5 Jun


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.

Adverse Effects

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).

Special Considerations

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.

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