, is one of the most devastating diseases
known to humanity. For centuries, repeated epidemics swept across continents, decimating
populations and changing the course of history.
In some ancient cultures, smallpox was such
a major killer of infants that custom forbade the naming of a newborn until the infant had
caught the disease and proved it would survive.
Smallpox killed Queen Mary II of England,
Emperor Joseph I of Austria, King Luis I of Spain, Tsar Peter II of Russia, Queen Ulrika
Elenora of Sweden, and King Louis XV of France.
The disease, for which no effective
treatment was ever developed, killed as many as 30% of those infected. Between 6580%
of survivors were marked with deep pitted scars (pockmarks), most prominent on the face.
Blindness was another complication. In 18th
century Europe, a third of all reported cases of blindness was due to smallpox. In a
survey conducted in Viet Nam in 1898, 95% of adolescent children were pockmarked and
nine-tenths of all blindness was ascribed to smallpox.
As late as the 18th century, smallpox killed
every 10th child born in Sweden and France. During the same century, every 7th child born
in Russia died from smallpox.
Edward Jenner's demonstration, in 1798,
that inoculation with cowpox could protect against smallpox brought the first hope that
the disease could be controlled.
In the early 1950s 150 years after
the introduction of vaccination an estimated 50 million cases of smallpox occurred
in the world each year, a figure which fell to around 1015 million by 1967 because
of vaccination.
In 1967, when WHO launched an intensified
plan to eradicate smallpox, the "ancient scourge" threatened 60% of the
world's population, killed every fourth victim, scarred or blinded most survivors,
and eluded any form of treatment.
Through the success of the global
eradication campaign, smallpox was finally pushed back to the horn of Africa and then to a
single last natural case, which occurred in Somalia in 1977. A fatal laboratory-acquired
case occurred in the United Kingdom in 1978. The global eradication of smallpox was
certified, based on intense verification activities in countries, by a commission of
eminent scientists in December 1979 and subsequently endorsed by the World Health Assembly
in 1980.
| About the virus |
Smallpox had two main forms: variola major and variola
minor. The two forms showed similar lesions. The disease followed a milder course in
variola minor, which had a case-fatality rate of less than 1 per cent. The fatality rate
of variola major was around 30%.
- There are two rare forms of smallpox: haemorrhagic and
malignant. In the former, invariably fatal, the rash was accompanied by haemorrhage into
the mucous membranes and the skin. Malignant smallpox was characterized by lesions that
did not develop to the pustular stage but remained soft and flat. It was almost invariably
fatal.
The incubation period of smallpox is usually
1214 days (range 717) during which there is no evidence of viral shedding.
During this period, the person looks and feels healthy and cannot infect others.
- The incubation period is followed by the sudden onset of
influenza-like symptoms including fever, malaise, headache, prostration, severe back pain
and, less often, abdominal pain and vomiting. Two to three days later, the temperature
falls and the patient feels somewhat better, at which time the characteristic rash
appears, first on the face, hands and forearms and then after a few days progressing to
the trunk. Lesions also develop in the mucous membranes of the nose and mouth, and
ulcerate very soon after their formation, releasing large amounts of virus into the mouth
and throat.
- In the past, smallpox was sometimes confused with
chickenpox, a worldwide infection of children that is seldom lethal. Chickenpox can be
distinguished from smallpox by its much more superficial lesions, their presence more on
the trunk than on the face and extremities, and by the development of successive crops of
lesions in the same area.
- Smallpox is a disease which can be easily diagnosed by
trained health workers without the need for laboratory support. During the eradication
campaign, WHO produced training materials designed to help health staff recognize
smallpox, distinguish it from chickenpox, and avoid common diagnostic errors. These
materials are now available electronically.
| WHO slide set on the
diagnosis of smallpox |
| WHO smallpox recognition card |
Persons carrying the virus during the incubation period
cannot infect others.
- The frequency of infection is highest after face-to-face
contact with a patient after fever has begun and during the first week of rash, when the
virus is released via the respiratory tract.
- Although patients remain infectious until the last scabs
fall off, the large amounts of virus shed from the skin are not highly infectious.
Exposure to patients in the late stages of the disease is much less likely to produce
infection in susceptible contacts.
- As a precaution, WHO isolation policy during the eradication
campaign required that patients remain in isolation, in hospital or at home, until the
last scab had separated.
In the absence of immunity induced by vaccination, human beings appear to be universally susceptible to
infection with the smallpox virus.
There is no animal reservoir. Insects play no role in
transmission.
- Smallpox is transmitted from person to person by infected
aerosols and air droplets spread in face-to-face contact with an infected person after
fever has begun, especially if symptoms include coughing. The disease can also be
transmitted by contaminated clothes and bedding, though the risk of infection from this
source is much lower.
- In the past, patients suffering from variola major (the more
severe form of the disease) became bedridden early (in the phase before the eruption of
rash) and remained so throughout the illness. Spread of infection was limited to close
contacts in a small vicinity. Variola minor, however, was so mild that patients infected
with this form frequently remained ambulatory during the infectious phase of their illness
and thus spread the virus far more widely.
- During the eradication campaign, investigations of outbreaks
caused by importations of cases into industrialized countries in temperate areas showed
that, in a closed environment, airborne virus could sometimes spread within buildings via
the ventilation system and infect persons in other rooms or on other floors in distant and
apparently unconnected spaces. This mode of transmission is not important in those
tropical areas where houses and hospitals do not use ventilation systems.
- Epidemics develop comparatively slowly. The interval between
each generation of cases is 23 weeks.
- When natural outbreaks occurred, the initial, or
"index", case rarely infected as many as 5 other persons, even during the peak
transmission season. On some occasions, such as the outbreak that followed importation of
a case into Yugoslavia in 1972, index cases infected more than a dozen people.
Unfortunately, historical data are available only from periods with substantial population
immunity either from vaccination or from having survived natural infection. In the absence
of natural disease and vaccination, the global population is significantly more
susceptible. Some experts have estimated today's rate of transmission to be more on
the order of 10 new infections per infected person.
- Vaccine administered up to 4 days after exposure to the
virus, and before the rash appears, provides protective immunity and can prevent infection
or ameliorate the severity of the disease.
- No effective treatment, other than the management of
symptoms, is currently available.
- A number of compounds are under investigation as
chemotherapeutic agents. One of these, Cidofovir, has produced promising results in
laboratory studies.
- Emphasis must be placed on preventing epidemic spread.
In doing so, it should be kept in mind that smallpox patients are not infectious during
the early stage of the disease but become so from the first appearance of fever and remain
so, though to a lesser degree, until all scabs have separated. Also, immunity develops
rapidly after vaccination against smallpox (see above).
- Surveillance of smallpox infection is probably easier than
for any other infectious disease. A distinctive rash is produced (see above) which is
wholly characteristic in the great majority of cases. The rash is most dense over the face
and hands unclothed and readily visible portions of the body.
- Experiences from the eradication campaign indicate that, in
the presence of a strong surveillance system sensitive to smallpox cases and backed by an
adequate infrastructure, small but rapid and thorough containment actions can break the
transmission chain and halt a smallpox outbreak within a relatively short time.
Containment involves efficient detection of cases and identification and vaccination of
contacts.
- Patients diagnosed with smallpox should be physically
isolated. All persons who have or will come into close contact with them should be
vaccinated. As hospitals have proven to be sites of epidemic magnification during smallpox
outbreaks, patient isolation at home is advisable where hospitals do not have isolation
facilities. Whatever the policy, isolation is essential to break the chain of
transmission.
- Patients who developed rash before their isolation should be
asked to recount all recent contacts. Contacts should be vaccinated. If it is not feasible
to vaccinate contacts, they should be placed on daily fever watch, which should continue
up to 18 days from the last day of contact with the case. If these contacts have two
consecutive readings of 38 degrees centigrade or above, they should be isolated.
- All specimen collectors, care givers and attendants coming
into close contact with patients should be vaccinated as soon as smallpox is diagnosed as
the cause of an outbreak.
- In the case of a widespread outbreak, people should be
advised to avoid crowded places and follow public health advice on precautions for
personal protection.
- Medical care givers, attendants, and mortuary workers, even
if vaccinated, should wear gloves, caps, gowns, and surgical masks.
- All contaminated instruments, excretions, fluids and other
materials should be decontaminated chemically or by heat or incineration.
- Contaminated clothing and bedding, if not incinerated,
should be autoclaved or washed in hot water containing hypochlorite bleach.
- Fumigation of premises may be done with formaldehyde.
- Cadavers should be cremated, in a properly designed
facility, whenever possible and all persons coming in contact with them should be
vaccinated or at least placed on daily fever watch. Body bags treated with hypochlorite
bleach can also be used.
- Laboratory manipulations with infective materials should be
done in high containment facilities at Biosafety Level IV, authorized only at two WHO
designated laboratories in the United States and the Russian Federation.
- Smallpox vaccine contains live vaccinia virus, a virus in
the orthopoxvirus family and closely related to variola virus, the agent that causes
smallpox. Immunity resulting from immunization with vaccinia virus (vaccination) protects
against smallpox.
- In December 1999, a WHO Advisory Committee on Variola Virus
Research concluded that, although vaccination is the only proven public health measure
available to prevent and control a smallpox outbreak, current vaccine supplies are
extremely limited. The Committee also noted that, at that time, several countries were
contemplating the need to produce more vaccine stocks. Now, a number of governments have
chosen to examine their stocks, test their potency, and consider whether more vaccine is
required.
- A WHO survey conducted in 1998 indicated that approximately
90 million declared doses of the smallpox vaccine were available worldwide. Storage
conditions and potency of these stocks are not known.
- Most existing vaccine stocks and the vaccine used in the WHO
eradication campaign consist of pulp scraped from vaccinia-infected animal skin, mainly
calf or sheep, with phenol added to a concentration sufficient to kill bacteria but not so
high as to inactivate the vaccinia virus. The vaccine is then freeze dried and sealed in
ampoules for later re-suspension in sterile buffer and subsequent intradermal inoculation
by multiple puncture with a bifurcated needle.
- The seed virus (vaccinia virus strain Lister Elstree) used
to produce the vaccine is being held for WHO by the WHO Collaborating Centre for Smallpox
Vaccine in Bilthoven, the Netherlands.
- This Centre also tests batches of the smallpox vaccine for
potency every five years. Vaccines properly stored for as long as 18 years have not lost
their potency.
| WHO instructions for vaccine
administration using the bifurcated needle |
- Vaccination usually prevents smallpox infection for at least
ten years.
- If symptoms appear, they are milder and mortality is less in
vaccinated than in nonvaccinated persons.
- Even when immunity has waned, vaccinated persons shed less
virus and are less likely to transmit the disease.
| Further
information on duration of protection following vaccination |
- Existing vaccines have proven efficacy but also have a high
incidence of adverse side-effects.
- The risk of adverse events is sufficiently high that
vaccination is not warranted if there is no or little real risk of exposure.
- Vaccine administration is warranted in individuals exposed
to the virus or facing a real risk of exposure (see above).
- A safer vaccinia-based vaccine, produced in cell culture, is
expected to become available shortly. There is also interest in developing monoclonal
anti-variola antibody for passive immunization of exposed and infected individuals, which
could also be administered to persons infected with HIV.
| Further information on
complications |
- Vaccination is contraindicated for certain groups. These
include pregnant women, persons with immune disorders or experiencing
therapeutically-induced immunosuppression, persons with HIV infection, and persons with a
history of eczema.
- Should national authorities decide that the risk of epidemic
spread is so great that such groups should receive protection, it may be advisable to
attempt to limit adverse effects through intramuscular administration of vaccinia immune
globulin, if available, from vaccinia-infected sheep or calves.
- The causative agent, variola virus, is a member of the genus
Orthopoxvirus, subfamily Chordopoxvirinae of the family Poxviridae.
Other members of the genus include cowpox, camelpox, and monkeypox. Monkeypox virus has
caused the most serious recent human poxvirus infections.
- Variola virus is relatively stable in the natural
environment. If aerosolized, it probably retains its infectivity for at least several
hours if not exposed to sunlight or ultraviolet light.
- The variola virus measures 260 by 150 nanometers and
contains a molecule of double-stranded DNA putatively coding for some 200 different
proteins, one of the largest viral genomes known. The size of the genome makes it
especially difficult to create a synthetic copy of the virus.
- The WHO Orthopoxvirus Committees meeting in 1994 and 1999
have recommended that no one other than the two WHO collaborating centres in the United
States and the Russian Federation may have in possession at one time more than 20% of the
viral DNA for variola virus.
1. Site of vaccination. Outer aspect of upper arm
over the insertion of deltoid muscle.
2. Preparation of skin. None. If site is obviously
dirty, a cloth moistened with water may be used to wipe the site. Use of a disinfectant
can kill the vaccine virus.
3. Withdrawal of vaccine from ampoule. A sterile
bifurcated needle (which must be cool) is inserted into the ampoule of reconstituted
vaccine. On withdrawal, a droplet of vaccine, sufficient for vaccination, is contained
within the fork of the needle.
4. Application of vaccine to the skin. The needle is
held at a 90 degree angle (perpendicular) to the skin. The needle then touches the skin to
release the droplet of vaccine. For both primary and revaccination, 15 up and down
(perpendicular) strokes of the needle are rapidly made in the area of about 5mm in
diameter (through the drop of vaccine deposited on the skin). The strokes should be
sufficiently vigorous so that a trace of blood appears at the vaccination site. If a trace
of blood does not appear, the strokes have not been sufficiently vigorous and the
procedure should be repeated. Although it is desirable not to induce frank bleeding, the
proportion of successful takes is not reduced if bleeding does occur.
5. Dressing. No dressing should be used after
vaccination.
6. Sterilization. WHO strongly recommends the use of
disposable needles.
7. Unused vaccine. Unused, reconstituted
freeze-dried vaccine should be discarded at the end of each working day.
Four main complications are associated with vaccination,
three of which involve abnormal skin eruption.
Eczema vaccinatum occurred in vaccinated
persons or unvaccinated contacts who were suffering from or had a history of eczema. In
these cases, an eruption occurred at sites on the body that were at the time affected by
eczema or had previously been so. These eruptions became intensely inflamed and sometimes
spread to healthy skin. Symptoms were severe. The prognosis was especially grave in
infants having large areas of affected skin.
Progressive vaccinia (vaccinia necrosum)
occurred only in persons who suffered from an immune deficiency. In these cases the local
lesion at the vaccination site failed to heal, secondary lesions sometimes appeared
elsewhere on the body, and all lesions spread progressively until as was likely
the patient died, usually 25 months later. As vaccination ceased in most
countries prior to the emergence of HIV/AIDS, the consequences of the currently much
larger pool of persons suffering from immunodeficiency were not reflected in recorded
cases of progressive vaccinia.
Generalized vaccinia occurred in otherwise
healthy individuals and was characterized by the development, from 69 days after
vaccination, of a generalized rash, sometimes covering the whole body. The prognosis was
good.
Postvaccinial encephalitis, the most serious
complication, occurred in two main forms. The first, seen most often in infants under 2
years of age, had a violent onset, characterized by convulsions. Recovery was often
incomplete, leaving the patient with cerebral impairment and paralysis. The second form,
seen most often in children older than 2 years, had an abrupt onset, with fever, vomiting,
headache, and malaise, followed by such symptoms as loss of consciousness, amnesia,
confusion, restlessness, convulsions and coma. The fatality rate was about 35%, with death
usually occurring within a week.
- The best estimates of the frequency of these complications
come from a 1968 study conducted by the United States involving over 14 million vaccinated
persons. Altogether nine deaths occurred.
Progressive vaccinia occurred in 11 persons, with 4
deaths.
Eczema vaccinatum was more common, with 74 cases and
no deaths. Sixty additional cases of eczema vaccinatum occurred in contacts of vaccinated
persons, with one death.
Generalized vaccinia occurred in 143 cases, with no
deaths.
Encephalitis was observed in 16 persons, with 4
deaths.
- On the basis of this study, it was estimated that
approximately one death per million resulted from complications following primary
vaccination and one death per four million following revaccination.
- How long does immunization remain effective a lifetime or only a certain
number of years?
This is difficult to answer with great precision, as
all available data come from the time prior to the global eradication of smallpox, which
was certified in 1979. When smallpox was still occurring naturally, populations in endemic
countries were exposed to the virus. In some countries, subclinical infection with the
virus occurred rather frequently among vaccinated persons, thus boosting their immunity.
Edward Jenner, who developed the vaccine in 1798,
believed that successful vaccination produced lifelong immunity to smallpox. That view was
clearly wrong.
Data from the eradication campaign make it clear
that immunity wanes with time. This is why, prior to the certification of eradication,
periodic revaccination was recommended, for example, for international travellers. For the
general population, revaccination at a 510-year interval for non-endemic countries
and at a 3-year interval for endemic countries was recommended. In certain high-risk
groups requiring maximum protection, such as staff working in smallpox diagnostic
laboratories, revaccination every year was recommended by WHO as a precaution.
Vaccination five years prior to exposure provides a
high level of protection against smallpox. High levels of protection are generally
believed to last 10 years after vaccination. Beyond this 10-year interval, where the
evidence of protection is strong, the data are conflicting and difficult to interpret.
Some studies found some degree of protection against smallpox for as long as 30 years
after vaccination. However, other studies demonstrated very little or no immunity 20 years
after vaccination. A large study, published in 1913, found substantial protection even in
persons, vaccinated as children, aged more than 50 years.
One study of smallpox following the importation of
cases into Europe and Canada (19501971) showed that mortality was 52% in
unvaccinated persons, 1.4% in those vaccinated up to 10 years before exposure, and only
11% in those vaccinated over 20 years before exposure. For the age group of 1049
years, the mortality rate was 49% in the unvaccinated and 4.3% in those vaccinated 20
years earlier.
- What age groups would need to worry about vulnerability
to smallpox if an outbreak occurred today?
Smallpox eradication was a global campaign, and
populations were protected by vaccination in every country. However, during the campaign,
different forms of smallpox occurred, and different vaccines and vaccination techniques
were used. The duration of protection can be influenced by the potency of the vaccine and
the inoculation procedure used. These factors make it difficult to give firm, precise
estimates that are relevant today, where populations no longer have widespread immunity,
either from vaccination or from having survived the disease (patients who survived
smallpox were immune for life).
Another factor that makes it difficult to make
projections today based on historical data is the much larger pool of persons suffering
from weakened immune systems. This can be because of immune disorders,
therapeutically-induced immunosuppression, as in the case of chemotherapy, or clinical
AIDS. A person's immune status affects both susceptibility to infection and the risk
of adverse outcomes following vaccination.
Immunization stopped in many countries, such as the
US, in 1972. In 1979, WHO recommended that vaccination against smallpox be stopped in all
countries, the only exception being special groups, such as researchers working with
smallpox and related viruses. By 1982, routine vaccination had been officially
discontinued in 149 of the 158 member countries of WHO. By 1986, routine vaccination had
ceased in all countries.
It is particularly important to understand that when
vaccinated persons nonetheless contracted smallpox, the illness was usually considerably
milder than that seen in unvaccinated persons. We know from experiences in early 19th
century Europe, when natural smallpox was still widespread, that when the disease appeared
in adults who had been vaccinated as children, the mortality rate was much lower and the
symptoms were different and milder than in unvaccinated persons. Patients also appeared to
be less infectious and thus less likely to spread the disease to close contacts. This
would certainly affect the dynamics of a smallpox outbreak today all over the world, where
the vast majority of adults were vaccinated as children.
Vaccination also influenced the frequency of
different clinical types of smallpox among persons who did contract the disease. Among
vaccinated persons who subsequently contracted the disease, a mild form of smallpox
(modified-type smallpox), which was hardly ever fatal, was much more common.
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