#58533: Smallpox Vaccination: An Update

This course provides a description of the vaccination program before a case of smallpox has occurred. Should there be a case of smallpox diagnosed either in the United States or elsewhere in the world, different guidelines would apply. Since 2001, the CDC has recommended that each state and territory in the United States create and maintain at least one smallpox response team. The persons identified as part of the response team will also be part of the pre-event vaccination program. To enhance public health preparedness, the CDC has recommended that specific teams at the federal, state, and local levels be established to facilitate diagnostic evaluation of initial suspected cases of smallpox and to initiate control measures. Considerations for additional teams should include population and geographic concerns and be developed to comply with federal, state, and local terrorism-response plans [7].

The CDC also has recommended that each acute-care hospital identify vaccinated personnel who may act to provide medical care for potential smallpox patients. This team should provide care 24 hours per day for the first two or more days after patients with smallpox have been identified and until additional healthcare personnel have been vaccinated. When possible, those healthcare personnel who have already been vaccinated should be considered for inclusion as a means to decrease the incidence of possible adverse effects of the vaccination. Additionally, all persons administering or handling vaccinia in a pre-event vaccination program should be vaccinated [8]. Nonvaccinated workers should be restricted from entering the rooms of smallpox patients or, under emergency conditions, should wear personal protective equipment. The size and composition of the response teams will vary according to institutions and their patient populations. Ideally, each hospital should have enough vaccinated personnel from a spectrum of healthcare occupational categories to ensure continuity of care. As stated, ACIP recommends routine vaccination against the disease for specific populations at high risk of occupational exposure to the smallpox virus [1].

Mainly, the effects described are for primary vaccinees, that is, those who have never had a prior smallpox vaccination or do not know if they have had one. People born before 1971 and those who have had one or more vaccinations are considered secondary vaccinees, and the side effects are expected to be mitigated, providing contraindications are closely followed. It is important to note, however, that with ACAM2000, there is no longer the need to differentiate between a primary and a secondary vaccinee, although this distinction may be useful should an adverse event occur [4].

All medical personnel should think through their volunteer participation in a pre-event vaccination program. Because the risk of smallpox occurrence is an unknown factor, as is the possibility of its being used as a weapon of bioterror, the risk/benefit equation that one would normally weigh when considering whether to receive an immunization does not apply. The primary benefit from choosing to receive the vaccine would be the protection of the nation. Personal benefit would likely be realized only in the event of exposure to smallpox; therefore, each healthcare professional should weigh the likelihood of personal exposure. Personnel working in critical care, emergency response, or public health are more likely to be exposed than those on a surgical ward. Obviously, members of the public health response teams and care provider teams should be vaccinated if they have no contraindications. Vaccinators are assumed to have a certain level of risk; protection cannot be considered absolute [7].

Before 2006, the data on adverse events resulting from smallpox vaccination had been based on studies done in 1968. Between December 2002 and December 2017, the Department of Defense (DoD) vaccinated more than 2.6 million select military personnel in a national program of preparedness against the use of smallpox as a weapon of bioterror. This provided a useful sample size of more current data on the side effects of the vaccine [9,10].

Comprehensive training programs in vaccination technique, infection-control safeguards, screening and education methods, adverse event monitoring, and product storage and handling made immediate vaccinations possible. As a testimony to the effectiveness of good education, the DoD reported no cases of transmission of vaccinia from worker to patient among 27,700 smallpox-vaccinated healthcare workers. Most adverse events occurred at rates below historical rates, leading researchers to conclude that mass smallpox vaccinations could be conducted safely [9,10].

Much conflicting information has been circulated in both the popular media and medical literature. For example, many have written about the smallpox "shot." It is a vaccination, not a shot. Some older medical personnel may remember using acetone to clean the arm before applying the vaccine, while literature today mentions using alcohol before the vaccination is given. The current CDC recommendation is that the arm is cleaned with soap and water only if there is gross contamination [7,8]. Because so much has been written about the vaccine against smallpox, inconsistencies may occur, even from trustworthy sources.

It is important to differentiate between methods of respiratory transmission, such as "airborne" and "droplet." Diseases such as rubeola (hard measles, red measles, or 14-day measles), chickenpox, and influenza are airborne and infect the respiratory system via nasal and pharyngeal passages. Micro-organisms spread by airborne transmission are smaller than 5 microns in size and thus are in the air for longer periods of time. For example, rubeola remains in the air for 90 minutes after the contagious person has left the room and may infect those without immunity who enter the room during that time. Smallpox, meningitis, and many respiratory diseases are transmitted through droplets and are less contagious. These micro-organisms are larger than 5 microns in size and do not stay suspended in the air as long as airborne micro-organisms. Prolonged close contact is required to transmit the organism [11].

Many experts believe that smallpox first appeared in northeastern Africa more than 12,000 years ago. Some evidence of lesions resembling smallpox has been found on the faces of mummies, including that of Ramses V. Egyptian merchants probably spread the disease to India. The first recorded smallpox epidemic occurred during the Egyptian-Hittite war and led to the decline of the Hittite empire. The first stages of the decline of the Roman Empire coincided with a large-scale epidemic. Several reigning monarchs died from smallpox. During the 18th century, the Hapsburg line of succession to European thrones changed four times in as many generations because heirs had succumbed to smallpox. During the same century in Europe, 400,000 people died each year of smallpox, and one-third of survivors were left blind [15].

Variola virus is the smallpox causative organism. It is a double-stranded DNA virus and a member of the family Poxviridae, subfamily Chordopoxvirinae, and genus Orthopoxvirus. It replicates in the cytoplasm of the host cell, rather than in the nucleus, as do other viruses [22]. Electron micrographs show that variola organisms are shaped like bricks. This brick shape distinguishes variola from the varicella zoster virus (the virus that causes chickenpox) [3].

As previously mentioned, smallpox is transmitted mainly from person to person by the respiratory route through droplets. Close personal contact (normally within six feet of a patient) over a prolonged period, such as in a household, is required for transmission to occur. Smallpox is not as infectious as measles, chickenpox, or influenza. As a result, transmission in the workplace and school is less than in the household [23]. Data collected in the 1960s showed that an estimated 80% of the cases were contracted from an individual in the household [23]. In this course, "household contact" will be used in a broad sense and includes intimate and sexual contact. There is some indication in the medical literature that inanimate objects also may transmit the disease, but this is less common [9,24,25]. Unfortunately, the use of variola as a biologic weapon is a threat because of the aerosol infectivity of the virus and the relative ease with which it can be mass produced [26].

Transmission

As noted, smallpox is transmitted from one person to another by droplets and close contact is required. Patients are most infectious during the first 7 to 10 days after rash onset, although infectivity may occur during the prodromal period, immediately before rash onset. Occasionally, transmission has been by direct contact or contact with fomites (e.g., clothes or bedding); airborne transmission has occurred rarely [7]. Droplets containing the variola virus may be transmitted through face-to-face contact while talking, singing, coughing, or sneezing. The disease also may be transmitted by saliva (through sharing food or drink) and by kissing on the mouth. In past centuries, most people did not share food or drink nor were children kissed on the mouth by adults. Today, people share food and drink and even kiss newborns on the mouth. These changes in lifestyle have contributed to a more vulnerable population than in the days before eradication.

The virus is not shed during the incubation period, which can be from 7 to 17 days, but most commonly is 10 to 14 days. During the incubation period, the virus enters the respiratory tract, seeds the mucous membranes, passes quickly to the lymph nodes, and then multiplies in the reticuloendothelial system [3,27]. Probably only a few virus particles (virions) are sufficient to cause the infection (Figure 1) [28].

COURSE OF SMALLPOX (VARIOLA)

Figure 1

Source : Compiled by Author

Monkeypox is considered a zoonotic disease and can spread to people when they come into physical contact with an animal host (typically rodents or primates). However, person-to-person transmission is possible through close contact with lesions, body fluids, respiratory droplets and contaminated materials. It is unclear if the virus is present in semen or vaginal fluids or if asymptomatic individuals can transmit the disease [99]. Droplet and Contact Precautions are advised when caring for persons with monkeypox.

The first symptoms of monkeypox include fever, malaise, headache, sore throat, and cough. It generally has a similar clinical presentation and course as smallpox. However, a distinguishing feature of monkeypox is lymphadenopathy, which typically occurs with fever onset, one to two days before rash onset, or rarely with rash onset. Enlarged lymph nodes may be noted in the bilateral or unilater and can occur in submandibular, cervical, axillary, or inguinal areas [100].

After infection with monkeypox, there is an incubation period of approximately 7 to 14 days (range: 5 to 21 days), followed by the prodromal period, characterized by onset of initial symptoms. Following the prodrome, which typically lasts days, is the rash stage; the first lesions to develop are on the tongue and in the mouth (enanthem). Following the enanthem, a macular rash appears on the skin, starting on the face and spreading to the arms and legs and then to the hands and feet, including the palms and soles [100]. The rash typically spreads to all parts of the body within 24 hours, becoming most concentrated on the face, arms, and legs (as with smallpox). By the third day of rash, lesions have progressed from macular (flat) to papular (raised). By the fourth to fifth day, lesions have become vesicular, and by the sixth to seventh day, lesions have become pustular and show signs of umbilication. The pustules will remain for approximately five to seven days before beginning to crust. By the end of the second week, pustules have crusted and scabbed over. Scabs will remain for about one week before beginning to fall off. After all scabs have fallen off, the patient is no longer contagious [100].

The prognosis of monkeypox infection varies depending on the variant contracted. There are two clades of monkeypox virus: the West African clade and the Congo Basin (Central African) clade. Human infections with the West African clade appear to cause less severe disease compared with the Congo Basin clade; the case fatality rate is 3.6% for the West African clade and 10.6% for the Congo Basin clade [99]. The 2022 outbreak cases have all been confirmed as having been infected with the West African clade.

In 1017, a hermit in China introduced the prime minister to "variolation," a type of inoculation using germs from smallpox survivors with mild cases. Various forms of smallpox material (e.g., vesicles, pus from pustules, or ground-up scabs) were administered to healthy adults through the nose or skin. These different methods were known as "variolation," which was spread by merchants traveling by caravan to distant lands. For example, Circassian traders introduced the practice in the Ottoman Empire. In 1717, Lady Mary Wortley Montagu accompanied her ambassador husband to Istanbul. In a letter to a friend in England, Lady Montagu described "ingrafting," which was her term for variolation. It was a procedure done by elderly women who made four or five scratches or slight punctures on the arm. Material from the pustules of patients with mild cases was introduced into the scratches or punctures. Lady Montagu had her son inoculated while in Istanbul and her daughter inoculated in the presence of the English court doctors. Variolation also was tried on prisoners, who were then exposed to smallpox; they did not develop the disease. After the two daughters of the Princess of Wales were treated in 1722, the procedure gained general acceptance [14,15].

Two to three percent of variolated persons died of smallpox, became the source of a new epidemic, or developed other illnesses, such as tuberculosis or syphilis. However, smallpox fatality rates were 10 times lower in those who had experienced variolation, which was widely practiced until Jenner's discovery [15].

In the rural areas of Europe, milkmaids who had previously had cowpox were noted to be immune to smallpox. Benjamin Jesty, an English farmer, vaccinated his wife and two sons with material taken from the udders of cows with cowpox. None of the Jestys developed smallpox during later epidemics nor did they have any reaction to variolation. However, Jesty's method was ignored because his wife nearly lost the arm in which she was vaccinated due to severe inflammation [15].

Edward Jenner was born in 1749 and, at 8 years of age, had the variolation procedure performed on him. Jenner developed an interest in medicine and later became a surgeon. He wrote several papers on other scientific studies; however, the connection between cowpox and smallpox continued to intrigue him throughout his medical career [15].

In 1796, a milkmaid named Sarah Nelmes developed cowpox. Jenner extracted fluid from a pustule on Sarah's hand and inserted it in two half-inch incisions on the arm of a healthy 8-year-old boy named James Phipps. Later, Jenner tried twice to inoculate James with smallpox samples; however, the boy did not develop the disease [14]. Jenner published a manuscript in which he described 10 cases of vaccination and 13 persons who had cowpox, in whom immunity was confirmed [14,15].

By 1800, most European countries were vaccinating for smallpox, mostly using pustule fluid. In 1801, U.S. President Thomas Jefferson had 18 family members, some neighbors, and the last of the Native American tribe of Mohicans vaccinated [15]. In 1805, Napoleon insisted that all his troops who had not had smallpox be vaccinated with the "Jennerian vaccine" [15,39].

This deliberate use of vaccination was the first scientific attempt to control an infectious illness. Technically, Jenner did not discover vaccination, but he was the first person to confer scientific status on the procedure. He named the procedure vaccinae after vaca, which is Latin for "cow." Jenner also stated that the universal use of the vaccine would lead to the eradication of smallpox. In 1977, less than 200 years after the vaccination of young James Phipps, a Somalian cook, Ali Maow Maalin, developed the characteristic smallpox rash. Maalin was the last person to develop natural smallpox as a result of contact with another person [15]. In honor of Jenner, all materials used to induce immunity are called "vaccines" [39].

Since the introduction of vaccination in 1796, controversy has existed as to the origin of Jenner's variolae vaccinae. In some cases, the vaccination was successful and it protected from smallpox; other times, there was either no "take" or an apparently successful vaccination did not protect the recipient from smallpox. Jenner suggested that other vaccinators had chosen material from cows with "spurious cowpox" rather than true cowpox. Jenner believed that his vaccine originated from an infection of the heels of horses, which he referred to as "grease," and that after passing through the cow, it was suitable for human use.

The debate has continued into the 21st century. The current vaccinia strains differ from cowpox and other poxviruses and also differ in various parts of the world. There is no natural host for vaccinia. Before vaccination programs were discontinued, the generally accepted view was that vaccinia was an artificially propagated virus that was modified in some way from the naturally occurring poxviruses. No one is sure of the origin of vaccinia [40,41].

It is important to remember that vaccinia has been tested in controlled experiments and proven to have no derivation from variola, the causative virus of smallpox. No one can develop smallpox from the vaccination as the organisms are different, even though both are orthopoxviruses [39].

In summary, vaccinia is the virus used to make the smallpox vaccine. Variola is the virus that causes smallpox; it is not used to make the vaccine. Vaccinia is spread only by direct contact and is not airborne. Variola also is spread by direct contact and by droplet aerosols in the air. Both viruses have more severe reactions or disease in immunocompromised individuals.

The underlying purpose in eradication of a disease is to give the causative organism no place to survive. This is very difficult when the organism has both a human host and an animal host. Thus, there are no plans to try to eradicate influenza, for example, in which the life cycle of the virus includes pigs, fowl, and humans. However, smallpox could be eradicated because only humans are susceptible to variola.

Total population vaccination (mass vaccination) is the theory behind the worldwide effort to eradicate polio. Realistically, one could never have every human protected against polio. The goal instead is to obtain "herd immunity," which means that enough people are immune so that the remaining few also are protected. In this theory, the organism fails to locate the few susceptible individuals and is thus unable to survive. The percentage of the world's population that would require vaccination to prevent smallpox through herd immunity is believed to be around 90% [42]. It is known that vaccinated populations have not approached this percentage in areas of Africa and Asia. This has led to the use of ring vaccination, commonly known as surveillance and containment [42].

The purpose of ring vaccination is to form a buffer of immune individuals around the organism to prevent the spread of the disease. It is incorrect to illustrate this concept by drawing a "ring" on a map, within which all individuals would be vaccinated. Ring vaccination is not a geographic designation. It is a social designation in which a "ring" is drawn around each smallpox victim, and it includes close household contacts who may have been exposed to the victim. (The victim must be isolated to limit the number of contacts.) There is a three- to four-day window in which a person exposed to smallpox may be vaccinated to prevent the disease, or at least make the symptoms milder. To help eradicate the disease, a second "ring" also is vaccinated. The second ring consists of those who have had contact with the individual(s) exposed to the smallpox victim and the members of their households [42]. These individuals also would need to be vaccinated because it is not possible to know exactly when a contact was exposed and whether the three- or four-day period had already lapsed. Contacts would be vaccinated up to seven days after exposure. They would still likely develop smallpox, but it would be less severe [17]. For anyone exposed to a smallpox patient, the pre-event contraindications will be modified, as the disease has a fatality rate of 30% [9]. This would mean 300,000 fatalities in one million cases of smallpox, compared to one to two fatalities in one million vaccinations.

For example, Mr. J has smallpox. The case investigation reveals that Mr. J lives with his wife, Mrs. J, and two children, JJ (4 years of age) and SJ (7 years of age). Mrs. J's niece, Miss L (7 years of age), has been staying with the family while her parents are on a trip and is in the household when Mr. J has the prodrome; she returns home the day he develops the smallpox rash. Mr. J is a farmer with no hired help. Mrs. J works for a guest home where she cares for six elderly residents. JJ attends preschool, and SJ is in the second grade. Miss L also is in the second grade in another city.

According to the ring vaccination protocol, who should be vaccinated? Obviously, Mrs. J, JJ, SJ, and Miss L should be vaccinated. Additional contacts in the "second ring" requiring vaccination would be the following: the six elderly residents exposed to Mrs. J; any family members who visited these elderly residents and the households of these family members; the cook at the guest home and the cook's household; the children and workers in JJ's preschool and their households; the children and teachers and their household contacts in both SJ's and Miss L's second grade classes; and Miss L's household contacts.

Please remember that this scenario describes the situation after a case of smallpox has been diagnosed. Vaccination is currently voluntary and done before a diagnosis of smallpox. Individuals with contraindications should not be vaccinated, nor is vaccination recommended for the general population. However, should an outbreak of smallpox occur, there is enough vaccine to vaccinate every person in the United States [43]. There are some individuals who, for religious, cultural or other reasons, will refuse to receive vaccinations; their wishes should be considered [44].

In 2007, prior to the removal of Dryvax from the SNS and other programs, the FDA licensed ACAM2000 (Sanofi Pasteur Biologics, formerly Acambis), a second-generation smallpox vaccine, for use in the United States. ACAM2000 is a live vaccinia virus derived from plaque purification cloning from Dryvax. Like Dryvax, ACAM2000 is contraindicated for immunocompromised individuals and has been associated with serious side effects, such as myocarditis, encephalitis, and ocular complications. Based on clinical studies, myocarditis and/or pericarditis have occurred in 1 in 175 adults who receive the vaccine for the first time [4]. Serious health problems, including those that are life-threatening, also may occur in unvaccinated individuals who are accidentally infected by someone who has recently been vaccinated [4]. The percentage of unvaccinated persons who develop a successful immunization reaction from ACAM2000 has been shown to be similar to that of Dryvax. ACAM2000 also has been found to be acceptable as a booster in those previously vaccinated for smallpox. It is important to note, however, that a 2008 study examining the continued immunity conferred by smallpox vaccination administered in childhood found that 97% of participants showed no decrease in vaccinia antibody titers (after a range of 13 to 88 years) [46]. As a result, there may be no need for booster vaccinations, and the available supplies of vaccinia may be better used in those who have not previously been vaccinated.

The CDC began distributing ACAM2000 to civilian laboratory personnel, the military, and state public health preparedness programs in 2008 [4,5]. Every person who receives the ACAM2000 vaccine must receive an FDA-approved medication guide, which contains information that may help patients avoid serious adverse events. These guides must be issued when the FDA has determined that [4]:

ACAM2000 is the first vaccine licensed with a medication guide. The guide answers questions about the vaccine, who should get it and why, possible side effects and adverse events, how to care for the vaccination site, and what to expect and avoid if vaccinated [2].

In 2007, the U.S. Department of Health and Human Services awarded a contract to Bavarian Nordic A/S to manufacture and deliver 20 million doses of Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), enough for 10 million individuals, to the SNS [47; 48]. This highly attenuated, third-generation vaccine cannot replicate in humans, and MVA-BN requires a booster at four weeks to achieve immune protection equivalent to ACAM2000 because of its low immunogenicity. However, this feature makes the vaccine appropriate for use in patients who have contraindications for ACAM2000, such as being a compromised immune system [2; 45]. There are approximately 10 million such individuals in the United States, and in the event of a possible smallpox or other orthopoxvirus outbreak, 20 million doses (a two-dose immunization schedule) of MVA-BN would be available to them [47,48].

Although MVA-BN was associated with dose-related local reactions, the events were self-limited and did not lead to the discontinuation of subjects from phase I studies. No vaccinia-associated cardiac complications occurred with MVA-BN in a phase II clinical trial (completed in 2015) in a study population of healthy young adults [49]. One serious adverse event (sarcoidosis) did occur, though the causation is uncertain [49]. MVA-BN was fast-tracked for approval by the FDA in 2008 [50].

In 2019, the FDA approved the MVA-BN vaccine JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non-Replicating) for the prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection [51]. The clinical efficacy of JYNNEOS (also known as Imvamune or Imvanex outside the United States) to generate an immune response has been evaluated in six published clinical studies [52,53,54,55,56,57]. The MVA-BN vaccine has been shown to be highly effective against monkeypox in healthcare workers in Africa, but the efficacy against smallpox has not been tested in humans [34,60]. JYNNEOS is stockpiled in the SNS, with a total 28 million doses available (as of 2018) [2; 58]. Bavarian Nordic A/S is working on providing a freeze-dried formulation of MVA-BN to the SNS after clinical trials are completed and approval is granted (perhaps as early as 2022) [59].

For years, the only vaccines available for smallpox were the Aventis Pasteur Smallpox Vaccine (APSV), also known as Wetvax, (produced in 1956–1957) and Dryvax (produced in 1978). However, the manufacturer of Dryvax announced its intent to withdraw the license and asked that all remaining quantities of the vaccine held by civilian and military programs be quarantined by February 29, 2008 (when the remaining lots were due to expire) for the purpose of destruction. All programs holding supplies of Dryvax were instructed to provide the CDC with documentation of the vaccine's destruction no later than March 31, 2008 [5]. APSV (Wetvax) is currently stockpiled at the SNS for emergency use and is tested annually for potency; however, it will only be used when supplies of ACAM2000 are depleted, not readily available, or in a case-by-case basis when ACAM2000 is contraindicated and JYNNEOS is not available [2,45]. The CDC holds investigational new drug (IND) applications for APSV use at full strength and 1:5 dilution.

The National Institute of Allergy and Infectious Diseases is supporting studies of other smallpox vaccines under IND applications. The National Institutes of Health is supporting the study of new-generation smallpox vaccines that are made using highly attenuated forms of the smallpox vaccine virus (third-generation vaccines) or using only selected DNA segments of the virus (fourth-generation vaccines). Third-generation attenuated vaccines being tested for use in the United States are ACAM3000 and LC16m8 [58]. LC16m8, which was produced by passage of vaccinia through rabbit kidney cells, was licensed for use in 1975 in Japan, which has an 80 million dose per year manufacturing capability [34; 60]. Fourth-generation vaccines are attenuated through direct genetic engineering rather than extensive passage through alternative hosts; examples of these vaccines are VacDelta6 (VECTOR), VACVvD4-ZG, and VACVΔE3L, with some currently in clinical trials.

Like many vaccines, vaccinia produces both humoral and cell-mediated immunity [14]. The humoral response results in the production of short-lived IgM antibody, persistent IgG antibody, and other types of antibodies. A convenient memory clue when reading laboratory results for infectious diseases is that IgM could mean "I get medicine," which indicates the short-lived antibody and is a marker for acute infection. Of course, there may be no medicine or treatment available, but this person is probably contagious if they are still exhibiting symptoms. IgG could be thought of as "I get germs" and indicates a persistent antibody that confers some degree of immunity. The person with these laboratory results has had the infection in the past and would not be a candidate for any available treatment or medicine, nor would that person be contagious. This is especially significant in reading laboratory results for a patient with a suspected disease, such as hepatitis A.

In most diseases, the IgG antibody is specific for a disease, and most viral vaccines are now specific for a certain virus. An example is the annual influenza vaccine developed by the CDC and the FDA. Each year, the vaccine is produced to overcome four specific viral strains that are expected, usually two type A strains and two type B strains [62]. Persons who have received their annual influenza vaccine may still become ill from other viruses not covered by the immunization and against which they have no immunity.

As this course has stressed, the vaccinia vaccine does not contain smallpox virus. However, vaccinia does cause the vaccinated individual to develop antibodies that are specific for the viruses in the orthopoxvirus group. In this case, one could think of the antibody produced by vaccinia as a "master vaccination" that can protect against all of the orthopoxviruses. Therefore, the vaccination also is effective in protecting against smallpox [31,63].

In addition, vaccinia produces cell-mediated immunity, which may be even more significant in preventing smallpox [14]. In every person with a healthy immune system, humoral and cellular immunity always operate simultaneously. The immune response is a complicated process. In the following section, the complicated immune response is simplified in an attempt to make it understandable and useful for all healthcare professionals. Those who are familiar with the immune process may find this section to be a review.

Three types of cells are involved—macrophages and two types of lymphocytes. Certain macrophages present the antigen (variola virus, in the case of smallpox) to the lymphocytes. The lymphocytes are either B-cells (so named because they are mainly formed in the bone marrow) or T-cells (from the thymus; there are several subclasses).

The B-cells have antibody-like receptors. When the macrophage presents the antigen, the B-cell differentiates to form an antibody-synthesizing plasma cell and also divides to form a clone of identical cells. The plasma cell leads to immunoglobulins that neutralize viral infectivity and kill infected cells. The clone cells are memory B-cells that mount a secondary response if re-infection occurs [64].

T-cells also react specifically to different antigens, as they too have different kinds of antibody-like receptors on their surface or "overcoat." T-cells expand clonally and save a small portion of each clone as long-lived memory T-cells that are available if re-infection occurs. In addition, T-cells liberate substances called "lymphokines" that serve to activate macrophage cells, with the result that infected host cells are killed nonspecifically. Subclasses of T-cells are helper T-cells (Th) and suppressor T-cells (Ts). The helper and suppressor T-cells modulate the activity of the antibody-producing B-cells and other T-cells [64]. Another T-cell subclass is cytotoxic T-cells (Tc), which actively destroy infected host cells and produce lymphokines. Delayed hypersensitivity T-cells (Td) differentiate on contact with the specific antigen, release lymphokines, activate macrophages, and produce delayed hypersensitivity reactions. T-cells also produce gamma interferon [31,63,64]. Thus, vaccination helps protect the vaccinee through humoral and cellular immunity. Several factors influence the degree of protection [63]:

Because vaccinia is a live vaccine and will be shed from the vaccination site, household contacts should be considered at risk if they have any contraindications to the vaccine. When screening for a pre-event program, household contacts include persons with prolonged intimate contact (e.g., sexual contact) with the potential vaccinee as well as anyone who might have direct contact with the vaccination site. The contraindications for household contacts include [7]:

Any candidate for vaccination who has a household contact with any contraindication should not be vaccinated. Because vaccination has been mandatory for select military personnel who have no contraindications, household contacts of vaccinated military personnel should be aware of the risks [10].

Contacts at most work sites and social events are not considered close contacts; therefore, their contraindication status does not need to be considered. However, when at work, in social situations, or when interacting with household members, all vaccinees should have the vaccination region covered with an appropriate dressing and a long sleeve until the scab falls off.

The presence of an adolescent or child (including an infant) in the household is not a contraindication to vaccination of adult members of the household. Nonetheless, programs might defer vaccination of household contacts of infants younger than 1 year of age because of data that has indicated a higher risk for adverse events among primary vaccinees in this age group, compared with that among older children. Neither the presence of a breastfeeding woman nor the presence of a person with a vaccine component allergy in the household are contraindications to vaccination of other household members [7].

Because all pre-event vaccinations are voluntary, it is important that each candidate thoroughly understand the vaccine's contraindications, actions, side effects, and possible adverse events and seek the advice of his/her medical provider, if needed. Developing knowledge of smallpox also is an effective way to counteract fear and cope with the threat of bioterrorism. Healthcare professionals should also evaluate personal hygiene habits, such as effective handwashing, to minimize any danger of exposing others.

The FDA has recommended that vaccinees defer donating blood for 21 days or until the scab has come off. Contacts of vaccinees who develop vaccinia should not donate blood for 14 days after full resolution of their complication [7].

ACAM2000 should only be reconstituted with 0.3 mL of the diluent provided. The vaccine vial should be removed from cold storage and brought to room temperature before reconstitution. Remove the flip-cap seals of the vaccine and diluent vials and wipe each rubber stopper with an isopropyl alcohol swab. Allow each stopper to dry thoroughly. Using aseptic technique and a sterile 1-mL syringe fitted with a 25-gauge, 5/8-inch needle (provided), draw up 0.3 mL of diluent, and transfer the entire contents of the syringe to the vaccine vial. Gently swirl to mix, but try not to get product on the rubber stopper. The reconstituted vaccine should be a clear to slightly hazy, colorless to straw-colored liquid that is free from extraneous matter. Reconstituted vaccine should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, the vaccine should not be used; the vial should be disposed of safely [66].

Personnel preparing and administering the vaccine should wear surgical or protective gloves and avoid contact of vaccine with skin, eyes, or mucous membranes. The vaccine vial, its stopper, the diluent syringe, the vented needle used for reconstitution, the bifurcated needle used for administration, and any gauze or cotton that came in contact with the vaccine should be discarded in leak-proof, puncture-proof biohazard containers. These containers should then be disposed of appropriately [66].

A package insert is included with each vaccine kit. ACIP recommendations are considered by the CDC and, if adopted as policy, published in the CDC's Morbidity and Mortality Weekly Reports. Although the bulk of recommendations related to smallpox vaccination are still valid, the CDC has encouraged providers to refer to the ACAM2000 package insert and follow the instructions regarding vaccine administration [8].

Because the CDC does not have enough information to determine the safety of administering the vaccine at other sites, the deltoid area of either arm is the preferred site for vaccination. This area offers ease of observation, ease of dressing changes, and is easier to keep dry while bathing or showering [8]. Some people may prefer that the nondominant arm be used. As previously stressed, alcohol should never be used as it inactivates the vaccine [7,8]. If there is visible dirt, the arm should be washed with soap and water and allowed to thoroughly dry to avoid inactivating the vaccine. Otherwise, no cleaning or site preparation is required unless the area is grossly contaminated [8].

Because vaccinating over a tattoo may change its appearance, the CDC has recommended that vaccinees be informed of this possibility and also that no data about what the use of an altered site means in terms of local adverse events or autoinoculation risk. Otherwise, the CDC has no standard policy concerning tattoos [8].

The vaccination needle is 6.5 cm in length and thin. The bifurcated prongs are approximately 2 mm in length. They are packaged for single-use and are sterile. The needle should be inserted into the vial just far enough to have the bifurcated tip touch the vaccine, allowing the needle to pick up a droplet of vaccine. If the needle is inserted too deeply, too much vaccine will be picked up because the vaccine is sticky. The needle should be inserted straight into the vial and then pulled straight out. The upper part of the needle (the part that has been in contact with fingers) should not be inserted into the vaccine vial [66]. The needle must not be reinserted into the vial after touching the patient's skin. Vaccinators who have presbyopia should wear their glasses, as the minute amount of vaccine is difficult to see.

The vaccinator's free hand should grasp the vaccinee's upper arm in a way to make the skin taut. Preferably, the arm should be held from underneath as the skin may be held taut effectively, and the vaccinator's hand may be protected from an accidental needle stick. The wrist of the hand holding the needle of the vaccinator should rest against the vaccinee's arm [66]. The vaccinator should rapidly make 15 jabs of the needle perpendicular to the skin through the vaccine droplet (approximately a 2.5-mcL dose) to puncture the skin, within a diameter of about 5 mm. The jabs should be vigorous enough to bring a drop of blood, after 15 to 20 seconds, at the vaccination site [66]. ACAM2000 uses 15 insertions for both primary (has not been previously vaccinated) and revaccination and has no provision for additional insertions if no trace of blood is visible after vaccination [8]. The needle should not be redipped into the vaccine after it has touched the vaccinee's skin. After use, the needle should be discarded in a suitable biohazard receptacle [66].

The vaccine site should be dabbed with a sterile gauze pad to remove any excess vaccine and blood; the gauze should then be discarded in a biohazard waste receptacle. Unless the vaccine vial will be immediately used to vaccinate another subject, the vial should be closed by reinserting the rubber cap; the vial should then either be returned to refrigerated storage or placed on ice [66].

The vaccination site should be covered loosely with a gauze bandage and secured with first aid adhesive tape to prevent spreading of the vaccinia virus. It is important to note that only persons working in healthcare settings should use semipermeable dressings. This is because additional coverings at the vaccination site may cause maceration and may increase and prolong irritation and itching, thereby increasing the potential for contamination of the hands. Dressings should be changed frequently to prevent the accumulation of exudates and consequent maceration [7]. Hospitals should designate staff to assess dressings for all vaccinated healthcare workers; when feasible, these staff should be vaccinated. All persons handling dressings should observe contact precautions [7].

After the site has been dressed, the vaccinator may remove the gloves and wash his/her hands with antimicrobial soap and warm water or with alcohol-based hand rubs (e.g., gels or foams). A new pair of gloves should be donned before the next person is vaccinated [8]. Good handwashing hygiene by the vaccinator is imperative to prevent any vaccine from being introduced inadvertently at any place other than the vaccine site [7,66].

Although "dry" hand wash preparations containing >60% alcohol are suitable for disinfecting the hands after touching one's own vaccine site, they should not be used in the vaccinated area because of the danger of accidentally inhibiting the vaccine [7].

In a post-event vaccination setting, the same administration dose (i.e., vaccine droplet of approximately 2.5-mcL dose) and procedure (i.e., scarification using 15 jabs of a stainless steel bifurcated needle) for ACAM2000 is also to be followed for the APSV formulation, if provided by CDC [45]. The administration of JYNNEOS/MVA-BV is one 0.5-mL subcutaneous injection at 0 and 4 weeks for primary vaccinees (i.e., two doses) and a single 0.5-mL dose for previously vaccinated individuals; these are supplied in single-dose vials. JYNNEOS/MVA-BV is indicated for healthy individuals and individuals with atopic dermatitis, other skin disorders, allergic rhinitis, and/or immunodeficiency [45].

There are three possibilities for care of the vaccination site: no dressing, simple gauze, or a two-layer dressing of gauze covered with a semi-permeable dressing [74]. The important point is to ensure that the vaccination site is covered to prevent dissemination of the virus [50].

Effective handwashing, using soap and water, results in the removal of the oils that are on the skin. Viruses and bacterial organisms are trapped in the oils produced by the skin. A quick pass under the faucet, even with some soap, may not be sufficient to remove the oils, and organisms may remain on the skin.

To remove the oils and organisms, soap must be used and the hands should be well lathered, vigorously rubbed, and then rinsed well under running water. A minimum of 20 seconds of lathering, rubbing, and rinsing are needed to assure that the oils and organisms are removed (imagine singing "Happy Birthday" twice through). Warm water, if available, is suggested for comfort, but the water used for hand washing would never be hot enough to kill the organisms. Rinse hands well under running water and then dry, using either a paper towel or an air dryer. Ideally, use the paper towel to turn off the faucet and then discard the towel appropriately; using an elbow to turn off the faucet is an alternative [75,76].

Soap and water are the preferred way to clean the hands, but in situations where soap and water are not available or are impractical, alcohol-based preparations may be used. It is important that these preparations have an alcohol content of >60% [75,77]. When using an alcohol-based hand sanitizer, apply the product to the palm of one hand, rub the hands together, and then rub the product over all surfaces of the hands and fingers until the hands are dry [75,76]. Never clean the vaccination site with a product containing alcohol and do not use an alcohol-based sanitizer near the site.

Usually, for the first two days after vaccination, the site appears unchanged and does not shed vaccinia (Figure 2). A papule will normally develop on either the third or fourth day. Whenever the site appears to have a "sore," vaccinia is shed and the vaccinee can transmit the virus to others or to other areas, especially the eyes. By the fifth to sixth day, the papule becomes a vesicle with erythema of various sizes around it. This vesicle will become depressed in the center. The vesicle becomes a well-formed pustule (mean diameter of 12 mm) by day eight or nine. After 12 or more days, the pustule crusts over and forms a scab. Normally, the scab falls off between the 17th and 21st days, revealing a scar. After the scab is gone, the vaccinee no longer has the potential to shed the virus and can no longer transmit vaccinia [78]. Images of these normal reactions may be seen on the CDC smallpox website.

COURSE OF VACCINIA

Figure 2

Source : Compiled by Author

The vaccine sites of both first-time vaccinees and revaccinees should be checked by a medical professional between days 6 and 8 [79]. Vaccine site evaluations on other days may not be reliable. For example, if the evaluation is done too early, certain "non-takes" may look reactive; if done too late, the vaccination "take" might be missed [79]. At the time the vaccine is administered, the vaccinee should be told where and when to have this check performed.

A"major reaction" or "take" indicates that the vaccination has been successful and the vaccinee should be developing immunity to orthopoxviruses. The take is characterized by a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which may be either a scab or an ulcer. All other responses should be considered "equivocal" (a"non-take") [79].

In some cases, the site has a large area of erythema with possible induration that some inspectors may think is infected. However, this is a robust or exuberant reaction to the vaccination. The edema and induration are uniform, versus the irregularly raised surface and signs of impetigo present in a bacterial cellulitis. The robust reaction resolves within a few days; it is not infected and antibiotics are not required [80].

On the seventh day following vaccination, if the site does not have the vesicle, it is termed "equivocal" (a"non-take"). Equivocal reactions consolidate a variety of previously used terms, including accelerated, modified, vaccinoid, immediate, early, or immune reactions. Equivocal reactions have been defined as all responses other than "major reactions." There also may be no reaction at all. About 5% of vaccinations are equivocal [74]. There may also be an allergic reaction, which does not indicate immunity. An equivocal reaction means that there is no immunity and the vaccination must be repeated, preferably immediately after the evaluation. Usually, the second vaccination results in a take, but occasionally there is an equivocal reaction or no reaction even with the second vaccination. Equivocal readings may be caused by a number of factors, including improper vaccination technique, use of vaccine that has lost its potency, or residual immunity among previously vaccinated individuals. Persons with an equivocal reaction cannot be presumed to be immune to smallpox; revaccination is recommended [79].

In addition to the reaction at the site that leads to immunity, there are other possible expected reactions. The most problematic of these is the robust or exuberant reaction or intense erythema and induration ringing the site [80]. As previously noted, practitioners unfamiliar with evaluating a vaccine site tend to incorrectly assume that a robust reaction is infected. Hopefully, as more practitioners become familiar with reading vaccinations, the diagnosis between a robust reaction and an infected vaccine site will be easier to make.

Other local reactions may include soreness at the vaccination site, reactions to the tape, and local lymphadenopathy [80,81]. Tape "burns" are distinguished by erythema corresponding to tape placement. Treatment consists of antihistamines and a change in type of tape or gauze wrap.

Systemic symptoms are expected and usually occur 8 to 10 days after vaccination when the vaccine site reaction reaches the peak of the inflammatory response. Occurrence of the following symptoms has been shown to vary considerably between primary vaccinees (higher rates) and revaccinees (lower rates) [78,81]:

Normal variants that are not considered adverse events include [78,81]:

None of these expected normal variants require treatment other than symptomatic relief [78].

Autoinoculation is the transfer of or appearance of vaccinia lesions elsewhere on the body. Because vaccinia is shed from the site after the vesicle appears and until the scab falls off, a vaccinee whose hand hygiene is inadequate may inadvertently inoculate other sites on his/her person. The most common sites are the face, eyelid, nose, mouth, genitalia, and anal region [80,81]. Infants and children are most susceptible because they tend to scratch the itching vaccination site [81]. Skin with disrupted integrity and the eyes are especially vulnerable as the infection may be extensive in skin lesions and a threat to eyesight. Data from the 1960s have revealed that accidental implantation of vaccinia is the most frequent complication of vaccination (i.e., 25.4 per million primary vaccinees, which accounted for approximately one-half of all the complications of primary vaccination and revaccination) [82]. This complication highlights the need for a proper dressing on the site and a sleeve that prohibits scratching, as well as attention by the vaccinee to good hand hygiene [80].

Lesions from autoinoculation will follow the same course as the vaccination site. Patients with cell-mediated immune dysfunction are at risk for lesions that will not heal and will expand. There is no treatment required if there are only a few lesions. Multiple lesions, especially if they are confluent and cover large portions of the body, should be treated with vaccinia immune globulin (VIG), which is discussed later in this course [81].

Vaccinia keratitis is a rare complication that results from the introduction of vaccinia from the vaccination site to the cornea. It is characterized by corneal lesions, abrasions, ulceration, and subsequent cloudiness [80,81]. The lesions are often indurated, edematous, and infiltrated. If the condition progresses untreated, it may lead to scarring and permanent impairment of vision. Individuals with pre-existing eye conditions, especially those that are inflammatory in nature, are more susceptible to implantation. Those who care for children who have received vaccinia are the most likely to develop vaccinia keratitis [80]. An ophthalmology consultation should be obtained for evaluation and management of keratitis and other eye complications resulting from inadvertent ocular implantation of vaccinia virus. The best method for diagnosis and monitoring of changes and response to treatment is slit-lamp evaluation. Treatment should include topical antiviral medications as advised by an experienced ophthalmologist. VIG is contraindicated and, if used, may increase the risk of scarring [83].

As with any skin lesion, other infectious organisms may be introduced, although this is an infrequent complication. Site manipulation increases the possibility of contamination, especially among children. Prolonged use of occlusive dressings may lead to maceration and increased risk of infection. The usual organisms are Staphylococcus aureus, group A streptococci, and group A beta hemolytic streptococci. Fecal contamination of skin is common in infants. Bacterial infection is common among the immunodeficient. There also may be anaerobic or mixed infections [80,81].

As discussed, the surface in a bacterial cellulitis infection will be irregularly raised, in contrast with an exuberant reaction in which the surface is of one level. After culture and sensitivities of the lesion, appropriate antibiotic treatment should be initiated [80,81].

Approximately 10 days after primary vaccination, one person in 1,000 will develop a toxic and/or hypersensitive rash [84]. The rash may be erythematous, vesicular/pustular, urticarial, or a typical "bull's-eye" lesion. All are grouped under the term "erythema multiforme." The vaccinee is usually afebrile, the rash does not progress, and it resolves spontaneously within two to four days. A more serious rash, bullous erythema multiforme (Stevens-Johnson syndrome), occurs, but rarely. Symptomatic treatment using antihistamines and other measures to counteract itching is usually sufficient. However, patients with Stevens-Johnson syndrome should be hospitalized for supportive care [81].

Generalized vaccinia (GV) is rare and probably caused by viremia. It consists of vesicles or pustules appearing on normal skin far from the vaccination site. The 1960s data has estimated that GV will occur in 242 per million primary vaccines [82]. Rates in the United States today may be higher because there may be more persons at risk from eczema or atopic dermatitis and immune suppression from cancer, cancer therapy, organ transplantation, and other illnesses (e.g., HIV/AIDS) [80]. The disease is usually mild, self-limited, and has little residual damage. Mild cases require no treatment, but more extensive lesions, especially in a vaccinee with an underlying immunosuppressed illness, may be toxic and treatment with VIG will be necessary [80,81,82].

Eczema vaccinatum is a localized or systemic spread of vaccinia on individuals who have eczema or atopic dermatitis, even if the skin condition is not active at the time of the vaccination [80]. There are an estimated 18 million adults and 9.6 million children younger than 18 years of age in the United States who have atopic dermatitis, many of whom would be susceptible to eczema vaccinatum if vaccinated or in contact with a vaccinee [86]. Data from the 1960s have indicated an occurrence of 10.6 cases of eczema vaccinatum per million among primary vaccinees 1 year of age or older [82].

The patient is infected through autoinoculation or from contact with a vaccinee who is shedding the virus. The virus is implanted into broken skin at one or multiple sites and it spreads, producing extensive lesions wherever there is abnormal skin. The patient should be hospitalized immediately and treated with VIG. Death has been prevented in patients with eczema vaccinatum by prompt and adequate treatment; however, even when there is a delay in recognition, prompt institution of VIG should be undertaken; scarring may be extensive [80,81,82].

In progressive vaccinia, also known as vaccinia necrosum, the vaccination site does not heal and continues to spread locally and by viremia to other parts of the body. There is no inflammatory response. If untreated, patients succumb to the viral effect or to secondary infections. A rare event in the past (i.e., 1 of every million primary vaccinations), progressive vaccinia may be a greater threat today given the larger proportion of susceptible persons in the population [82].

Progressive vaccinia occurs mainly in persons with T-cell deficient diseases (e.g., cancer, immunosuppressive therapy, HIV/AIDS). Viral and immunologic studies should be conducted after consultation with state or local health authorities, infectious disease or immunology experts with experience in complications of vaccination, and/or the CDC [80].

The treatment is VIG in massive doses [80,81,82,83]. (Up to 10 mL/kg of intramuscular VIG has been used.) Research is being conducted on VIG, and there are IND protocols that may result in new formulations of the drug. Both intravenous and intramuscular preparations are being produced. Immediate consultation with the CDC has been recommended to determine if any experimental antiviral drugs are available [80]. Future dosing will depend on the manufacturer's recommendations and experience [80,81,82].

Post-vaccinial encephalitis or meningoencephalitis is a rare event of primary vaccination, occurring in approximately 12.3 per million vaccinees [82]. Ten to fourteen days after vaccination, the patient will have initial symptoms of headache, vomiting, drowsiness, and fever. Approximately 15% to 25% of vaccinees with this complication die, and another 25% develop permanent neurologic sequelae [80]. There is no specific therapy. Supportive care, anticonvulsants, and intensive care may be required [81]. VIG is not effective and has not been recommended [82].

Fetal vaccinia is infection of the fetus in the last trimester with evidence of disease in the newborn infant. It is so rare that there are fewer than 50 known cases [82]. Most of these occurred in primary vaccinees who were vaccinated in early pregnancy. The result usually was stillbirth or death of the infant soon after birth. Vaccinia is not known to cause congenital malformations [82].

As discussed, vaccinia has complications that are mild to moderate and usually self-limited. Fortunately, serious adverse events are rare, but may be fatal; however, they require immediate evaluation for diagnosis and treatment. Currently, there are two available treatments: VIG, the first-line therapy, and cidofovir, the second-line therapy [82,83].

Informed consent is now the backbone of Western bioethics; however, it was not an ethical mandate until 1957, when it was explicitly formalized in the Code of Ethics of the American Medical Association [90]. The Code of Ethics requires physicians and any helping professionals to communicate diagnoses, prognoses, courses of treatment or intervention, and alternative options in such a manner that is understood, so an informed decision regarding treatment may be made by the client/patient [90]. An individual's ability and prerogative to make one's own decision about treatment is now seen as a vital expression of autonomy and a prerequisite to participation in treatment or interventions [91].

The process of informed consent entails the explicit communication of information in order for the individual to make a decision. Western cultures value explicit information, which is centered on American consumerism, that is, the belief that having and exercising choice extends to healthcare purchases [92]. However, some cultures believe that language and information also shape reality [93]. In other words, explicit information, particularly if it is bad information, will affect the course of reality.

A signature is required on most Western informed consent forms to represent understanding and agreement on the part of the individual involved. Yet, this might be viewed as a violation of social etiquette in some cultures. For example, in Egypt, signatures are usually associated with major life events and legal matters. Therefore, requiring a signature outside these circumstances would imply a lack of trust, particularly when verbal consent has been given [94].

Consent forms also often contain technical and legal jargon that may be overwhelming to the native English-speaking individual, but can be much more daunting for immigrants who may not be proficient in English or familiar with various legal concepts. Asking for a signature on a consent form that contains foreign legal and technical terms may place some immigrants at risk for secondary traumatization, as some were persecuted, tortured, and forced to sign documents in their homelands [95].

Cultural dissonance can be a challenge to many general healthcare and mental health practitioners. Cultural experts may help mitigate this challenge by assisting with the interpretation and navigation of the complex web of cultural interactions. It is vital to keep these cultural concerns and possible barriers to understanding in mind when considering a vaccinee for participation in a pre-event vaccination program.