In 1796, Edward Jenner ﬁrst demonstrated that inoculation of cowpox virus into human skin could lead to protection from subsequent smallpox infection (3). He named the inoculation substance vaccine, based on the Latin word, vacca, meaning cow. The more effective vaccines used for smallpox vaccination are derived from the vaccinia virus that is similar to cowpox. Several strains of the live attenuated virus vaccine were employed in eradication of the disease. The smallpox vaccine has been the prototype of success of a viral vaccine. Prior to immunization, smallpox infection relentlessly killed hundreds of millions of persons and left many badly scarred and/or blind. The mortality rate ranged between 20–30%. The world- wide eradication of this disease in 1977 is considered the greatest success story in medical history. The recent acciden- tal introduction of monkeypox into the United States via the Gambian pouched rat illustrates the need for better vaccines and perhaps vaccines with a broader range of targets. Immu- nity provided by the current smallpox vaccination reduces the effects of monkeypox virus on humans by 85%.
Vaccine production ended two decades ago and most Amer- icans under the age of 35 have not been vaccinated. Smallpox eradication occurred because every child was immunized before attending public school, thus reducing the exposure of infected children to nonimmunized children and their families (4). Approximately 60 million vaccine doses remain worldwide and more vaccine is bring produced (5). Immunologic status of the older population is questionable but there are some reports of
lingering immunity (6–8). At least 119,000,000 people in the United States have never been immunized (9). There are some indications from recent revaccinations of older persons that some degree of immunity still exists, albeit variable among the population. The destruction of the two remaining smallpox virus reserves in Atlanta and near Moscow has been a source of ongo- ing debate. Opponents of destruction contend that the virus stocks would be helpful for future research, such as smallpox pathogenesis and the production of new antiviral agents (10,11). Fear of undisclosed reserves is also a concern. Proponents argue that the virus genome has already been cloned and sequenced and is unnecessary for research (12).
Destruction of the virus reserves will likely be halted as concerns for bioterrorism increase. Of concern since the col- lapse of the Soviet Union is that existing stocks of virus, com- bined with the technology for maintaining and activating the stocks, may have passed into non-Russian hands (13). Should these undocumented virus stocks fall into the domain of ter- rorists, strategic outbreaks among the unvaccinated or under- immunized could begin an epidemic that would be difﬁcult to contain. Smallpox is considered to be an ideal bioterroist ave- nue as it is easily transmitted, has a high mortality rate, requires speciﬁc action for public health response, and could cause social and community disarray (14). Models based on the assumption that 100 persons are initially infected and each infects three more predict that quarantine could stop or eradicate such an outbreak if 50% of those with overt symp- toms were quarantined. At risk would be family members (50% risk to the unvaccinated), school children, health-care workers, etc. Vaccination alone would only stop the transmis- sion within a year if the disease transmittal rate were reduced to <0.85 persons infected per initially infected person. There- fore, a combination vaccination-quarantine program is neces- sary (25% daily quarantine and a vaccination reduction of smallpox transmission by >33%). Given the scenario, approx- imately 4,200 cases would occur over the period of a year. Approximately 215,500 vaccine doses would need to be admin- istered to stop the outbreak (15). Vaccination distribution using two distinct models predicts that mass vaccination (MV)
is superior over traced vaccination (TV). TV involves contact tracing with susceptible and exposed individuals being administered the vaccine, whereas MV occurs when everyone is vaccinated simultaneously according to a schedule. In these models, MV results in both fewer deaths and more rapid reso- lution of an epidemic (16). Vaccine production remains limited although numbers of available vaccine stock are increasing. Plans are to voluntarily vaccinate smallpox response teams, public health authorities and staff, and some law enforcement staff. The military were the ﬁrst to be vaccinated (17).
Smallpox transmission occurs via droplets or as an aero- sol from the respiratory tract or by fomite exposure to bed- ding or clothing. An incubation period of 7–17 days (average of
12 days) is followed by a fever for 2–4 days. A rash ensues that lasts for weeks as papules become vesicles, followed by pus- tules and scabs. A characteristic of smallpox that separates it from the initial chickenpox diagnosis is that all skin eruptions in a localized area are in the same stage at any given point in time. Chickenpox lesions are more superﬁcial than the hard, deep-seated lesions of smallpox. Localized eruptions of HSV-2 may mimic smallpox (18). Disease transmission may occur as the fever (prodrome) phase ends and during the rash phase. As the lesions scab over, transmission decreases (19).
The smallpox vaccination is a suspended live vaccine derived from vaccinia. To prevent bacterial contamination of the lyophilized vaccine, polymyxin B, dihydrostreptomycin, chlortetracycline, and neomycin are included in the prepara- tion. Other preparations under study include a calf-derived vaccine and a vaccinia virus grown in monkey kidney and human ﬁbroblast cells.
Live vaccine can cause many adverse effects. (20,21). In a mass smallpox vaccination plan, to immunize 75% of the population (aged 1–65), 4600 serious adverse events and 285 deaths will occur (22).
Pustule formation. One of the negative impacts of the cur- rent smallpox vaccine program has been the realization
that smallpox vaccine causes a noticeable pustule when immunization occurs. Many people currently be- ing vaccinated have no prior experience with this type of vaccine. We have become accustomed to viral vac- cines that are administered as a “shot”—i.e., inﬂuenza, hepatitis, MMR (measles, mumps and rubella), and VZV (chickenpox)—where an adverse effect consists of a little erythema and edema surrounding the injection sites. An open wound, improperly cared for, can become infected or can cause variolation on other body parts. The eyes are particularly sensitive to keratitis from fo- mite transmittal.
Allergy to vaccine components or residual immunity.
Presence of a rapidly-forming erythema without develop- ment of the vesicle or pustule may indicate past vaccina- tion immunity and/or allergy to vaccine compounds.
Death. Approximately one death per million vaccina- tions occurs. These usually occur among infants.
Local reactions. Most brief symptomatic reactions include fever, muscle aches, headache, nausea, and/or fatigue. Eczema vaccinatum. Where active (or even healed)
eczema/atopic dermatitis occurs, eczema vaccinatum can occur.
Immunocompromised. Progressive vaccinia may occur in patients with depressed cell-mediated immunity with increased numbers of HIV-positive patients and widespread use of immunosuppressive drugs.
Neurologic implications. Post vaccinal encephalomy- elitis (PVEM) may occur even if there is no contraindi- cation for vaccination (23). There are few signs of viral dissemination on the vaccine skin site, but neurologic symptoms may begin in 2–30 days after rash onset. Ini- tial complaints are very similar to local reactions re- ported by others except that high fevers and other neurologic signs occur. Seizures are most frequent in children. Rates of PVEM differ and this is attributed to: 1) strain of vaccinia virus; 2) vaccine preparation; 3) viability of vaccinia virus used; 4) method of vaccine delivery; and 5) level of post vaccine surveillance (23).
Vaccination of pregnant women. There are reported cases of fetal vaccinia occuring after vaccination dur- ing pregnancy.
Coadministration of vaccine immune globin (VIG) with smallpox vaccine. VIG may prevent or de- crease the severity of smallpox. Post-exposure vaccina- tion may also be effective if it is administered with in
4 days of known exposure.
Exposed persons with vaccine contraindications.
Administration of smallpox vaccine and VIG simulta- neously can reduce side effects for those with vaccine con- traindications who are exposed to an infected person (24).
New Vaccines for Poxviruses Currently under Investigation
Cell culture and recombinant vaccines may produce solid immu- nity with fewer complications. Should monkeypox continue to be transmitted from animal reservoirs to humans, there may be some effort to develop a vaccine. Fortunately, some immunity to many of the poxviruses is provided by the smallpox vaccination. One of the positions against destroying the remaining smallpox cultures is that the smallpox virus, itself, may become the back- bone for a multiple-pox virus that would extend protection against orf, molluscum contagiosum, vaccinia, and other poxvi- ruses. Others respond that the manipulated poxvirus strains are now the most important as they can confer immunity and do not cause disease. Obviously, the threat of poxviruses being used for terrorism is factored into the decision-making process.