INTRODUCTION — Vaccinia virus was the live poxvirus used throughout the world as the vaccine against smallpox. With the worldwide eradication of smallpox, routine vaccination with vaccinia virus is no longer performed.

While there remains a potential need to revaccinate an at-risk population due to concerns about bioterrorism with smallpox, vaccinia virus has remained important to understand because of its widespread use as an expression vector in research laboratories and because of its potential use as a vector for recombinant vaccines or as an oncolytic agent. In addition, the military continues to routinely vaccinate recruits against smallpox.

Infectious diseases clinicians may see patients with complications from smallpox vaccination or after accidental laboratory exposure; they may also be asked about the advisability of vaccination for occupational exposures to vaccinia virus or other orthopoxviruses. Since routine vaccination was stopped in the United States in the 1970s, current decisions about vaccination with the live replication competent vaccine (ACAM2000) typically involve students and researchers who work with vaccinia virus but who were never vaccinated as children.

Issues related to vaccinia virus in the research setting will be reviewed here. Vaccinia virus as the smallpox vaccine to prevent smallpox is discussed separately. (See "Vaccinia virus as the smallpox vaccine".)

GUIDELINE RECOMMENDATIONS FOR RESEARCHERS — Controversy exists as to whether to vaccinate all researchers working with vaccinia virus [1-6] since the live-replicating smallpox vaccine has had an imperfect safety record resulting in both mild and severe adverse reactions:

●The United States Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) recommend routine vaccination of laboratory workers handling vaccinia virus or other nonvariola orthopoxviruses as well as persons who directly handle animals infected with orthopoxviruses [7].

●In contrast, the United Kingdom Joint Advisory Committees on Dangerous Pathogens and Genetic Modification does not support routine vaccination of all researchers working with vaccinia virus [8].

In the United States, this controversy may end once the US Food and Drug Administration (FDA)-approved nonreplicating smallpox vaccine (MVA/Jynneos) becomes available. (See 'New vaccine options' below.)

INSTITUTIONAL POLICIES — Many institutions in the United States have set policies that strictly follow the current Advisory Committee on Immunization Practices (ACIP) recommendations and only allow work with vaccinia virus to be carried out by vaccinated individuals.

Other institutions allow the individual researcher, after talking to healthcare providers in occupational health, to decide to accept or decline vaccination. This approach is similar to policies that allow healthcare workers to decline recommended vaccines that confer protection against substantially more dangerous or contagious infections. An example of such documentation can be found at the University of Pennsylvania Office of Environmental Health and Safety website.

PROS AND CONS OF VACCINATION — The pros and cons of vaccinating all research workers who work with live, replication-competent vaccinia virus are discussed below [1,7,9-12].

Arguments for vaccination — Over the years there have been a number of published case reports of laboratory accidents involving vaccinia virus [13]. From 2005 to 2007, five cases of laboratory-acquired vaccinia virus infection were reported to the Centers for Disease Control and Prevention (CDC) during informal consultations regarding management [14]. Two patients had no history of prior vaccination, one refused immunization, and another did not have follow-up for a failed vaccination. Of note, all the cases reported were from accidental needle sticks. Because there is no official national surveillance system for the reporting of laboratory accidents, the extent of the problem is unknown.

Supporters of immunization stress that vaccination:

●Provides exposure to a measured (rather than unknown) dose of a well-characterized virus formulation, which results in local infection [14].

●May prevent an uncontrolled infection with unknown pathogenicity after an accidental exposure in the laboratory [14,15].

●In the specific circumstance when a researcher is working with vaccinia virus expressing HIV proteins, vaccination with vaccinia virus may protect the researcher from unintentional seroconversion to HIV antigens after an accidental exposure.

Arguments against vaccination — On the other hand, many argue that the risks outweigh the theoretical benefits of routine vaccination of all workers in the postsmallpox era [2,3,5,6]. The arguments against vaccination include:

●If one uses proper and careful microbiological techniques similar to those used when handling other viruses like HIV or HSV, there should not be accidental exposures when working with vaccinia virus. If the worker uses appropriate precautions, the hazard is a personal one and not significant for coworkers, family, or the public health, and thus, the question of vaccination should be an individual decision.

●The risks of complications from intentional vaccination are greater than the chance of an accidental exposure potentially causing a problem. In addition, there is a potential risk of spread of the virus after vaccination to the ever-growing group of unvaccinated contacts [16-19].

●It is not certain that vaccination will prevent an infection caused by a laboratory accident since there is evidence of what appears to be a primary infection in some previously vaccinated people. Most of the known complications of vaccination can also occur during revaccination.

●Vaccination may give a false reassurance of protection to the worker. The presence of neutralizing vaccinia virus antibody may not prevent infection [20].

●It is theoretically possible that vaccination with the current vaccine might prevent a later immune response to a recombinant vaccinia virus-based vaccine. Previously vaccinated workers might make antivaccinia immune responses that could negate a superior response to the foreign antigen expressed by a recombinant vaccine.

●Many do not like the permanent scar that develops at the vaccination site. Also, if generalized vaccinia occurs there is a risk of the development of disfiguring scars on other parts of the body.

RISK OF EXPOSURE — The risk of exposure is influenced by the work environment, work-related procedures, and the virulence of the laboratory vaccinia virus strain.

Work environment — Research with a recombinant vaccinia virus expressing a potentially dangerous protein should be performed in a biosafety level 3 containment facility.

Work-related procedures — Occupational health and safety offices that provide the vaccine at academic and industrial centers should inquire about:

●What will the researcher be doing with the vaccinia virus, and what titer stocks will be used? It is important to know the circumstances of the vaccinia use, since work with animals, sharps, or high titer virus stocks increase the possibility of an accidental exposure. As an example, this type of questioning might have mitigated the accidental vaccinia virus infections that occurred in China among workers who were handling rabbit skins from rabbits that had been infected with vaccinia virus [21].

●What antigen will the recombinant vaccinia virus express? Will any foreign genes be inserted into the vaccinia virus that may increase virulence?

Laboratory strains — It is important to realize that the majority of work done with vaccinia virus in the laboratory setting is done with the laboratory-adapted vaccinia virus strain Western Reserve (WR). This strain was selected for its neurovirulence in mice and is more pathogenic in the mouse model than the human vaccine strain, ACAM2000. While the preponderance of recombinant viruses used in the research setting have foreign genes inserted into the thymidine kinase (TK) gene of laboratory strain WR, which significantly attenuates the virus in animals [22,23], it is not clear if these viruses are attenuated in humans. For example, when these TK-negative viruses are given to humans by scarification, the same sized lesions are produced as the TK-positive vaccine strain, suggesting that virulence in humans is comparable [9,24,25].

TARGET GROUPS — It is highly recommended that the following researchers should be vaccinated:

●Those exposed to monkeypox or to high titer vaccinia virus (that is, an accidental exposure with a droplet would produce an infectious dose)

●Those directly working with needles while vaccinating animals with recombinant vaccinia viruses (see 'Laboratory strains' above)

●Those working with vaccinia viruses that may have enhanced virulence

Informed consent for vaccination describing the relative benefits and risks should be obtained from any worker receiving the vaccine.

RISK FACTORS FOR ADVERSE EVENTS — Clinicians should also remember that there is a higher risk of serious adverse reactions after exposure to vaccinia virus in people with the following conditions:

●Patients with immunodeficiencies (natural, acquired, or drug-induced)

●Individuals with a history of eczema, atopic dermatitis, or other exfoliative skin condition

●Pregnant women

●Patients with cardiac disease

Individuals in the research setting with these contraindications should not receive vaccinia vaccine. Individuals with contraindications to vaccination should probably consider not working with vaccinia virus or other human orthopoxviruses.

Relative contraindications to vaccination would be close contact of the vaccinee with people who have any of the above-mentioned conditions, although this is debatable. (See "Vaccinia virus as the smallpox vaccine", section on 'Smallpox (vaccinia) vaccine'.)

NEW VACCINE OPTIONS — A modified vaccinia Ankara (MVA) vaccine (sold under the trade names Imvamune and Jynneos) is made from a highly attenuated, nonreplicating vaccinia virus and has an excellent safety profile, even in immunocompromised people and those with skin disorders. This vaccine is the approved smallpox vaccine in Canada and the European Union and was approved for use in the United States in September 2019 [26]. It is expected that this vaccine will be an alternative to ACAM2000 when vaccination is used for pre-exposure prophylaxis of smallpox, and it should be a good choice for laboratory workers who work with replication-competent vaccinia viruses. In November 2021, the Advisory Committee on Immunization Practices (ACIP) voted in support of this vaccine, but official recommendations from the Centers for Disease Control and Prevention (CDC) are pending. This vaccine will become available through the CDC. (See "Vaccinia virus as the smallpox vaccine", section on 'Modified vaccinia Ankara vaccine'.)

SUMMARY AND RECOMMENDATIONS

●Vaccinia virus was the live poxvirus used throughout the world as the vaccine against smallpox. With the worldwide eradication of smallpox, routine vaccination with vaccinia virus is no longer performed. Vaccinia virus has remained an important microbial agent because of its widespread use as an expression vector in research laboratories and its potential role in recombinant vaccines. (See 'Introduction' above.)

●Controversy exists as to whether to vaccinate all researchers working with vaccinia virus since the live-replicating smallpox vaccine has been sometimes associated with severe adverse reactions. Routine immunization of laboratory workers handling vaccinia virus as well as persons working with animals infected with vaccinia virus is recommended in the United States, but not in the United Kingdom. (See 'Guideline recommendations for researchers' above.)

●Supporters of immunization stress that smallpox vaccination may prevent accidental infection with a virus of unknown pathogenicity. Opponents of immunization argue that the risk of an adverse event associated with the live-replicating smallpox vaccine is greater than the risk of occupational exposure, when appropriate safeguards are taken. Opponents also argue that immunization should be an individual decision since the personal risk of infection does not pose a hazard to public health. (See 'Pros and cons of vaccination' above.)

●Research with a recombinant vaccinia virus expressing a potentially dangerous protein should be performed in a biosafety level 3 containment facility. (See 'Risk of exposure' above.)

●Target groups for immunization include those exposed to high-titer vaccinia virus and those who vaccinate animals with recombinant vaccinia viruses. (See 'Target groups' above.)

●Smallpox immunization should be deferred among persons at risk for serious adverse events related to the vaccine, including patients with immunodeficiency, persons with certain skin conditions (eg, eczema, atopic dermatitis), pregnant women, and patients with cardiac disease. (See 'Risk factors for adverse events' above.)