Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: email@example.com. Type 508 Accommodation and the title of the report in the subject line of e-mail.
Vaccinia (Smallpox) Vaccine
Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001
Advisory Committee on Immunization Practices
Membership List, March 2001
John F. Modlin, M.D.
Professor of Pediatrics and Medicine
Dartmouth Medical School
Lebanon, New Hampshire
Dixie E. Snider, Jr., M.D., M.P.H.
Associate Director for Science
Centers for Disease Control and Prevention
Dennis A. Brooks, M.D., M.P.H.
Johnson Medical Center
Richard D. Clover, M.D.
University of Louisville School of Medicine
Jaime Deseda-Tous, M.D.
San Jorge Children's Hospital
San Juan, Puerto Rico
Charles M. Helms, M.D., Ph.D.
University of Iowa Hospital and Clinics
Iowa City, Iowa
David R. Johnson, M.D., M.P.H.
Michigan Department of Community Health
Myron J. Levin, M.D.
University of Colorado School of Medicine
Paul A. Offit, M.D.
Children's Hospital of Philadelphia
Margaret B. Rennels, M.D.
University of Maryland School of Medicine
Natalie J. Smith, M.D., M.P.H.
California Department of Health Services
Lucy S. Tompkins, M.D., Ph.D.
Stanford University Medical Center
Bonnie M. Word, M.D.
Monmouth Junction, New Jersey
Carole Heilman, M.D.
National Institutes of Health
Karen Midthun, M.D.
Food and Drug Administration
Martin G. Myers, M.D.
National Vaccine Program Office
Kristin Lee Nichol, M.D., M.P.H.
VA Medical Center
James E. Cheek, M.D., M.P.H.
Indian Health Service
Albuquerque, New Mexico
Col. Benedict M. Didiega, M.D.
Department of Defense
Falls Church, Virginia
Geoffrey S. Evans, M.D.
Health Resources and Services Administration
T. Randolph Graydon
Health Care Financing Administration
American Academy of Family Physicians
Martin Mahoney, M.D., Ph.D.
Clarence, New York
Richard Zimmerman, M.D.
American Academy of Pediatrics
Larry Pickering, M.D.
Jon Abramson, M.D.
Winston-Salem, North Carolina
American Association of Health Plans
Eric K. France, M.D.
American College of Obstetricians and Gynecologists
Stanley A. Gall, M.D.
American College of Physicians
Kathleen M. Neuzil, M.D., M.P.H.
American Hospital Association
William Schaffner, M.D.
American Medical Association
H. David Wilson, M.D.
Grand Forks, North Dakota
Association of Teachers of Preventive Medicine
W. Paul McKinney, M.D.
Canadian National Advisory Committee
Victor Marchessault, M.D.
Cumberland, Ontario, Canada
Hospital Infection Control Practices Advisory Committee
Jane D. Siegel, M.D.
Infectious Diseases Society of America
Samuel L. Katz, M.D.
Durham, North Carolina
London Department of Health
David M. Salisbury, M.D.
London, United Kingdom
National Immunization Council
and Child Health Program, Mexico
Jose Ignacio Santos, M.D.
Mexico City, Mexico
National Medical Association
Rudolph E. Jackson, M.D.
National Vaccine Advisory Committee
Georges Peter, M.D.
Providence, Rhode Island
Pharmaceutical Research and Manufacturers of America
Barbara J. Howe, M.D.
Members of the Smallpox Working Group
Advisory Committee on Immunization Practices (ACIP)
Charles M. Helms, M.D., M.P.H.
Advisory Committee on Immunization Practices
Martin G. Myers, M.D.
Georges Peter, M.D.
National Vaccine Advisory Committee
Pierce Gardner, M.D.
American College of Physicians
Samuel Katz, M.D.
Infectious Diseases Society of America
Richard Whitley, M.D.
American Academy of Pediatrics
J. Michael Lane, M.D., M.P.H., Retired
Emory University School of Medicine
Patricia Quinlisk, M.D., M.P.H.
Iowa Department of Public Health
Lt.C. John Grabenstein, Ph.D.
Capt. David Trump, M.C., U.S.N.
U.S. Department of Defense
Karen Goldenthal, M.D.
Michael Merchlinsky, Ph.D.
Food and Drug Administration
Ali S. Khan, M.D., M.P.H.
Inger K. Damon, M.D., Ph.D.
Joseph J. Esposito, Ph.D.
Clare A. Dykewicz, M.D., M.P.H.
David A. Ashford, D.V.M., M.P.H., D.Sc.
Michael McNeil, M.D., M.P.H.
Lisa D. Rotz, M.D.
Janice C. Knight
John A. Becher
Debra A. Dotson
Scott D. Holmberg, M.D., M.P.H.
Jonathan E. Kaplan, M.D.
Centers for Disease Control and Prevention
The following CDC staff members prepared this report:
Lisa D. Rotz, M.D.
Debra A. Dotson
Office of Bioterrorism Preparedness and Response Activity
Inger K. Damon, M.D., Ph.D.
Division of Viral and Rickettsial Diseases
John A. Becher
Scientific Resources Program
National Center for Infectious Diseases
These revised recommendations regarding vaccinia (smallpox)
vaccine update the previous Advisory Committee on Immunization Practices
(ACIP) recommendations (MMWR 1991;40; No.
RR-14:1--10) and include current information regarding the nonemergency use of vaccinia vaccine
among laboratory and health-care workers occupationally exposed to vaccinia
virus, recombinant vaccinia viruses, and other Orthopoxviruses that can
infect humans. In addition, this report contains ACIP's recommendations for the use
of vaccinia vaccine if smallpox (variola) virus were used as an agent of
biological terrorism or if a smallpox outbreak were to occur for another
Variola virus is the etiological agent of smallpox. During the smallpox era, the
only known reservoir for the virus was humans; no known animal or insect reservoirs
or vectors existed. The most frequent mode of transmission was
person-to-person, spread through direct deposit of infective droplets onto the nasal, oral, or
pharyngeal mucosal membranes, or the alveoli of the lungs from close, face-to-face contact
with an infectious person. Indirect spread (i.e., not requiring face-to-face contact with
an infectious person) through fine-particle aerosols or a fomite containing the virus
was less common (1,2).
Symptoms of smallpox begin 12--14 days (range: 7--17) after exposure,
starting with a 2--3 day prodrome of high fever, malaise, and prostration with severe
headache and backache. This preeruptive stage is followed by the appearance of
a maculopapular rash (i.e., eruptive stage) that progresses to papules 1--2 days after
the rash appears; vesicles appear on the fourth or fifth day; pustules appear by
the seventh day; and scab lesions appear on the fourteenth day (Figures 1,2)
(3). The rash appears first on the oral mucosa, face, and forearms, then spreads to the trunk
and legs (3,4). Lesions might erupt on the palms and soles as well. Smallpox skin
lesions are deeply embedded in the dermis and feel like firm round objects embedded in
the skin. As the skin lesions heal, the scabs separate and pitted scarring
gradually develops (Figure 2) (4). Smallpox patients are most infectious during the first week
of the rash when the oral mucosa lesions ulcerate and release substantial amounts
of virus into the saliva. A patient is no longer infectious after all scabs have
separated (i.e., 3--4 weeks after the onset of the rash).
During the smallpox era, overall mortality rates were approximately 30%.
Other less common but more severe forms of smallpox included a) flat-type smallpox with
a mortality rate >96% and characterized by severe toxemia and flat, velvety,
confluent lesions that did not progress to the pustular stage; and b) hemorrhagic-type
smallpox, characterized by severe prodromal symptoms, toxemia, and a hemorrhagic rash
that was almost always fatal, with death occurring 5--6 days after rash onset
Vaccinia vaccine is a highly effective immunizing agent that enabled the
global eradication of smallpox. The last naturally occurring case of smallpox occurred
in Somalia in 1977. In May 1980, the World Health Assembly certified that the world
was free of naturally occurring smallpox (5). By the 1960s, because of
vaccination programs and quarantine regulations, the risk for importation of smallpox into
the United States had been reduced. As a result, recommendations for routine
smallpox vaccination were rescinded in 1971
(6). In 1976, the recommendation for
routine smallpox vaccination of health-care workers was also discontinued
(7). In 1982, the only active licensed producer of vaccinia vaccine in the United States
discontinued production for general use, and in 1983, distribution to the civilian population
was discontinued (8). All military personnel continued to be vaccinated, but that
practice ceased in 1990. Since January 1982, smallpox vaccination has not been required
for international travelers, and International Certificates of Vaccination forms no
longer include a space to record smallpox vaccination
In 1980, the Advisory Committee on Immunization Practices (ACIP)
recommended the use of vaccinia vaccine to protect laboratory workers from possible infection
while working with nonvariola Orthopoxviruses (e.g., vaccinia and monkeypox)
(10). In 1984, those recommendations were included in guidelines for biosafety in
microbiological and biomedical laboratories
(11). The guidelines expanded the recommendations
to include persons working in animal-care areas where studies with
Orthopoxviruses were being conducted. They further recommended that such workers
have documented evidence of satisfactory smallpox vaccination within the preceding
3 years. CDC has provided vaccinia vaccine for these laboratory workers since
1983 (12). In 1991, ACIP further expanded smallpox vaccination recommendations
to include health-care workers involved in clinical trials using recombinant vaccinia
virus vaccines and lengthened the recommendations for revaccination for persons
working with vaccinia virus, recombinant vaccinia viruses, or other nonvariola
Orthopoxviruses to every 10 years (13).
Currently, international concern is heightened regarding the potential use
of smallpox (variola) virus as a bioterrorism agent
(14,15). Because of these concerns, ACIP has developed recommendations for vaccinia (smallpox) vaccine regarding
the potential use of smallpox virus as a biological weapon. Additionally,
recommendations regarding vaccination of persons working with highly attenuated strains
or recombinant vaccines derived from highly attenuated strains of vaccinia virus
have been revised.
Dryvax,® the vaccinia (smallpox) vaccine currently licensed in the United States,
is a lyophilized, live-virus preparation of infectious vaccinia virus (Wyeth
Laboratories, Inc., Marietta, Pennsylvania). Vaccinia vaccine does not contain smallpox
virus. Previously, the vaccine had been prepared from calf lymph with a seed
virus derived from the New York City Board of Health (NYCBOH) strain of vaccinia virus
and has a minimum concentration of 108 pock-forming units (PFU)/ml. Vaccine
was administered by using the multiple-puncture technique with a bifurcated needle.
A reformulated vaccine, produced by using cell-culture techniques, is now
Neutralizing antibodies induced by vaccinia vaccine are genus-specific and
cross-protective for other Orthopoxviruses (e.g., monkeypox, cowpox, and variola
viruses) (16--18). Although the efficacy of vaccinia vaccine has never been measured
precisely during controlled trials, epidemiologic studies demonstrate that an increased level
of protection against smallpox persists for
<5 years after primary vaccination and substantial but waning immunity can persist for
>10 years (19,20). Antibody
levels after revaccination can remain high longer, conferring a greater period of
immunity than occurs after primary vaccination alone
(3,19). Administration of vaccinia vaccine within the first days after initial exposure to smallpox virus can reduce symptoms
or prevent smallpox disease (2--4).
Although the level of antibody that protects against smallpox infection is
unknown, after percutaneous administration of a standard dose of vaccinia vaccine, >95%
of primary vaccinees (i.e., persons receiving their first dose of vaccine) will
experience neutralizing or hemagglutination inhibition antibody at a titer of
>1:10 (21). Neutralizing antibody titers of
>1:10 persist among 75% of persons for 10 years after
receiving second doses and <30 years after receiving three doses of vaccine
(22,23). The level of antibody required for protection against vaccinia virus infection is unknown
also. However, when lack of local skin response to revaccination with an
appropriately administered and potent vaccine dose is used as an indication of immunity, <10%
of persons with neutralizing titers of >1:10 exhibit a primary-type response
at revaccination, compared with >30% of persons with titers <1:10
(24). Lack of major or primary-type reaction can indicate the presence of neutralizing antibody
levels sufficient to prevent viral replication, although it can also indicate
unsuccessful vaccination because of improper administration or less potent vaccine.
Recombinant Vaccinia Viruses
Vaccinia virus is the prototype of the genus Orthopoxvirus. It is a
double-stranded DNA (deoxyribonucleic acid) virus that has a broad host range under
experimental conditions but is rarely isolated from animals outside the laboratory
(25,26). Multiple strains of vaccinia virus exist that have different levels of virulence for humans
and animals. For example, the Temple of Heaven and Copenhagen vaccinia strains
are highly pathogenic among animals, whereas the NYCBOH strain, from which the
Wyeth vaccine strain was derived, had relatively low pathogenicity
Vaccinia virus can be genetically engineered to contain and express foreign
DNA with or without impairing the ability of the virus to replicate. Such foreign DNA
can encode protein antigens that induce protection against one or more infectious
agents. Recombinant vaccinia viruses have been engineered to express immunizing
of herpesvirus, hepatitis B, rabies, influenza, human immunodeficiency virus (HIV),
and other viruses (27--32).
Recombinant vaccinia viruses have been created from different strains of
vaccinia virus. In the United States, recombinants have been made from a
nonattenuated NYCBOH strain, or a mouse neuroadapted derivative, the WR strain.
Recombinants have also been made by using the Copenhagen and Lister vaccinia strains, which
are more pathogenic among animals than the NYCBOH strain. Additionally, certain
highly attenuated, host-restricted, non- or poorly replicating poxvirus strains have
been developed for use as substrates in recombinant vaccine development. These
strains include the Orthopoxviruses, modified vaccinia Ankara (MVA) and NYVAC
(derived from the Copenhagen vaccinia strain), and the Avipoxviruses, ALVAC and
TROVAC (derived from canarypox and fowlpox viruses, respectively)
(33--36) (Table 1).
Animal studies indicate that recombinants are less pathogenic than the
parent strain of vaccinia virus (37). Laboratory-acquired infections with nonhighly
attenuated vaccinia and recombinant viruses derived from nonhighly attenuated vaccinia
strains have been reported (38--41). However, highly attenuated poxvirus strains
(MVA, NYVAC, ALVAC, and TROVAC) are unable to replicate (MVA, ALVAC, and TROVAC)
or replicate poorly (NYVAC) in mammalian host cells; therefore, highly
attenuated poxvirus strains do not create productive infections
These highly attenuated strains have also been reported to be avirulent
among normal and immunosuppressed animals (MVA, NYVAC, ALVAC, or TROVAC) and
safe among humans (MVA) (33,35,42,43). Although no formal surveillance system has
been established to monitor laboratory workers, no laboratory-acquired infections
resulting from exposure to these highly attenuated strains or recombinant vaccines
derived from these strains have been reported in the scientific literature or to CDC. Because
of the biological properties and accumulated attenuation data for NYVAC, ALVAC,
and TROVAC, the Recombinant DNA Advisory Committee of the National Institutes
of Health (NIH) reduced the biosafety level for these viruses to biosafety level 1
(44). The Occupational Safety and Health Board of NIH no longer requires vaccinia
(smallpox) vaccination for personnel manipulating MVA or NYVAC in a laboratory where no
other vaccinia viruses are being manipulated
During human trials of recombinant vaccines, physicians, nurses, and other
health-care personnel who provide clinical care to recipients of these vaccines could
be exposed to both vaccinia and recombinant viruses. This exposure could occur
from contact with dressings contaminated with the virus or through exposure to
the vaccine. Although the risk for transmission of recombinant vaccinia viruses to
exposed health-care workers is unknown, no reports of transmission to health-care
personnel from vaccine recipients have been published. If appropriate
infection-control precautions are observed
(46,47), health-care workers are at less risk for
infection than laboratory workers because of the smaller volume and lower titer of virus
in clinical specimens compared with laboratory material. However, the potential
does exist of nonhighly attenuated vaccinia viruses or recombinant viruses derived
from these strains being transmitted to health-care personnel. Therefore, those
workers who have direct contact with contaminated dressings or other infectious material
from volunteers in clinical studies where such strains are used can be offered
vaccination. Vaccination is not indicated for health-care personnel who are exposed to
clinical materials contaminated with highly attenuated poxvirus strains used to
develop vaccine recombinants.
Laboratory and other health-care personnel who work with highly
attenuated strains of vaccinia virus (e.g., MVA and NYVAC) do not require routine
vaccinia vaccination. Laboratory and other health-care personnel who work with
the Avipoxvirus strains ALVAC and TROVAC also do not require routine
vaccinia vaccination because these viruses do not grow in mammalian cells and, therefore,
do not produce clinical infections among humans. In addition, antibodies induced
by vaccinia vaccine are genus-specific (16) and would probably not inhibit the
expression of genes incorporated into recombinant vaccines derived from ALVAC and
TROVAC. Therefore, vaccination would provide no theoretical benefit in
preventing seroconversion to the foreign antigen expressed by a recombinant virus if
an inadvertent exposure occurred. Laboratory and other health-care personnel who
work with viral cultures or other infective materials should always observe
appropriate biosafety guidelines and adhere to published infection-control procedures
Routine Nonemergency Vaccine Use
Vaccinia vaccine is recommended for laboratory workers who directly handle
a) cultures or b) animals contaminated or infected with, nonhighly attenuated
vaccinia virus, recombinant vaccinia viruses derived from nonhighly attenuated
vaccinia strains, or other Orthopoxviruses that infect humans (e.g., monkeypox,
cowpox, vaccinia, and variola). Other health-care workers (e.g., physicians and nurses)
whose contact with nonhighly attenuated vaccinia viruses is limited to
contaminated materials (e.g., dressings) but who adhere to appropriate infection control
measures are at lower risk for inadvertent infection than laboratory workers. However,
because a theoretical risk for infection exists, vaccination can be offered to this
group. Vaccination is not recommended for persons who do not directly handle
nonhighly attenuated virus cultures or materials or who do not work with animals
contaminated or infected with these viruses.
Vaccination with vaccinia vaccine results in high seroconversion rates and
only infrequent adverse events (see Side Effects and Adverse Reactions). Recipients
of standard potency vaccinia vaccine (Dryvax) receive controlled percutaneous
doses (approximately 2.5 × 105 PFU
) of relatively low pathogenicity vaccinia virus.
The resulting immunity should provide protection to recipients against infections
resulting from uncontrolled, inadvertent inoculation by unusual routes (e.g., the eye) with
a substantial dose of virus of higher or unknown pathogenicity. In addition, persons
with preexisting immunity to vaccinia might be protected against seroconversion to
the foreign antigen expressed by a recombinant virus if inadvertently exposed
(41). However, persons with preexisting immunity to vaccinia might not receive the
full benefit of recombinant vaccinia vaccines developed for immunization against
other infections (31,49).
Routine Nonemergency Revaccination
According to data regarding the persistence of neutralizing antibody
after vaccination, persons working with nonhighly attenuated vaccinia viruses,
recombinant viruses developed from nonhighly attenuated vaccinia viruses, or other
nonvariola Orthopoxviruses should be revaccinated at least every 10 years
(13). To ensure an
increased level of protection against more virulent nonvariola Orthopoxviruses
(e.g., monkeypox), empiric revaccination every 3 years can be considered
Side Effects and Adverse Reactions
Side Effects and Less Severe Adverse
Reactions. In a nonimmune person who is not immunosuppressed, the expected response to primary vaccination is
the development of a papule at the site of vaccination 2--5 days after
percutaneous administration of vaccinia vaccine. The papule becomes vesicular, then
and reaches its maximum size in 8--10 days. The pustule dries and forms a scab,
which separates within 14--21 days after vaccination, leaving a scar (Figure 3).
Primary vaccination can produce swelling and tenderness of regional lymph nodes,
beginning 3--10 days after vaccination and persisting for 2--4 weeks after the skin lesion
has healed. Maximum viral shedding from the vaccination site occurs 4--14 days
after vaccination, but vaccinia can be recovered from the site until the scab separates
from the skin (50).
A fever is also common after the vaccine is administered. Approximately 70%
of children experience >1 days of temperatures
>100 F for 4--14 days after primary vaccination
(21), and 15%--20% of children experience temperatures
>102 F. After revaccination, 35% of children experience temperatures
>100 F, and 5% experience temperatures of
>102 F (24). Fever is less common among adults after vaccination
or revaccination (CDC, unpublished data, undated).
Inadvertent inoculation at other sites is the most frequent complication of
vaccinia vaccination and accounts for approximately half of all complications of
primary vaccination and revaccination (Tables 2,3). Inadvertent inoculation usually results
from autoinoculation of vaccinia virus transferred from the site of vaccination. The
most common sites involved are the face, eyelid, nose, mouth, genitalia, and rectum
(Figure 4). Most lesions heal without specific therapy, but vaccinia immunoglobulin (VIG)
can be useful for cases of ocular implantation (see Treatment for Vaccinia
Vaccine Complications). However, if vaccinial keratitis is present, VIG is
contraindicated because it might increase corneal scarring
Erythematous or urticarial rashes can occur approximately 10 days after
primary vaccination and can be confused with generalized vaccinia. However, the vaccinee
is usually afebrile with this reaction, and the rash resolves spontaneously within
2--4 days. Rarely, bullous erythema multiforme (i.e., Stevens-Johnson syndrome)
Moderate to Severe Adverse Reactions. Moderate and severe complications
of vaccinia vaccination include eczema vaccinatum, generalized vaccinia,
progressive vaccinia, and postvaccinial encephalitis (Table 2). These complications are rare
but occur >10 times more often among primary vaccinees than among revaccinees
and are more frequent among infants than among older children and adults
(53--55) (Table 3). A study of Israeli military recruits aged
>18 years, who were vaccinated during 1991--1996, reported rates of the severe complications progressive vaccinia
(i.e., vaccinia necrosum rate: 0/10,000 vaccinees) and postvaccinial encephalitis (rate:
0/10,000 vaccinees) similar to those reported in previous studies
Eczema vaccinatum is a localized or systemic dissemination of vaccinia
virus among persons who have eczema or a history of eczema or other chronic
or exfoliative skin conditions (e.g., atopic dermatitis) (Figure 5). Usually, illness is mild
and self-limited but can be severe or fatal. The most serious cases among
vaccine recipients occur among primary vaccinees and are independent of the activity of
the underlying eczema (57). Severe cases have been observed also after contact
of recently vaccinated persons with persons who have active eczema or a history
of eczema (see Contacts of Vaccinees) (Figure 6).
Generalized vaccinia is characterized by a vesicular rash of varying extent that
can occur among persons without underlying illnesses (Figure 7). The rash is
generally self-limited and requires minor or no therapy except among patients whose
conditions might be toxic or who have serious underlying immunosuppressive illnesses
(e.g., acquired immunodeficiency syndrome [AIDS])
Progressive vaccinia (vaccinia necrosum) is a severe, potentially fatal
illness characterized by progressive necrosis in the area of vaccination, often with
metastatic lesions (Figure 8). It has occurred almost exclusively among persons with
cellular immunodeficiency. The most serious complication is postvaccinial encephalitis. In
the majority of cases, it affects primary vaccinees aged <1 year or adolescents and
adults receiving a primary vaccination (3). Occurrence of this complication was influenced
by the strain of vaccine virus and was higher in Europe than in the United States.
The principle strain of vaccinia virus used in the United States, NYCBOH, was
associated with the lowest incidence of postvaccinial encephalitis
(3). Approximately 15%--25% of affected vaccinees with this complication die, and 25% have permanent
neurological sequelae (52--54). Fatal complications caused by vaccinia vaccination are rare,
with approximately 1 death/million primary vaccinations and 0.25
deaths/million revaccinations (54). Death is most often the result of postvaccinial encephalitis
or progressive vaccinia.
Contacts of Vaccinees
Transmission of vaccinia virus can occur when a recently vaccinated person
has contact with a susceptible person. In a 1968 10-state survey of complications
of vaccinia vaccination, the risk for transmission to contacts was 27
infections/million total vaccinations; 44% of those contact cases occurred among children aged
<5 years (53). Before the U.S. military discontinued routine smallpox vaccination in
1990, occurrences of contact transmission of vaccinia virus from recently vaccinated
military recruits had been reported, including six cases resulting from transmission from
one vaccine recipient (59--61).
Approximately 60% of contact transmissions reported in the 1968 10-state
survey resulted in inadvertent inoculation of otherwise healthy persons. Approximately
30% of the eczema vaccinatum cases reported in that study were a result of
contact transmission (53). Eczema vaccinatum might be more severe among contacts
than among vaccinated persons, possibly because of simultaneous multiple inoculations
at several sites (54,62). Contact transmission rarely results in postvaccinial
encephalitis or vaccinia necrosum.
Precautions and Contraindications
Routine Nonemergency Laboratory and Health-Care
The following contraindications to vaccination apply to routine nonemergency
use of vaccinia vaccine (see Smallpox Vaccine for Bioterrorism Preparedness
for information regarding precautions and contraindications to vaccination during
a smallpox outbreak emergency) (Table 4). Before administering vaccinia vaccine,
the physician should complete a thorough patient history to document the absence
of vaccination contraindications among both vaccinees and their household
contacts. Efforts should be made to identify vaccinees and their household contacts who
have eczema, a history of eczema, or immunodeficiencies. Vaccinia vaccine should not
be administered for routine nonemergency indications if these conditions are
present among either recipients or their household contacts.
History or Presence of Eczema or Other Skin Conditions
Because of the increased risk for eczema vaccinatum, vaccinia vaccine should
not be administered to persons with eczema of any degree, those with a past history
of eczema, those whose household contacts have active eczema, or whose
household contacts have a history of eczema. Persons with other acute, chronic, or
exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, or varicella zoster) might
also be at higher risk for eczema vaccinatum and should not be vaccinated until
the condition resolves.
Live-viral vaccines are contraindicated during pregnancy; therefore,
vaccinia vaccine should not be administered to pregnant women for routine
nonemergency indications. However, vaccinia vaccine is not known to cause congenital
malformations (63). Although <50 cases of fetal vaccinia infection have been reported, vaccinia
virus has been reported to cause fetal infection on rare occasions, almost always
after primary vaccination of the mother (64). Cases have been reported as recently as
1978 (55,65). When fetal vaccinia does occur, it usually results in stillbirth or death of
the infant soon after delivery.
Replication of vaccinia virus can be enhanced among persons
with immunodeficiency diseases and among those with immunosuppression (e.g., as
occurs with leukemia, lymphoma, generalized malignancy, solid organ transplantation,
cellular or humoral immunity disorders, or therapy with alkylating agents,
antimetabolites, radiation, or high-dose corticosteroid therapy [i.e.,
>2 mg/kg body weight or 20 mg/day of prednisone for
>2 weeks] ). Persons with immunosuppression also
include hematopoietic stem cell transplant recipients who are <24 months posttransplant,
and hematopoietic stem cell transplant recipients who are
>24 months posttransplant but who have graft-versus-host disease or disease relapse. Persons with such
conditions or whose household contacts have such conditions should not be
administered vaccinia vaccine.
Persons Infected with HIV
Risk for severe complications after vaccinia vaccination for persons infected
with HIV is unknown. One case of severe generalized vaccinia has been reported
involving an asymptomatic HIV-infected military recruit after the administration of
multiple vaccines that included vaccinia vaccine
(58). Additionally, a 1991 report indicated
that two HIV-infected persons might have died of a progressive vaccinia-like illness
after treatment with inactivated autologous lymphocytes infected with a recombinant
HIV-vaccinia virus (67). No evidence exists that smallpox vaccination accelerates
the progression of HIV-related disease. However, the degree of immunosuppression
that would place an HIV-infected person at greater risk for adverse events is
unknown. Because of this uncertainty, until additional information becomes available,
not vaccinating persons (under routine nonemergency conditions) who have HIV
infection is advisable.
Infants and Children
Before the eradication of smallpox, vaccinia vaccination was
administered routinely during childhood. However, smallpox vaccination is no longer indicated
for infants or children for routine nonemergency indications.
Persons with Allergies to Vaccine Components
The currently available vaccinia vaccine (i.e., Dryvax) contains trace amounts
of polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride,
and neomycin sulfate. Persons who experience anaphylactic reactions (i.e., hives,
swelling of the mouth and throat, difficulty breathing, hypotension, and shock) to any of
these antibiotics should not be vaccinated. Vaccinia vaccine does not contain
penicillin. Future supplies of vaccinia vaccine will be reformulated and might contain
other preservatives or stabilizers. Refer to the manufacturer's package insert for
Treatment for Vaccinia Vaccine Complications
The only product currently available for treatment of complications of
vaccinia vaccination is VIG, which is an isotonic sterile solution of the immunoglobulin
fraction of plasma from persons vaccinated with vaccinia vaccine. It is effective for
treatment of eczema vaccinatum and certain cases of progressive vaccinia; it might be
useful also in the treatment of ocular vaccinia resulting from inadvertent implantation
(68,69). However, VIG is contraindicated for the treatment of vaccinial keratitis
(51,54). VIG is recommended for severe generalized vaccinia if the patient is extremely ill or has
a serious underlying disease. VIG provides no benefit in the treatment of
postvaccinial encephalitis and has no role in the treatment of smallpox. Current supplies of VIG
are limited, and its use should be reserved for treatment of vaccine complications
with serious clinical manifestations (e.g., eczema vaccinatum, progressive vaccinia,
severe generalized vaccinia, and severe ocular viral implantation) (Table 2).
The recommended dosage of the currently available VIG for treatment
of complications is 0.6 ml/kg of body weight. VIG must be administered
and should be administered as early as possible after the onset of symptoms.
Because therapeutic doses of VIG might be substantial (e.g., 42 ml for a person weighing 70
kg), the product should be administered in divided doses over a 24- to 36-hour
period. Doses can be repeated, usually at intervals of 2--3 days, until recovery begins (e.g.,
no new lesions appear). Future reformulations of VIG might require
intravenous administration, and health-care providers should refer to the manufacturer's
package insert for correct dosages and route of administration. CDC is currently the only
source of VIG for civilians (see Vaccinia Vaccine Availability for contact information).
Other Treatment Options for Vaccinia Vaccine Complications
The Food and Drug Administration has not approved the use of any
antiviral compound for the treatment of vaccinia virus infections or other
Orthopoxvirus infections, including smallpox. Certain antiviral compounds have been reported to
be active against vaccinia virus or other Orthopoxviruses in vitro and among test
animals (70--75). However, the safety and effectiveness of these compounds for
treating vaccinia vaccination complications or other Orthopoxvirus infections among humans
is unknown. Questions also remain regarding the effective dose and the timing
and length of administration of these antiviral compounds. Insufficient information
exists on which to base recommendations for any antiviral compound to
treat postvaccination complications or Orthopoxvirus infections, including
smallpox. However, additional information could become available, and health-care
providers should consult CDC to obtain up-dated information regarding treatment options
for smallpox vaccination complications (see Consultation Regarding Complications
of Vaccinia Vaccine).
Consultation Regarding Complications of Vaccinia Vaccine
CDC can assist physicians in the diagnosis and management of patients
with suspected complications of vaccinia vaccination. VIG is available when
indicated. Physicians should telephone CDC at (404) 639-3670 during Mondays--Fridays,
except holidays, or (404) 639-3311 during evenings, weekends, and holidays.
Health-care workers are requested to report complications of vaccinia vaccination to the
Vaccine Adverse Event Reporting System at (800) 822-7967, or to their state or local
PREVENTING CONTACT TRANSMISSION OF VACCINIA VIRUS
Vaccinia virus can be cultured from the site of primary vaccination beginning at
the time of development of a papule (i.e., 2--5 days after vaccination) until the
scab separates from the skin lesion (i.e., 14--21 days after vaccination). During that
time, care must be taken to prevent spread of the virus to another area of the body or
to another person by inadvertent contact. Thorough hand-hygiene with soap and
water or disinfecting agents should be performed after direct contact with the site
or materials that have come into contact with the site to remove virus from the
hands and prevent accidental inoculation to other areas of the body
(76). In addition, care should be taken to prevent contact of the site or contaminated materials from the
site by unvaccinated persons. The vaccination site can be left uncovered, or it can
loosely covered with a porous bandage (e.g., gauze) until the scab has separated on
its own to provide additional barrier protection against inadvertent inoculation.
An occlusive bandage should not be routinely used because maceration of the site
might occur. Bandages used to cover the vaccination site should be changed frequently
(i.e., every 1--2 days) to prevent maceration of the vaccination site secondary to
fluid buildup. Hypoallergenic tape should be used for persons who experience
tape hypersensitivity. The vaccination site should be kept dry, although normal bathing
can continue. No salves or ointments should be placed on the vaccination
site. Contaminated bandages and, if possible, the vaccination site scab, after it has
fallen off, should be placed in sealed plastic bags before disposal in the trash to
further decrease the potential for inadvertent transmission of the live virus contained in
the materials. Clothing or other cloth materials that have had contact with the site can
be decontaminated with routine laundering in hot water with bleach
Recently vaccinated health-care workers should avoid contact with
unvaccinated patients, particularly those with immunodeficiencies, until the scab has separated
from the skin at the vaccination site. However, if continued contact with
unvaccinated patients is unavoidable, health-care workers can continue to have contact
with patients, including those with immunodeficiencies, as long as the vaccination site
is well-covered and thorough hand-hygiene is maintained. In this setting, a
more occlusive dressing might be required. Semipermeable polyurethane dressings
(e.g., Opsite®) are effective barriers to vaccinia and recombinant vaccinia viruses
(31). However, exudates can accumulate beneath the dressing, and care must be taken
to prevent viral contamination when the dressing is removed. In addition,
accumulation of fluid beneath the dressing can increase the maceration of the vaccination
site. Accumulation of exudates can be decreased by first covering the vaccination site
with dry gauze, then applying the dressing over the gauze. The dressing should also
be changed at least once a day. To date, experience with this type of
containment dressing has been limited to research protocols. The most critical measure
in preventing inadvertent implantation and contact transmission from
vaccinia vaccination is thorough hand-hygiene after changing the bandage or after any
other contact with the vaccination site.
The skin over the insertion of the deltoid muscle or the posterior aspect of the
arm over the triceps muscle are the preferred sites for smallpox vaccination. Alcohol
or other chemical agents are not required for skin preparation for vaccination unless
the area is grossly contaminated. If alcohol is used, the skin must be allowed to
dry thoroughly to prevent inactivation of the vaccine by the alcohol. The
multiple-puncture technique uses a presterilized bifurcated needle that is inserted vertically into
the vaccine vial, causing a droplet of vaccine to adhere between the prongs of the
needle. The droplet contains the recommended dosage of vaccine, and its presence within
the prongs of the bifurcated needle should be confirmed visually. Holding the
bifurcated needle perpendicular to the skin, 15 punctures are rapidly made with strokes
vigorous enough to allow a trace of blood to appear after 15--20 seconds
(3). Any remaining vaccine should be wiped off with dry sterile gauze and the gauze disposed of in
a biohazard waste container.
EVIDENCE OF IMMUNITY AND VACCINATION-RESPONSE INTERPRETATION
Appearance of neutralizing antibodies after vaccination with live vaccinia
virus indicates an active immune response that includes the development of antibodies to
all viral antigens and increased vaccinia-specific cell-mediated immunity. In a person
with normal immune function, neutralizing antibodies appear approximately 10 days
after primary vaccination and 7 days after revaccination
(3). Clinically, persons are considered fully protected after a successful response is demonstrated at the site
The vaccination site should be inspected 6--8 days after vaccination and
the response interpreted at that time. Two types of responses have been defined by
the World Health Organization (WHO) Expert Committee on Smallpox. The
responses include a) major reaction, which indicates that virus replication has taken place
and vaccination was successful; or b) equivocal reaction, which indicates a
possible consequence of immunity adequate to suppress viral multiplication or
allergic reactions to an inactive vaccine without production of immunity.
Major (i.e., primary) reaction is defined as a vesicular or pustular lesion or an
area of definite palpable induration or congestion surrounding a central lesion that might
be a crust or an ulcer. The usual progression of the vaccination site after
primary vaccination is as follows:
The inoculation site becomes reddened and pruritic 3--4 days after vaccination.
A vesicle surrounded by a red areola then forms, which becomes
umbilicated and then pustular by days 7--11 after vaccination.
The pustule begins to dry; the redness subsides; and the lesion becomes
crusted between the second and third week. By the end of approximately the third
week, the scab falls off, leaving a permanent scar that at first is pink in color
but eventually becomes flesh-colored (77).
Skin reactions after revaccination might be less pronounced with more
rapid progression and healing than those after primary vaccinations. Revaccination
is considered successful if a pustular lesion is present or an area of definite induration
or congestion surrounding a central lesion (i.e., scab or ulcer) is visible upon
examination 6--8 days after revaccination
Equivocal reaction, including accelerated, modified, vaccinoid, immediate, early,
or immune reactions, are defined as all responses other than major reactions. If
an equivocal reaction is observed, vaccination procedures should be checked and
the vaccination repeated by using vaccine from another vial or vaccine lot, if
available. Difficulty in determining if the reaction was blunted could be caused by
immunity, insufficiently potent vaccine, or vaccination technique failure. If the repeat
vaccination by using vaccine from another vial or vaccine lot fails to elicit a major reaction,
care providers should consult CDC or their state or local health department
before attempting another vaccination.
MISUSE OF VACCINIA VACCINE
Vaccinia vaccine should not be used therapeutically for any reason. No
evidence exists that vaccinia vaccine has any value in treating or preventing recurrent
herpes simplex infection, warts, or any disease other than those caused by
human Orthopoxviruses (78). Misuse of vaccinia vaccine to treat herpes infections has
been associated with severe complications, including death
VACCINIA VACCINE AVAILABILITY
CDC is the only source of vaccinia vaccine and VIG for civilians. CDC will
provide vaccinia vaccine to protect laboratory and other health-care personnel
whose occupations place them at risk for exposure to vaccinia and other closely
related Orthopoxviruses, including vaccinia recombinants. Vaccine should be
administered under the supervision of a physician selected by the institution. Vaccine will be
shipped to the responsible physician. Requests for vaccine and VIG, including the reason for
the request, should be referred to
Centers for Disease Control and Prevention
Drug Services, National Center for Infectious Diseases
Atlanta, GA 30333
Telephone: (404) 639-3670
Facsimile: (404) 639-3717
SMALLPOX VACCINE FOR BIOTERRORISM PREPAREDNESS
Although use of biological agents is an increasing threat, use of
conventional weapons (e.g., explosives) is still considered more likely in terrorism scenarios
(81). Moreover, use of smallpox virus as a biological weapon might be less likely than
other biological agents because of its restricted availability; however, its use would
have substantial public health consequences. Therefore, in support of current public
health bioterrorism preparedness efforts, ACIP has developed the
following recommendations if this unlikely event occurs.
A suspected case of smallpox is a public health emergency. Smallpox
surveillance in the United States includes detecting a suspected case or cases, making a
definitive diagnosis with rapid laboratory confirmation at CDC, and preventing further
smallpox transmission. A suspected smallpox case should be reported immediately
by telephone to state or local health officials and advice obtained regarding isolation
and laboratory specimen collection. State or local health officials should notify
CDC immediately at (404) 639-2184, (404) 639-0385, or (770) 488-7100 if a suspected
case of smallpox is reported. Because of the problems encountered previously in
Europe with health-care--associated smallpox transmission from imported cases present in
hospital setting (82,83), health officials should be diligent regarding use of
adequate isolation facilities and precautions (see Infection Control Measures). Currently,
specific therapies with proven treatment effectiveness for clinical smallpox are
unavailable. Medical care of more seriously ill smallpox patients would include
supportive measures only. If the patient's condition allows, medical and public health
authorities should consider isolation and observation outside a hospital setting to prevent
health-care--associated smallpox transmission and overtaxing of medical resources.
Clinical consultation and a preliminary laboratory diagnosis can be completed within
8--24 hours. Surveillance activities, including notification procedures and
laboratory confirmation of cases, might change if smallpox is confirmed.
The risk for smallpox occurring as a result of a deliberate release by terrorists
is considered low, and the population at risk for such an exposure cannot be
determined. Therefore, preexposure vaccination is not recommended for any group other
than laboratory or medical personnel working with nonhighly attenuated
Orthopoxviruses (see Routine Nonemergency Vaccine Use).
Recommendations regarding preexposure vaccination should be on the basis of
a calculable risk assessment that considers the risk for disease and the benefits
and risks regarding vaccination. Because the current risk for exposure is considered
low, benefits of vaccination do not outweigh the risk regarding vaccine complications. If
the potential for an intentional release of smallpox virus increases later,
preexposure vaccination might become indicated for selected groups (e.g., medical and
public health personnel or laboratorians) who would have an identified higher risk
for exposure because of work-related contact with smallpox patients or
If an intentional release of smallpox (variola) virus does occur, vaccinia vaccine
will be recommended for certain groups. Groups for whom vaccination would be
persons who were exposed to the initial release of the virus;
persons who had face-to-face, household, or close-proximity contact (<6.5 feet
or 2 meters) (84) with a confirmed or suspected smallpox patient at any time
from the onset of the patient's fever until all scabs have separated;
personnel involved in the direct medical or public health evaluation, care,
or transportation of confirmed or suspected smallpox patients;
laboratory personnel involved in the collection or processing of
clinical specimens from confirmed or suspected smallpox patients; and
other persons who have an increased likelihood of contact with
infectious materials from a smallpox patient (e.g., personnel responsible for medical
waste disposal, linen disposal or disinfection, and room disinfection in a facility
where smallpox patients are present).
Using recently vaccinated personnel (i.e., <3 years) for patient care activities
would be the best practice. However, because recommendations for routine
smallpox vaccination in the United States were rescinded in 1971 and smallpox vaccination
is currently recommended only for specific groups (see Routine Nonemergency
Vaccine Use), having recently vaccinated personnel available in the early stages of a
smallpox emergency would be unlikely. Smallpox vaccine can prevent or decrease the
severity of clinical disease, even when administered 3--4 days after exposure to the
smallpox virus (2,4,85). Preferably, healthy persons with no contraindications to
vaccination, who can be vaccinated immediately before patient contact or very soon after
patient contact (i.e., <3 days), should be selected for patient care activities or
activities involving potentially infectious materials. Persons who have received a
previous vaccination (i.e., childhood vaccination or vaccination >3 years before)
against smallpox might demonstrate a more accelerated immune response
after revaccination than those receiving a primary vaccination
(3). If possible, these persons should be revaccinated and assigned to patient care activities in the early stages of
a smallpox outbreak until additional personnel can be successfully vaccinated.
Personnel involved with direct smallpox patient care activities should observe
strict contact and airborne precautions (47) (i.e., gowns, gloves, eye shields, and
correctly fitted N-95 masks) for additional protection until postvaccination immunity has
been demonstrated (i.e., 6--8 days after vaccination). Shoe covers should be used in
addition to standard contact isolation protective clothing to prevent transportation of the
virus outside the isolation area. After postvaccination immunity has occurred,
contact precautions with shoe covers should still be observed to prevent the spread
of infectious agents (see Infection Control Measures). If possible, the number
of personnel selected for direct contact with confirmed or suspected smallpox patients
or infectious materials should be limited to reduce the number of vaccinations and
to prevent unnecessary vaccination complications.
Children who have had a definite risk regarding exposure to smallpox (i.e.,
face-to-face, household, or close-proximity contact with a smallpox patient) should
be vaccinated regardless of age (20,52). Pregnant women who have had a
definite exposure to smallpox virus (i.e., face-to-face, household, or close-proximity
contact with a smallpox patient) and are, therefore, at high risk for contracting the
disease, should also be vaccinated (52). Smallpox infection among pregnant women has
been reported to result in a more severe infection than among nonpregnant women
(3). Therefore, the risks to the mother and fetus from experiencing clinical
smallpox substantially outweigh any potential risks regarding vaccination. In addition,
vaccinia virus has not been documented to be teratogenic, and the incidence of fetal vaccinia
is low (52,63,86,87). When the level of exposure risk is undetermined, the decision
to vaccinate should be made after assessment by the clinician and patient of the
potential risks versus the benefits of smallpox vaccination.
In a postrelease setting, vaccination might be initiated also for other groups
whose unhindered function is deemed essential to the support of response activities
(e.g., selected law enforcement, emergency response, or military personnel) and who
are not otherwise engaged in patient care activities but who have a reasonable
probability of contact with smallpox patients or infectious materials. If vaccination of these
groups is initiated by public health authorities, only personnel with no contraindications
to vaccination should be vaccinated before initiating activities that could lead to
contact with suspected smallpox patients or infectious materials. Steps should be taken
reassignment of duties) to prevent contact of any unvaccinated personnel
with infectious smallpox patients or materials.
Because of increased transmission rates that have been described in
previous outbreaks of smallpox involving aerosol transmission in hospital settings
(1,82,83), potential vaccination of nondirect hospital contacts should be evaluated by
public health officials. Because hospitalized patients might have other contraindications
to vaccination (e.g., immunosuppression), vaccination of these nondirect
hospital contacts should occur after prudent evaluation of the hospital setting
with determination of the exposure potential through the less-common
aerosol transmission route.
Contraindications to Vaccination During a
No absolute contraindications exist regarding vaccination of a person with a
high-risk exposure to smallpox. Persons at greatest risk for experiencing
serious vaccination complications are also at greatest risk for death from smallpox
(20,52). If a relative contraindication to vaccination exists, the risk for experiencing
serious vaccination complications must be weighed against the risk for experiencing
a potentially fatal smallpox infection. When the level of exposure risk is
undetermined, the decision to vaccinate should be made after prudent assessment by the
clinician and the patient of the potential risks versus the benefits of smallpox vaccination.
Infection Control Measures
Isolation of confirmed or suspected smallpox patients will be necessary to limit
the potential exposure of nonvaccinated and, therefore, nonimmune persons.
Although droplet spread is the major mode of person-to-person smallpox transmission,
airborne transmission through fine-particle aerosol can occur. Therefore, airborne
precautions using correct ventilation (e.g., negative air-pressure rooms with
high-efficiency particulate air filtration) should be initiated for hospitalized confirmed or
suspected smallpox patients, unless the entire facility has been restricted to smallpox
patients and recently vaccinated persons
(88,89). Although personnel who have been vaccinated recently and who have a demonstrated immune response should be
fully protected against infection with variola virus (see Evidence of Immunity
and Vaccination-Response Interpretation), they should continue to observe standard
and contact precautions (i.e., using protective clothing and shoe covers) when in
contact with smallpox patients or contaminated materials to prevent inadvertent spread
of variola virus to susceptible persons and potential self-contact with other
infectious agents. Personnel should remove and correctly dispose of all protective
clothing before contact with nonvaccinated persons. Reuseable bedding and clothing can
be autoclaved or laundered in hot water with bleach to inactivate the virus
(2,4). Laundry handlers should be vaccinated before handling contaminated materials.
Nonhospital isolation of confirmed or suspected smallpox patients should be of
a sufficient degree to prevent the spread of disease to nonimmune persons during
the time the patient is considered potentially infectious (i.e., from the onset of
symptoms until all scabs have separated). Private residences or other nonhospital facilities
that are used to isolate confirmed or suspected smallpox patients should have
ventilation, heating, and air-conditioning systems. Access to those facilities should
be limited to recently vaccinated persons with a demonstrated immune response.
If suspected smallpox patients are placed in the same isolation facility, they should
be vaccinated to guard against accidental exposure caused by misclassification
as someone with smallpox.
In addition to isolation of infectious smallpox patients, careful surveillance
of contacts during their potential incubation period is required. Transmission of
smallpox virus rarely occurs before the appearance of the rash that develops 2--4 days after
the prodromal fever (3). If a vaccinated or unvaccinated contact experiences a fever
>101° F (38° C) during the 17-day period after his or her last exposure to a smallpox
patient, the contact should be isolated immediately to prevent contact with nonvaccinated
or nonimmune persons until smallpox can be ruled out by clinical or
VIG for Prophylaxis and Treatment of Adverse
Reactions During a Smallpox Emergency
If vaccination of persons with contraindications is required because of exposure
to smallpox virus after an intentional release as a bioterrorism agent, current stores
of VIG are insufficient to allow its prophylactic use with vaccination. Because of
the limited stores of VIG, its use in such a scenario should be reserved for severe,
life-threatening complications (e.g., progressive vaccinia, eczema vaccinatum, or
severe, toxic generalized vaccinia). If additional VIG becomes available in sufficient
quantities to allow its prophylactic use, VIG should be administered intramuscularly as a dose
of 0.3 mg/kg along with vaccinia vaccine to persons with contraindications who
Development and Evaluation of New Vaccinia Vaccine
Current supplies of vaccinia vaccine are limited to remaining stores of vaccine
that were produced before the discontinuation of production by Wyeth Laboratories, Inc.,
in 1981. Although viral titer evaluations have indicated that the vaccine has
remained potent, additional quantities of vaccine are needed to augment the current stores
and replace expired vaccine. Previous methods of vaccine production that used calf
lymph are no longer available; therefore, virus produced for use in a new vaccine must
be grown by using a Food and Drug Administration-approved cell-culture substrate.
Any new cell-culture vaccine should be evaluated for safety and efficacy by
direct comparison with Dryvax by using appropriate animal models, serologic and
cell-mediated immunity methods, and cutaneous indicators of successful
vaccination (major reaction).
Treatment and Prevention Alternatives for Vaccine
Regarding alternatives to VIG for potential treatment and prevention of
vaccine adverse reactions, research priorities include a) evaluating antivirals for
activity against vaccinia virus by using in vitro assays and test animals that
demonstrate vaccinia virus pathogenicity, and b) developing and evaluating monoclonal
antibodies against vaccinia virus. Antivirals or monoclonal antibodies that demonstrate
activity against vaccinia virus in vitro and efficacy in protecting against dissemination
of vaccinia virus among test animals without compromising vaccine effectiveness
could provide medical personnel with alternatives to VIG.
The members of the Advisory Committee on Immunization Practices, Smallpox
Working Group, are grateful for the contributions of Carlton K. Meschievitz, M.D., M.P.H.,
Aventis Pasteur, Swiftwater, Pennsylvania; Donald A. Henderson, M.D., M.P.H., John Hopkins
Center for Civilian Biodefense, Baltimore, Maryland; and John W. Huggins, Ph.D., U.S.
Department of Defense, Ft. Detrick, Maryland, during the preparation of these recommendations.
Wehrle PF, Posch J, Richter KH, Henderson DA. Airborne outbreak of smallpox in
a German hospital and its significance with respect to other recent outbreaks in
Europe. Bull World Health Organ 1970;43:669--79.
Henderson DA. Looming threat of bioterrorism. Science 1999;283:1279--82.
Moyer RW, Arif BM, Boyel DB, et al.
Poxviridae. In: van Regenmortel MHV, Fauquet
CM, Bishop DHL, et al., eds. Virus taxonomy: classification and nomenclature of
viruses; seventh report of the International Committee on Taxonomy of Viruses. San Diego,
CA: Academic Press, 2000;137--57.
Jezek Z, Fenner F. Human monkeypox. In: Melnick, JL, ed. Monographs in virology.
Vol 17. Basel, Switzerland: Karger, 1988.
Lublin-Tennenbaum T, Katzenelson E, El-Ad B, Katz E. Correlation between
cutaneous reaction in vaccinees immunized against smallpox and antibody titer determined
by plaque neutralization test and ELISA. Viral Immunol 1990;3:19--25.
El-Ad B, Roth Y, Winder A, et al. Persistence of neutralizing antibodies
after revaccination against smallpox. J Infect Dis 1990;161:446--8.
McIntosh K, Cherry JD, Benenson AS, et al. Standard percutaneous revaccination
of children who received primary percutaneous vaccination. J Infect Dis 1977;135:155--66.
Fenner F, Wittek R, Dumbell KR. Orthopoxviruses. San Diego, CA: Academic Press,
Damaso CRA, Esposito JJ, Condit RC, Maussatché N. Emergent poxvirus from
humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian
smallpox vaccine. Virology 2000;277:439--49.
Kieny MP, Lathe R, Drillien R, et al. Expression of rabies virus glycoprotein from
a recombinant vaccinia virus. Nature 1984;312:163--6.
Smith GL, Mackett M, Moss B. Infectious vaccinia virus recombinants that
express hepatitis B virus surface antigen. Nature 1983;302:490--5.
Smith GL, Murphy BR, Moss B. Construction and characterization of an
infectious vaccinia virus recombinant that expresses the influenza hemagglutinin gene
and induces resistance to influenza virus infection in hamsters. Proc Natl Acad Sci
Zagury D, Leonard R, Fouchard M, et al. Immunization against AIDS in humans.
Cooney EL, Collier AC, Greenberg PD, et al. Safety and immunological response to
a recombinant vaccinia virus vaccine expressing HIV envelope glycoprotein.
Graham BS, Belshe RB, Clements ML, et al. Vaccination of vaccinia-naive adults
with human immunodeficiency virus type 1 gp160 recombinant vaccinia virus in a
blinded, controlled, randomized clinical trial. J Infect Dis 1992;166:244--52.
Paoletti E, Taylor J, Meignier B, Meric C, Tartaglia J. Highly attenuated poxvirus
vectors: NYVAC, ALVAC and TROVAC. Dev Biol Stand 1995;84:159--63.
Perkus ME, Taylor J, Tartaglia J, et al. Live attenuated vaccinia and other poxviruses
as delivery systems: public health issues. Ann N Y Acad Sci 1995;754:222--33.
Sutter G, Moss B. Novel vaccinia vector derived from the host range restricted
and highly attenuated MVA strain of vaccinia virus. Dev Biol Stand 1995;84:195--200.
Moss B. Replicating and host-restricted non-replicating vaccinia virus vectors
for vaccine development. Dev Biol Stand 1994;82:55--63.
Lee MS, Roos M, McGuigan LC, et al. Molecular attenuation of vaccinia virus:
mutant generation and animal characterization. J Virol 1992;66:2617--30.
Pike RM. Laboratory-associated infections: summary and analysis of 3,921
cases. Health Lab Sci 1976;102:105--14.
Jones L, Ristow S, Yilma T, Moss B. Accidental human vaccination with vaccinia
virus expressing nucleoprotein gene [Letter]. Nature 1986;319:543.
Shimojo J. Virus infections in laboratories in Japan. Bibl Haematol 1975;40:771--3.
Openshaw PJM, Alwan WH, Cherrie AH, Record FM. Accidental infection of
laboratory worker with recombinant vaccinia virus [Letter]. Lancet 1991;338:459.
Tartaglia J, Cox WI, Taylor J, Perkus M, et al. IX. Live vectors as vaccines:
highly attenuated poxvirus vectors. AIDS Res Hum Retroviruses 1992;8:1445--7.
Mayr A, Stickl H, Muller HK, Danner K, Singer H. Smallpox vaccination strain
MVA: marker, genetic structure, experience gained with the parenteral vaccination
and behavior in organisms with a debilitated defense mechanism. Zentralbl
National Institutes of Health. Appendix D-56 [NIH Guidelines]. Bethesda, MD:
US Department of Health and Human Services, National Institutes of Health, 1993.
National Institutes of Health. Modifications to NIH vaccinia immunization
policy [Memorandum dated 8 Aug 1996]. Bethesda, MD: US Department of Health and
Human Services, National Institutes of Health, 1996.
Bolyard EA, Tablan OC, Williams WW, the Hospital Infection Control Practices
Advisory Committee, et al. Guideline for infection control in health care personnel, 1998. Am
J Infect Control 1998;26:289--354.
Garner JS, the Hospital Infection Control Practices Advisory Committee. Guideline
for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17:53--80.
CDC, National Institutes of Health. Biosafety in microbiological and
biomedical laboratories. 4th ed. Atlanta, GA: US Department of Health and Human Services, 1999.
Advisory Committee on Dangerous Pathogens, Advisory Committee on
Genetic Modification. Vaccination of laboratory workers handling vaccinia and
related poxviruses infectious for humans. United Kingdom, 1990.
Koplan JP, Marton KI. Smallpox vaccination revisited. Am J Trop Med Hyg
Fulginiti VA, Winograd LA, Jackson M, Ellis P. Therapy of experimental
vaccinial keratitis: effect of idoxuridine and VIG. Arch Ophthalmol 1965;74:539--44.
Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination
reactions, prophylaxis, and therapy of complications. Pediatrics 1975;55:342--7.
Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination,
1968: results of ten statewide surveys. J Infect Dis 1970;122:303--9.
Lane JM, Millar JD, Neff JM. Smallpox and smallpox vaccination policy. Annu Rev
Haim M, Gdalevich M, Mimouni D, Ashkenazi I, Shemer J. Adverse reactions
to smallpox vaccine: the Israel defense force experience, 1991 to 1996: a comparison
with previous surveys. Mil Med 2000;165:287--9.
Waddington E, Bray PT, Evans AD, Richards IDG. Cutaneous complications of
mass vaccination in South Wales, 1962. Trans St Johns Hosp Derm Soc 1964;50:22--42.
Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS.
Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N
Engl J Med 1987;316:673--6.
CDC. Contact spread of vaccinia from a recently vaccinated Marine---Louisiana.
Guillaume JC, Saiag P, Wechsler J, et al. Vaccinia from recombinant virus
expressing HIV genes [Letter]. Lancet 1991;377:1034--5.
Sharp JCM, Fletcher W. Experience of anti-vaccina immunoglobulin in the
United Kingdom. Lancet 1973:656--9.
Kempe CH. Studies on smallpox and complications of smallpox vaccination.
De Clercq E, Bergstrom DE, Holy A, Montgomery J, Montgomery A.
Broad-spectrum antiviral activity of adenosine analogues. Antiviral Res 1984;4:119--33.
Tseng CKH, Marquez VE, Fuller RW, et al. Synthesis of 3-deazaneplanocin A, a
powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro
and in vivo antiviral activities. J Med Chem 1989;32:1442--6.
Tignor GH, Kende M, Hanham CA. Chemotherapeutic prevention of
complications caused by vaccinia virus-vectored immunogen. Ann N Y Acad Sci 1992;653:334--43.
Bray M, Martinez M, Smee DF, Kefauver D, Thompson E, Huggins JW.
Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect
Dis 2000;181: 10--9.
Neyts J, De Clercq E. Efficacy of
(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine for the treatment of lethal vaccinia
virus infections in severe combined immune deficiency (SCID) mice. J Med Virol
De Clercq E, Luczak M, Shugar D, Torrance PF, Waters JA, Witkop B. Effect of
cytosine arabinoside, iododeoxyuridine, ethyldeoxyuridine, thiocyanatodeoxyuridine,
and ribavirin on tail lesion formation in mice infected with vaccinia virus. Proc Soc Exp
Biol Med 1976;151:487--90.
Larson EL, 1992, 1993, and 1994 Guidelines Committee. APIC guideline for
hand washing and hand antisepsis in health-care settings. Am J Infect Control
Krugman S, Ward R, eds. Infectious Diseases of Children.
4th ed. Saint Louis, MO: C.V. Mosby, Co., 1968.
Kern AB, Schiff BL. Smallpox vaccination in the management of recurrent
herpes simplex: a controlled evaluation. J Invest Dermatol 1959;33:99--102.
CDC. Vaccinia necrosum after smallpox vaccination---Michigan. MMWR 1982;31:501--2.
Food and Drug Administration. Inappropriate use of smallpox vaccine. FDA
Drug Bulletin 1982;12:12.
Federal Bureau of Investigation, Counterterrorism Threat Assessment and
Warning Unit, National Security Division. Terrorism in the United States, 1998. Washington,
DC: US Department of Justice, FBI, 1998. Available at
<http://www.fbi.gov/publications/terror/terror98.pdf>. Accessed May 2, 2001.
Mack TM. Smallpox in Europe, 1950--1971. J Infect Dis 1972;125:161--9.
Gelfand HM, Posch J. Recent outbreak of smallpox in Meschede, West Germany. Am
J Epidemiol 1971;93:234--7.
Dixon CW. Smallpox in Tripolitania, 1946: an epidemiological and clinical study of
500 cases, including trials of penicillin treatment. J Hyg 1948;46:351--77.
Green DM, Reid SM, Rhaney K. Generalized vaccinia in the human fetus.
Harley JD, Gillespie AM. Case of complicated congenital vaccinia. Pediatrics
Garner JS, Simmons BP. Guideline for isolation precautions in hospitals. Infect
Advisory Committee on Infection Control (APIC), CDC Hospital Infections
Program Bioterrorism Working Group. Bioterrorism readiness plan: a template for
healthcare facilities. Atlanta, GA: US Department of Health and Human Services, CDC,
1999. Available at <http://www.cdc.gov/ncidod/hip/Bio/13apr99APIC-CDCBioterrorism.pdf>.
Accessed May 2, 2001.
All MMWR HTML versions of articles are electronic conversions from ASCII text
into HTML. This conversion may have resulted in character translation or format errors in the HTML version.
Users should not rely on this HTML document, but are referred to the electronic PDF version and/or
the original MMWR paper copy for the official text, figures, and tables.
An original paper copy of this issue can be obtained from the Superintendent of Documents,
U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800.
Contact GPO for current prices.
**Questions or messages regarding errors in formatting should be addressed to