Before the global eradication efforts, smallpox was among highly hazardous infectious diseases of humans. The causative agent of this disease is variola virus, which is (together with a number of animal poxviruses) a member of the family Poxviridae, subfamily Chordopoxvirinae and genus Orthopoxvirus.
Historically, it was understood that individuals who survived an initial smallpox infection never developed the disease again. The eminent scientist Edward Jenner was a pioneer in demonstrating that vaccination was an effective means of preventing this disease, which has resulted in the eradication of once-dreaded scourge of smallpox.
During the first decades after Jenner’s discovery most of the material for vaccination purposes was taken either from fresh cowpox cases in cattle, or maintained by passaging from one vaccinee to another. The vaccine used in modern times was made from a live virus called vaccinia, which is a “pox”-type virus related to variola virus.
One of the specific features of smallpox vaccine, which separated it from other live vaccines, was a plethora of different strains used for its manufacture. In the late 1960s and early 1970s, practically every laboratory manufacturing the vaccine had a production strain and a passage scheme. Nevertheless, two lineages predominated: the New York Board of Health strain and Lister strain.
The nominal dose of live vaccinia virus suspension was approximately 105 virions, which was placed as a drop on the skin and pricked with a bifurcated (two-pronged) needle. Following such introduction into the skin, the virus replicated in basal layer keratinocytes causing a local cellular reaction and formed discrete vesicles.
Within a week, the vesicle evolved into a pustule (also known as Jennerian pustule) surrounded by inflammation, which scabed over within 10-14 days and eventually shed. The Jennerian pustule was an indication of a successful primary vaccination, whereas successful revaccination was indicated by palpable inflammation at 6-8 days.
The success of global smallpox eradication in 1980 led to the discontinuation of smallpox vaccination. However, a potential threat of deliberate release of smallpox virus as a result of bioterrorism has prompted health authorities to reconsider smallpox vaccination and, at the same time, to urge to evaluate duration of the immunity of the population vaccinated before the year 1980.
Cutaneous application of smallpox vaccine is followed by both local reaction and general response. The manifestation of the latter can vary in dependence of the individual sensitivity, reactogenicity of the vaccine and several other factors. The replacement of highly reactogenic vaccine strains with low and moderately reactogenic variants reduced the severity of vaccination reactions.
Virus-neutralizing antibodies to smallpox in vaccinees appear after 10-14 days (reaching the maximum titer in approximately 3-4 weeks) and are retained for up to 5 years after the vaccination. No correlation between the antibody level in blood serum and type of skin response is observed.
The protective effect of vaccination is induced quite rapidly, which is proven by various epidemiological studies of vaccination efficiency after a contact with a smallpox case. Still, initial practice has shown that a single vaccination was insufficient, thus revaccination was accepted as a rule after its introduction in Germany.
However, vaccination was not without complications. In rare instances significant adverse reactions occurred, such as generalized vaccinia, bacterial infections, eczema vaccinatum and vaccinia gangraenosum. Vaccination encephalitis was also described in the literature, and occasionally fatal outcomes were observed (1 in 1 million).
Such adverse effects prompted efforts to develop attenuated smallpox vaccine for eventual future usage, and two candidates surfaced – modified vaccinia virus Ankara (MVA) and LC16m8. In Japan, LC16m8 has recently obtained a marketing authorization as vaccine from the national authority.