Live-attenuated viral vaccines are composed of viruses that are traditionally grown in cultured cells. Viruses are typically selected for preferential growth in nonhuman cells, and, in the course of selection, become less capable of growth in human cells. Since these attenuated strains do not replicate well in human hosts, they induce immunity but not disease when given to individuals. There may be a slight possibility that the pathogenic virus can reemerge by a further series of mutations even though attenuated virus strains contain multiple mutations in their genome. Further, attenuated viral vaccines can cause significant damage by inducing viral opportunistic infections in those that are immunodeficient [39]. Live-attenuated viral vaccines are currently in use for smallpox, measles, mumps, rubella, varicella, herpes zoster, polio, influenza (intranasal), yellow fever, and rotavirus. The vaccines targeting diseases that cause cutaneous manifestations are discussed in this section and throughout the chapter.

Edward Jenner, in 1796, was the first to demonstrate that inoculation of cowpox virus into human skin could lead to protection from subsequent smallpox infection [40]. Jenner named the inoculation substance vaccine, based on the Latin word vacca, meaning “cow.” The vaccines used for smallpox vaccination are derived from vaccinia virus, a species similar to cowpox. The virus that causes smallpox is the variola virus, which belongs to the Poxviridae family and Orthopoxvirus genus, which also includes the vaccinia, cowpox, and monkeypox viruses. The smallpox vaccine, consisting of several types of strains of the live attenuated vaccinia virus, has served as the prototype of success of a viral vaccine; it was employed in the eradication of the disease. Prior to immunization, smallpox infection killed hundreds of millions of people unremittingly. The eradication of smallpox has been viewed as one of the greatest achievements in medicine.

Approximately two decades ago, after the complete elimination of smallpox, vaccine production ceased [41]. However, due to the recent concerns about biologic warfare and the use of smallpox as an agent, the danger of this disease has not been eliminated. Thus, renewed interest has been developed in production of the smallpox vaccines. ACAM2000 (Acambis) is the currently licensed vaccine used for immunization against smallpox in public health, health-care-response teams, and laboratory workers involved with vaccinia virus research. It is derived from the formerly used vaccine Dryvax, with the main difference being vaccine preparation; ACAM2000 is prepared in cell culture rather than calf lymph, which gives it a lesser risk of causing rare but serious complications [42].

Contraindications to the use of this vaccine in the absence of circulating smallpox include allergies to polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride, and neomycin sulfate. Patients in an immunocompromised state or women who are pregnant or intend to become pregnant or who are breastfeeding should also not receive the vaccine. The vaccine should be administered concurrently with antihistamines or glucocorticoids to individuals who have allergic symptoms to the above compounds and have contact with individuals with smallpox. Further, the use of the smallpox vaccine is cautioned in persons with a history of eczema or atopic dermatitis; in persons who have acute, chronic, or exfoliative skin conditions; in persons who are using topical ocular steroid medications; and in persons who are younger than 18 years of age [43].

Vaccination for the three classic childhood diseases of measles, mumps, and rubella (MMR) includes live attenuated viruses, and was introduced in the 1960s. The annual reported cases of these infections have declined by more than 98 % in the United States and Europe [44]. This decrease in incidence is largely due to the recommendation that all states require a two-dose MMR vaccination prior to children entering school. The two-dose MMR vaccine is advocated to induce immunity in the small percentage of individuals who do not respond to one or more components of the first dose. The most updated recommendations from the CDC are vaccination with the first MMR dose at 12–15 months and the second dose at 4–6 years of age [45]. Table 49.2 summarizes the childhood immunization schedule for MMR, as well as other vaccines described in this chapter [46]. Immunization evokes a mild subclinical infection that is noncommunicable.

Since the vaccines are composed of live attenuated viruses, they are not recommended for pregnant women or those planning to become pregnant within the next 3 months. The primary concern with pregnant women has been the risk of eliciting the congenital rubella syndrome (CRS). However, a study of 321 women who received the vaccine 3 months prior to or after conception demonstrated no congenital malformations compatible with congenital rubella infection [47]. Another contraindication is a history of anaphylactic hypersensitivity to neomycin. Persons with asymptomatic HIV infection or with mild immunosuppression can get vaccinated with MMR. Further, healthy persons with minor illnesses with or without fever, and those with an allergy to eggs can receive the vaccine as well. The risk of severe anaphylactic shock reaction is exceedingly low in individuals with a history of allergy to eggs [45].

The recommendation is to observe these patients for up to 90 minutes after immunization [48]. Also, despite suggestions that the MMR vaccine has a reported association to autism, studies have proved strong evidence against that hypothesis [49–53].

Prior to the prevalent use of varicella vaccine, annual U.S. figures for varicella infection included an estimate of 4 million cases, 11,000 hospitalizations, and 100 deaths [82]. The annual incidence of varicella has decreased significantly since the use of this vaccine. The vaccine, Varivax, developed by Takahashi in 1974 and approved in 1995, is a live attenuated Oka strain vaccine that has been shown to be very safe and effective [83–85]. In May 2006 the Food and Drug Administration (FDA) approved a vaccine, Zostavax (Merck) which is 14 times more concentrated than the varicella vaccine, against herpes zoster in individuals 60 years age and older [86]. After further studies showed its efficacy in a younger cohort, the vaccine was subsequently approved by the FDA for use in individuals aged 50–59 in 2011. Cell-mediated immunity is increased following vaccination in immunocompetent older adults, and the incidence and severity of herpes zoster [87–91] is reduced. The vaccine lessened the overall incidence of herpes zoster by 51.3 % and notably reduced the pain and discomfort by 66.5 % among subjects in whom herpes zoster developed. The zoster vaccine had low rates of serious adverse events, which were similar to the placebo vaccine.

Long-term follow-up data of the varicella vaccine depicted protection against chickenpox for at least 17–19 years, and, furthermore, all of the subjects vaccinated continue to have persistent antibodies and delayed-type skin reaction to the varicella-zoster antigen [92]. In a double-blind, placebo-controlled study of the Oka vaccine in 914

U.S. children, the varicella vaccine demonstrated an efficacy of 100 % at 9 months [93, 94]. Following 7 years of vaccination, 95 % of the subjects remained without chickenpox clinically [81]. Additional studies in the U.S. have demonstrated that the Oka vaccine induces humoral and cell-mediated immunity in healthy children [94–97], with protection for at least 8 years, while other data have suggested effectiveness decreases markedly after 1 year postvaccination [98]. Further, case series depict that vaccinated individuals have less severe varicella (<50 lesions, no fever, and shorter duration of illness) than those who are unvaccinated [99, 100].

The vaccine is recommended as part of the childhood immunization schedule, and all susceptible children from 12 months of age to 18 years of age should receive the varicella vaccine. The first dose of the Oka vaccine should be administered at 12–15 months and the second dose should be given at 4–6 years of age [86]. Those over the age of 13 years should receive two doses, 4–8 weeks apart, to generate seroconversion rates and antibody responses comparable to those attained in healthy children [83–85]. In the US, childhood vaccination with a single dose continues to provide up to 95 % protection 10 years after immunization; children with two doses can see up to 98 % protection [101]. The vaccine is also recommended for susceptible adults, notably those in high-risk situations (e.g., health care personnel); children who have no prior history of chickenpox and are required to be present in school; and immunosuppressed subjects, particularly those with acute lymphocytic leukemia (ALL) [102–104]. The varicella-zoster virus (VZV) vaccination is safe for all patients with lymphocyte counts >700/mm [3]. Further, recent data suggest that varicella vaccine is >95 % effective for prevention of disease and 100 % for prevention of moderate or severe disease in susceptible contacts when given within 36 h of exposure [105].

A combination vaccine with the live attenuated viruses of MMR and VARIVAX is also available (ProQuad; Merck) and it is administered to individuals 12 months to 12 years of age. Post-licensing studies have shown the combination vaccine to be as effective as separate injections of MMR and Varivax [106].

Varicella transmission is approximately one- fourth the rate of natural varicella (20–25 % vs. 87 %) [107] if a rash develops in the immunized individual. In children, the incidence of primary varicella is between 18 and 77 per 1 million person years of follow-up [108]. Herpes zoster can later develop from this vaccine type virus or from natural wild-type varicella-zoster virus [109, 110]. Although there are reports of herpes zoster in healthy children vaccinees, the incidence is less than that seen in children with prior chickenpox, suggesting that vaccinated children may have a decreased risk for herpes zoster [111].

The most common side effects from the vaccine include mild tenderness, erythema, induration at the injection site (19.3–24.4 %), fever (10.2–14.7 %), and a localized or generalized varicella- like rash (3.8–5.5 %). The transmission rate of the varicella vaccine virus from a healthy vaccinated individual is low, but may be more likely if a rash appears subsequent to vaccination, particularly in those who are immunocompromised. Vaccinated individuals should avoid close contact with susceptible high-risk individuals for up to 6 weeks. The vaccine is contraindicated in pregnant women or any woman planning to become pregnant within 3 months since the vaccine uses a live attenuated virus and natural varicella can cause fetal harm [111].

A separate adjuvant subunit vaccine has recently been shown in Phase 3 clinical studies to be advantageous in reducing the risk of herpes zoster in adults over 50 years of age by up to 97 % [112]. The efficacy of this vaccine was shown to be similar across age group stratifications, making it more effective than Zostavax which has waning efficacy as patients increase in age. While still currently under investigation, this new adjuvant subunit vaccine represents a significant improvement in providing protection to those at highest risk for developing herpes zoster.

A live attenuated vaccine produced from the 17D strain of yellow fever virus is available for subcutaneous administration. It is recommended for travelers to areas where yellow fever is endemic or enzootic, such as tropical parts of South America and Africa. Booster immunizations are required every 10 years. This vaccine is contraindicated in persons allergic to eggs, in pregnant women, in immunocompromised persons, and in children younger than 4 months of age.

The only currently used live-attenuated bacterial vaccine in the U.S. is against the causative agent of typhoid fever, Salmonella typhi. This vaccine, given orally, was first developed through chemical mutagenesis in vitro. Protection is conferred by mucosal and serum antibodies as well as cell-mediated immunity [113]. The induction of mucosal antibodies offers protection against infection and disease [114].

In the second generation of Hib vaccines, the polyribosylribitol phosphate (PRP) vaccine has been covalently conjugated with various protein molecules to form the Hib conjugate vaccine. This has resulted in a vaccine that is able to stimulate the immunologic system to produce a T-dependent response, for use in infants [131]. Four different types of the Hib conjugate vaccine have been licensed for use: PRP conjugated to the diphtheria toxoid (PRP-D), PRP conjugated to the outer membrane protein of Neisseria meningitidis group B (PRP- OMP), PRP conjugated to tetanus toxoid (PRP-T), and PRP oligosaccharides conjugated to mutant diphtheria toxin CRM (HbOC) [132]. Recommended immunization involves three doses of the Hib vaccine given at 2, 4, and 12 months of age [46].

Bacterial meningitis remains a severe threat to global health, with an estimated 500,000 cases worldwide with at least 50,000 deaths and as many cases of neurological damage [133]. Neisseria meningitidis is responsible for 60–65 % of cases of bacterial meningitis, and it is the only bacterium that is able to generate epidemics of meningitis [134].

It is also associated with a petechial eruption or more severe hemorrhagic lesions on the trunk and lower extremities.

The significant determinant of virulence in N. meningitidis is the polysaccharide capsule. Among the 13 distinct N. meningitidis serogroups that have been defined on the immunohistochemistry of their polysaccharide group, groups A, B, C, W135, and Y account for over 90 % of severe meningitis and septicemia. Two meningococcal vaccines, each containing antigens to serogroups A, C, Y, and W-135, are licensed in the U.S. In 2015 the FDA approved the first vaccine that provides immunity against serogroup B, which accounts for an estimated one third of cases of meningococcal disease. This recombinant serogroup B vaccine, Bexero (Novartis) has been licensed for use in Europe, Canada, and Australia; before being licensed for use in the US, it was used to control two separate outbreaks of meningococcal disease within the US and had been allowed by the FDA to treat certain outbreak situations [135, 136].

Over 30 years ago, the first meningococcal polysaccharide vaccine (MPSV4 or Menomune, Sanofi Pasteur), was developed against serogroups A and C among U.S. military recruits [137–139]. It is approved for all ages in which meningococcal vaccine is currently recommended. Further, the vaccine is safe and bestows protection to 90–95 % of people. However, there are limitations to the vaccine. First, the vaccine offers a short duration of immunity: 1–3 years in children younger than 5 years of age [134, 140] and 3–5 years in adolescents and adults. Second, like other polysaccharide vaccines, this vaccine could not elicit memory T cells, and even after repeated injections, booster responses are low [141, 142]. In addition, like other polysaccharide vaccines, this vaccine does not prevent mucosal colonization and hence does not offer herd immunity by breaking up the transmission of N. meningitidis [143, 144]. This vaccine is a logical option for individuals requiring protection for a limited amount of time.

The second vaccine, meningococcal conjugate vaccine A, C, Y, and W135 (MCV4 or Menactra, Sanofi Pasteur), was approved in January 2005 for use in individuals 11–55 years of age. This conjugate vaccine contains the same antigen as that found in the meningococcal polysaccharide vaccine, but it is conjugated to 48 μg of diphtheria toxoid [145]. What is different regarding this vaccine is that immunity is more durable, and revaccination can generate a rise in antibody level. Although not yet proved, it is suggested that, like other conjugate vaccines, it is likely that this vaccine will offer more durable protection than the polysaccharide vaccine alone and will further reduce nasopharyngeal carriage, allowing herd immunity to occur.

The serogroups A and C vaccines have demonstrated estimated clinical efficacies of >85 % among school-aged children and adults and are useful in controlling outbreaks. Serogroups Y and W-135 polysaccharides are safe and immunogenic among adults and children aged >2 years. The advantages of the meningococcal conjugate vaccine have led the Advisory Committee on Immunization Practices (ACIP) of the CDC to extensively widen the recommendations for immunization, with routine vaccination of all persons aged 11 through 18 years old, composed of a single dose at age 11–12 years and a booster dose at age 16 [146].

Both vaccines are currently recommended for use in control of outbreaks as a result of N. meningitidis serogroups A, C, Y, and W-135 [145]. However, due to its enhanced booster effect, the conjugate vaccine is favored when revaccination is indicated for individuals who have received the meningococcal polysaccharide vaccine before and who remain at higher risk. Long-term follow-up studies are still needed for those that have been immunized with the meningococcal conjugate vaccine to establish if boosters are needed.