Vaccines and Immunotherapies for the Prevention of Infectious Diseases Having Cutaneous Manifestations

CONTINUING MEDICAL EDUCATION

Vaccines and immunotherapies for the prevention of infectious diseases having cutaneous manifestations

Jashin J. Wu, MD,a David B. Huang, MD, MPH,b Katie R. Pang, MD,a and Stephen K. Tyring, MD, PhD, MBAc Houston, Texas

Although the development of antimicrobial drugs has advanced rapidly in the past several years, such agents act against only certain groups of microbes and are associated with increasing rates of resistance. These limitations of treatment force physicians to continue to rely on prevention, which is more effective and cost-effective than therapy. From the use of the smallpox vaccine by Jenner in the 1700s to the current concerns about biologic warfare, the technology for vaccine development has seen numerous advances. The currently available vaccines for viral illnesses include Dryvax for smallpox; the combination measles, mumps, and rubella vaccine; inactivated vaccine for hepatitis A; plasma-derived vaccine for hepatitis B; and the live attenuated Oka strain vaccine for varicella zoster. Vaccines available against bacterial illnesses include those for anthrax, Haemophilus inﬂuenzae, and Neisseria meningitidis. Currently in development for both prophylactic and therapeutic purposes are vaccines for HIV, herpes simplex virus, and human papillomavirus. Other vaccines being investigated for prevention are those for cytomegalovirus, respiratory syncytial virus, parainﬂuenza virus, hepatitis C, and dengue fever, among many others. Fungal and protozoan diseases are also subjects of vaccine research. Among immunoglobulins approved for prophylactic and therapeutic use are those against cytomegalovirus, hepatitis A and B, measles, rabies, and tetanus. With this progress, it is hoped that effective vaccines soon will be developed for many more infectious diseases with cutaneous manifestations. (J Am Acad Dermatol 2004;50:495-528.)

Learning objective: At the completion of this learning activity, participants should be familiar with the current and experimental vaccines and immunotherapies for infectious diseases with cutaneous manifestations.

he medical approach to infectious diseases is fraught with limitations. Antimicrobial drugs are available for only a few groups of mi- From the Center for Clinical Studiesa; Department of Internal T crobes. These drugs provide no cure for infections Medicine, Division of Infectious Diseases, Baylor College of such as HIV or herpes simplex virus (HSV) but Medicineb; and Departments of Dermatology, Microbiology- Immunology, and Internal Medicine, University of Texas merely alter the clinical course of disease while the Medical Branch.c medication is being taken. Because of the void of Funding sources: None. adequate antimicrobial treatment, the prevention of Disclosure: Dr Tyring has conducted research on vaccines for vesic- these infections is all the more crucial. ular stomatitis virus, herpes simplex virus, human papillomavi- Vaccination, with public health measures, is the ruses, and HIV with grants from Merck, Chiron, GlaxoSmithKline, MedImmune, and VaxGen to the University of Texas Medical best option for controlling the spread of infectious Branch and the Center for Clinical Studies. diseases. Vaccination is ranked as the greatest Presented in part at the 61st Annual Meeting of the American Acad- public health achievement in the last century, con- emy of Dermatology, San Francisco, California, March 21, 2003. tributing the most to decreased global morbidity Also presented in part at the 62nd Annual Meeting of the Amer- and mortality.1,2 Since 1988 more than 2 billion ican Academy of Dermatology, Washington, DC, February 6-11, 2004. children have been immunized, saving more than Reprint requests: Stephen K. Tyring, MD, PhD, MBA, Professor of 3 million pediatric lives per year.3 The signiﬁcant Dermatology, University of Texas Health Science Center, impact of immunization is well illustrated by the Houston, 2060 Space Park Dr, Ste 200, Houston, TX 77058. E-mail: complete eradication of smallpox in 1977. Global [email protected]. 0190-9622/$30.00 eradication of poliomyelitis is currently under © 2004 by the American Academy of Dermatology, Inc. way, and although the goal of total elimination of doi:10.1016/j.jaad.2003.12.003 this disease by the end of 2000 unfortunately was

495 496 Wu et al JAM ACAD DERMATOL APRIL 2004

Table I. Timeline of vaccine development* Abbreviations used: 1796—Smallpox AVA: anthrax vaccine adsorbed CDC: Centers for Disease Control and 1800 1881—Anthrax Prevention 1885—Rabies CRM197: cross-reacting, mutant, nontoxic 1900 1945—Influenza diphtheria toxin 1953—Yellow fever DTaP: diphtheria and tetanus toxoids and acellular pertussis vaccine 1963—IPV, OPV (Poliomyelitis) DTP: diphtheria and tetanus toxoids and 1963—Measles whole-cell pertussis vaccine 1967—Mumps HbOC: Haemophilus influenzae type b 1969—Rubella (polyribosyl ribitol phosphate) 1975—Neisseria meningitidis oligosaccharides conjugated to CRM197 HBsAg: hepatitis B surface antigen 1980—Adenovirus Hib: Haemophilus influenzae type b 1980—Rabies (IMOVAX: first FDA-approved HPV: human papillomavirus rabies vaccine) HSV: herpes simplex virus 1981—Hepatitis B IVIG: intravenous immunoglobulin LACK: Leishmania homologue of receptors for 1987—Haemophilus influenzae activated C kinase 1992—Japanese encephalitis MMR: measles-mumps-rubella 1992—DTaP (diphtheria-tetanus-acellular OspA: 31-kd outer-surface protein pertussis) OspC: 23-kd outer-surface protein 1995—Hepatitis A, Varicella PA: protective antigen † PGA: poly-␥-linked D-glutamic acid 1998—Lyme disease PRP: polyribosyl ribitol phosphate 1998—Rotavirus† PRP-D: polyribosyl ribitol phosphate conjugated 2000 2000—Streptococcus pneumoniae to diphtheria toxoid 2000—Dryvax (smallpox) PRP-OMP: polyribosyl ribitol phosphate conjugated to an outer-membrane protein complex 2002—Pediarix (DTaP-HepB-IPV) rOspA: recombinant 31-kd outer-surface protein SSPE: subacute sclerosing panencephalitis *Dates for smallpox, anthrax, and rabies vaccines are of the first pub- VIG: vaccinia immunoglobulin lished results of vaccine usage. Remaining dates are those of ap- VLP: virus-like particles proval of vaccines by the Food and Drug Administration (FDA). †No longer available.

CURRENTLY LICENSED VACCINES Viruses not met,4 the eradication is estimated to be com- Smallpox. In 1796 Edward Jenner first demon- plete by 2005.5 A number of other vaccines have strated that inoculation of cowpox virus into human led to notable decreases in infections and compli- skin could lead to protection from subsequent small- cations. For instance, after years of widespread pox infection.8 He named the inoculation substance measles vaccination, a record low of 37 measles vaccine, based on the Latin word vacca, meaning cases was reported in the United States in 2002.6 cow. The most recent vaccines used for smallpox Vaccines for Haemophilus influenzae and Neisse- vaccination were derived from a species similar to ria meningitidis have greatly decreased the inci- cowpox, called vaccinia virus. Vaccinia virus is a dence of these diseases. These currently available member of the orthopox virus family, which in- vaccines also provide a basic framework of cludes variola virus, the virus that causes smallpox, knowledge and experience with which other vac- and other viruses such as cowpox and monkeypox. cines can be developed. Several strains of the live attenuated virus vaccine Unfortunately, the progress in finding new vac- were employed in the eradication of disease. The cines cannot be rapid enough. The incidence of smallpox vaccine has been the prototype of success many viral infections, such as HIV, HSV, and hu- of a viral vaccine. Prior to immunization, smallpox man papillomaviruses (HPVs), is increasing de- infection relentlessly killed hundreds of millions of spite the currently available antiviral agents. The persons. The complete eradication of this disease development of prospective vaccines is generally could easily be considered the greatest success story measured in decades (Table I), marked by small in medical history. increments of advancement before the final prod- Vaccine production ended 2 decades ago after uct becomes available.7 Numerous different vac- the eradication of smallpox,9 and approximately 60 cine candidates often are developed and evalu- million vaccine doses remain worldwide.10 Because ated over many years before a single effective of recent concerns over potential biologic warfare in vaccine is licensed. the future, the threat of smallpox may not have been JAM ACAD DERMATOL Wu et al 497 VOLUME 50, NUMBER 4

completely eliminated with eradication of the disease. Therefore, renewed interest in the production of smallpox vaccines has developed. The destruction of the 2 remaining smallpox virus reserves, in Atlanta and Moscow, has been a source of ongoing debate. Opponents of destruction con- tend that the virus stocks would be helpful for future research, such as smallpox pathogenesis and the production of new antiviral agents.11,12 Proponents argue that the virus genome has already been cloned and sequenced and is unnecessary for such research.13 The World Health Assembly in May 1999 Fig 1. Ocular vaccinia secondary to digital spread from resolved to postpone the previously arranged small- the inoculation site. pox destruction scheduled for June 30 of that year.14 All US smallpox vaccine formulations contain the New York City Board of Health vaccinia strain, The CDC is holding the other 3 vaccines in re- which is less reactogenic than other strains.15 The serve.17 Studies are currently under way to deter- U.S. National Pharmaceutical Stockpile contains 4 mine the reactogenicity of the 2 newer cell culture formulations of smallpox vaccine: 2 previously man- vaccines. The tissue culture cell vaccines are being ufactured calf-lymph-derived vaccines, Dryvax developed in hopes of supplanting the calf-lymph (Wyeth Laboratories, Marietta, Pa) and Aventis Pas- vaccine if a more extensive vaccination program is teur vaccine (Swiftwater, Pa); and two newly devel- needed.18 oped vaccines from Acambis/Baxter Pharmaceuti- All 4 vaccines are administered by means of in- cals (Cambridge, Mass), ACAM1000 and ACAM2000 oculation into the superficial layers of the skin, (Centers for Disease Control [CDC] Drug Services, which allow the virus to grow and induce an immu- unpublished data, 2002). ACAM1000 is grown in nologic response that protects the host against human embryonic lung cell culture (MRC-5), and smallpox. The vaccines elicit antibody and cell-me- ACAM2000 is grown in African green monkey kid- diated immunity. A successful vaccination, defined ney cells (Vero cells). as an antibody titer of 1:10 or greater, occurs in more Dryvax is licensed and is currently being used for than 95% of persons within 1-2 weeks of immuniza- 19 immunization against smallpox in public health and tion. The protective duration of the vaccine occurs health-care response teams and laboratory workers for 3-5 years and begins fading after 5 years, with minimal protection after 20 years. In persons who who are involved with research activities that in- have undergone revaccination with smallpox, resid- volve vaccinia virus. This vaccine will be used to ual immunity may last 30 years or more. Individuals fulfill the recommendations of the national Advisory undergoing postexposure vaccination should re- Committee on Immunization Practices. An emer- ceive the smallpox vaccination within 3 days of gency vaccination strategy has been developed in exposure to prevent the natural history of small- the event of confirmed cases of smallpox. Priority pox.20 Some epidemiologic evidence suggests that will be given to those with early diagnosis, all who vaccination up to 4-7 days after exposure also may had been in contact with the patient since onset of alter the severity of the disease and provide protec- fever, all household members of the contacts, and tion from death.19 health-care workers, public health personnel, first Adverse reactions of the smallpox vaccine are responders, and other personnel who will be assist- similar to those caused by other vaccines and in- ing with outbreak control measures and emergency clude local skin reactions, fever, erythema multi- response activities.16 Dryvax is freeze-dried and re- forme, and anaphylaxis. There recently have been constituted before use with a diluent that contains 30 cases of cardiac-related events, such as myocar- 50% glycerin and 0.25% phenol. Contraindications to ditis, pericarditis, myocardial infarction, and angina use of this vaccine in the absence of smallpox in- during the civilian smallpox vaccination program.21 clude allergies to polymyxin B sulfate, streptomycin Other adverse effects specific to smallpox vacci- sulfate, chlortetracycline hydrochloride, and neomy- nation include eczema vaccinatum, fetal vaccinia, cin sulfate. In the case of contact with persons with generalized vaccinia, inadvertent inoculation, ocular smallpox or in the presence of smallpox, the vaccine vaccinia (Fig 1), progressive vaccinia, and postvac- should be administered along with antihistamines or cinial encephalopathy and encephalomyelitis.22 glucocorticoids. These specific complications of smallpox vaccina- 498 Wu et al JAM ACAD DERMATOL APRIL 2004

tion can be treated with vaccinia immunoglobulin months before or after conception revealed no con- (VIG), cidofovir, and ophthalmic antiviral agents, genital malformations compatible with congenital although none of these therapies have undergone rubella infection.26 Immunization is also contraindi- clinical trials.22 VIG is considered first-line treatment cated in immunosuppressed patients, although it because of worldwide historical experience with it can be administered to individuals with asymptom- in the treatment of vaccinia-related adverse events. atic HIV infection as well as to persons with mild However, supplies of VIG are limited. Although ci- immunosuppression. In healthy individuals, minor dofovir has never been used to treat vaccinia infec- illnesses with or without fever are not a contraindi- tions in human beings, the first use of cidofovir in 3 cation to vaccination. Patients with a history of ana- HIV-positive men with recurrent molluscum conta- phylactic hypersensitivity to neomycin should not giosum virus cleared the lesions.23 These were the receive the MMR vaccine. The vaccine can be ad- first documented cases in which cidofovir was used ministered to patients with an allergy to eggs, since to treat poxvirus infections in human beings. the risk of severe anaphylactic reactions is exceed- Smallpox vaccination is contraindicated for per- ingly low.25 It is recommended that these patients be sons with any of the following conditions or who observed for 90 minutes after immunization.27 have had close contact with any of the following Measles. Measles virus has been noted to be conditions: atopic dermatitis or active acute or the most infectious disease of humankind in terms of chronic exfoliative skin conditions that disrupt the the minimal number of virions necessary to produce epidermis, Darier disease, pregnancy or a desire to infection.28 An estimated 75% of susceptible family become pregnant within the 28 days after vaccina- contacts who are exposed to a case of measles tion, and compromised immune systems.22 Other develop the disease.29 Because human beings are contraindications that apply only to potential vac- the only reservoir for measles virus, global eradica- cine candidates but do not include their close con- tion is technically feasible. The World Health Orga- tacts are moderate to severe intercurrent illness, nization, the CDC, and the Pan American Health smallpox vaccine-component allergies, age Ͻ18 Organization convened in 1996 and adopted the years, breastfeeding, and the use of topical ocular goal of global eradication by 2005-2010.30 Owing to steroid medications.22 universal childhood immunization in the United Measles, mumps, and rubella. Vaccination for States, measles is no longer considered an indige- these 3 classic childhood diseases typically is admin- nous disease in this country.31 The reported inci- istered as a combination measles-mumps-rubella dence of measles has decreased by Ͼ99% since the (MMR) vaccine (Tables II and III). Live virus vac- measles vaccine became available. cines for all 3 viruses were introduced in the 1960s, In 2000 there were 86 reported measles cases, of and after widespread implementation in the United which 26 were internationally imported. Of the re- States, the number of cases of these infections remaining 60 indigenous cases, 9 were definitely due ported annually has declined by more than 98%.24 to imported virus, 18 were linked to imported virus, This result is largely due to the recommendation that and 33 were of unknown source.32 In 2001 there all states require a 2-dose MMR vaccine in children were 116 reported cases of measles, 33 but in 2002 before they enter school. The use of 2-dose MMR only 37 measles cases were reported in the United vaccine is to induce immunity in that small percent- States.33 The increase of 35% from 2000 to 2001 age of persons with failure to develop an immuno- should remind us that we need to guard against logic response to one or more components of the complacency. Lack of compliance with routine MMR first dose. The most recent recommendations by the vaccination in the past led to a resurgence of mea- CDC are that vaccination with the first MMR dose be sles infection in the United States between 1989 and administered at 12-15 months and the second dose 1991, with some deaths reported.30 Moreover, more at 4-6 years of age.25 Each MMR vaccine contains 0.3 than 1 million children die of measles each year in mg of human albumin, 25 ␮g of neomycin, 14.5 mg third-world countries.34 of sorbitol, and 14.5 mg of hydrolyzed gelatin In 1963 the initial measles vaccine, which was a (Merck, manufacturer’s package insert). Because live attenuated vaccine, was licensed. In 1968 the these vaccines consist of live attenuated viruses, current measles vaccine was licensed. It uses the they should not be administered to pregnant women Enders-Edmonston virus strain, a further attenuated or those planning to become pregnant within the version of the live preparations previously available, following 3 months. The theoretical risk of congen- resulting in fewer adverse reactions in recipients. It ital rubella syndrome after immunization has been is produced by culturing the Moraten virus strain in the primary concern. However, a study of 321 chick embryo cells. Measles vaccination produces a women who had received the rubella vaccine 3 mild or unapparent infection that is noncommuni- JAM ACAD DERMATOL Wu et al 499 VOLUME 50, NUMBER 4

Table II. Vaccines: recommendations for immunizations in adults

Vaccine Target population Route Dosage Comments Adenovirus Military personnel Oral 1 dose Anthrax Military personnel, and SC 3 doses: 0, 2, and 4 wk; Current recommendation those involved in boosters at 6, 12, and is for annual boosters. producing quantities or 18 mo concentrations of Bacillus anthracis cultures, or those with high potential for aerosol exposure DT (diphtheria-tetanus) All adults IM 1 dose booster every Give 1 dose if patient had 10 y; for adults, the received the primary primary series is 3 series and the last doses; the ﬁrst 2 doses vaccination was Ն10 y given at least 4 wk ago. apart and the third dose, 6-12 mo after the second Hepatitis A* Persons with behavioral, IM 2 doses: 0 and 6-12 mo Other indications are medical, or occupational travel to or work in indications countries that have high incidence of hepatitis A. Hepatitis B* Persons with behavioral, IM 3 doses: 0, 1-2, and 4-6 Other target populations medical, or occupational mo are inmates of indications correctional facilities, home contacts and sex partners of persons with chronic hepatitis B viral (HBV) infection, and travelers to countries with high prevalence of chronic HBV infection. Inﬂuenza Persons over 50 y; those IM 1 dose annually October or November is with medical or the optimal time, but occupational indications, December to March is and home contacts of acceptable. persons with indications Cont’d on page 500

HDCV, Human diploid cell vaccine; ID, intradermal; IM, intramuscular; PCEC, puriﬁed chick embryo cell culture vaccine; SC, subcutaneous. *A combination vaccine (Twinrix), now available, contains Havrix (Hepatitis A) and Engerix-B (Hepatitis B). It thus reduces the number of vaccinations from 5 to 3.

cable. Both humoral and cellular immune responses develop a transient viral exanthem.24 An associ- develop as a result.35 After receiving 2 doses of ated encephalitis or encephalopathy rarely has vaccine, 95% to 99% of recipients develop serologic been reported after immunization and occurs in evidence of immunity to measles.36,37 Immunity is fewer than 1 in 1 million vaccinees.42 There have thought to be lifelong, similar to that acquired after been early concerns about the association of mea- infection with the wild-type virus.38 However rare, sles vaccination and subacute sclerosing panen- measles infection has been reported in patients cephalitis (SSPE), since this complication may oc- with previously documented postimmunization cur with natural infection. A small number of seroconversion.39,40 reports have described the occurrence of SSPE in Adverse effects after measles vaccination typi- persons with a history of vaccination but no cally are mild. Five percent to 15% of recipients known history of infection.43-45 More recent evi- develop a fever of at least 103°F for 1 to 2 days, dence indicates that at least some of those cases generally 5 to 12 days after immunization.41 These had unrecognized natural measles infection prior persons are largely asymptomatic, but some may to vaccination, and the SSPE was directly related 500 Wu et al JAM ACAD DERMATOL APRIL 2004

Table II. Cont’d

Vaccine Target population Route Dosage Comments Japanese encephalitis Persons traveling to Asia SC 3 doses: 0, 7, and 30 d Lyme disease* Consider for persons 15-70 IM 3 doses: 0, 1, 12 mo Doses 1 and 3 to be given years old who are several wk before tick exposed to areas of season. moderate to high risk MMR (measles-mumps- Adults born in or after 1957 SC 1 dose if measles, Second dose of MMR rubella) should receive at least 1 mumps, or rubella vaccine is dose of MMR vaccine vaccination history is recommended for those unless they have unreliable; if second who work in health care acceptable evidence of dose is recommended, facilities, plan to travel immunity or a medical administer no sooner internationally, were contraindication. than 4 wk after ﬁrst recently exposed to dose. measles, were previously vaccinated with killed measles vaccine, were vaccinated with an unknown vaccine between 1963 and 1967, or are students in post secondary educational institutions. Neisseria meningitidis Consider vaccination for SC 1 dose; revaccination at Another indication is persons with medical 3-5 years may be travel to countries in indications (anatomic or indicated for persons which disease is functional asplenia, at high risk for epidemic. terminal complement infection. component deﬁciencies) and college students who live in dormitories. Poliomyelitis Not recommended for IM or SC Those who never received persons Ͼ18 y old. or completed the pediatric series do not need to be vaccinated unless they travel to areas where wild-type virus exposure may occur.

*Lyme disease vaccine no longer available. to the infection.25 Widespread measles immuniza- have reported lower efﬁcacy rates, ranging from tion has nearly eliminated SSPE in the United 75% to 95% protection from infection.49-52 Although States, and the live measles vaccine does not in- the duration of immunity in vaccine recipients is not crease the risk for this complication.25 completely known, serologic and epidemiologic ev- Mumps. Since the introduction of live mumps idence suggests that immunity persists for at least 30 vaccine in 1967 and its recommended use in 1977, years.53-56 the incidence of mumps has decreased steadily by Adverse reactions generally are mild and uncom- more than 99%. The live attenuated mumps vaccine mon after mumps vaccination. Low-grade fever, (Jeryl-Lynn strain) is prepared in chick embryo cell mild parotitis, and a viral exanthem have been re- culture. Immunization produces a mild subclinical ported. Serious reactions, such as adverse neuro- infection that is noncommunicable. Early clinical logic effects, are extremely rare and have not been studies have shown that 97% of children and 93% of causally associated with the mumps vaccine.57 adults develop serologic evidence of immunity after Rubella. Two different live attenuated rubella vaccination.46-48 Outbreak-based studies, however, vaccine strains, HPV-77 and Cendehill, were initially JAM ACAD DERMATOL Wu et al 501 VOLUME 50, NUMBER 4

Table II. Cont’d

Vaccine Target population Route Dosage Comments Rabies Persons at risk of rabies Preexposure: 3 doses at Previously vaccinated exposure or those 0, 7, and 21 or 28 d persons require only 2 recently exposed. IM HDCD: Imovax doses after rabies IM PCEC: PabAvert exposure at 0 and 3 d. IM Rabies Vaccine Absorbed ID HDCD: Imovax Rabies ID Postexposure: 5 doses at 0, 3, 7, 14, and 28 d IM HDCV IM Rabies Vaccine Absorbed IM PCEC Smallpox Those with early diagnosis, SC 1 dose; if there is no Postexposure vaccination; all who had been in evidence of a local should receive the contact with the patient vaccine reaction, can smallpox vaccination since onset of fever, all repeat vaccination within 3 d. household members of after 7 d. the contacts, smallpox public health and health- care response teams, and laboratory workers who are involved with vaccinia virus Streptococcus Persons Ͼ 65 years old and IM or SC 1 dose Other populations are pneumoniae those with chronic Alaskan natives, certain cardiovascular, hepatic, American Indian pulmonary, or renal populations, and diseases, diabetes residents of nursing mellitus, anatomic or homes and other long- functional asplenia, or term-care facilities. immunosuppression Varicella zoster Susceptible adults; SC 2 doses: 0, and 4-8 wk recommended for those who do not have reliable clinical history of varicella infection or serologic evidence of varicella zoster virus infection Yellow fever Persons traveling to SC 1 dose Booster is given every 10 endemic countries (parts years for recertiﬁcation of Africa, South America, for travel into endemic and southeast Asia) countries.

developed and licensed in the United States in 1969. adverse events compared with the previous rubella They were replaced in 1979 by the RA 27/3 (rubella vaccines. abortus 27, explant 3) vaccine, which is grown in Adverse effects after rubella vaccination typically human diploid ﬁbroblast cell culture. This vaccine are mild. Five percent to 15% of vaccinated children produces nasal antibodies, as well as higher and develop fever, lymphadenopathy, or a viral exan- more persistent antibody titers, that better mimic the them, usually 5 to 12 days after vaccination.57,63 immune protection developed after natural infec- Arthralgias and arthritis are frequent complications tion.58,59 Vaccination induces an antibody response in adult vaccinees, particularly women, and may in more than 97% of recipients.47,60 Immunity in develop in 25% to 40% of this population,64-66 but vaccine recipients is thought to be lifelong and has occurrences in children are rare (0.5%).64 These joint been shown to persist for at least 16 years.61,62 In symptoms typically begin within the ﬁrst 3 weeks addition, this vaccine was associated with fewer after vaccination and remit within 11 days.26 The 502 Wu et al JAM ACAD DERMATOL APRIL 2004

Table III. Vaccines: recommendations for immunizations in children

Vaccine Target population Route Dosage Comments DTaP (diphtheria, Infants and toddlers IM 4 doses: 2, 4, 6, and 15-18 The fourth dose of DTaP tetanus, acellular mo may be given as early pertussis) as age 12 mo if 6 mo have elapsed since the third dose, and the child is unlikely to return at age 15-18 mo. DT (diphtheria- Children aged 11-12 y IM Recommended if at least Recommended routine tetanus) 5 y have elapsed since DT boosters every 10 y the last dose of diphtheria and tetanus toxoid-containing vaccine. Hepatitis A* Children IM 2 doses: Havrix, Ͼ2y:0 Minimum interval and 6-12 mo between doses is 6 mo. Vaqta, 2-17 y: 0 and 6-18 mo; Ͼ17 y: 0 and 6 mo Hepatitis B* Children IM 3 doses: infants, birth to Infants with HBsAg- 2 mo, 1-4 mo, and 6-18 positive mothers mo; children and receive first dose within adolescents; 0, 2, and 12 h of birth, second 4 months dose at 1 mo, and third dose at 6 mo. Hib (Haemophilus Infant and toddlers IM 4 doses: 2, 4, 6, and If PRP-OMP (Pedvax HIB influenzae type b) 12-15 mo or ComVax [Merck]) is given at ages 2 and 4 mo, the 6-mo dose is not required. Influenza Children older than 6 mo who IM 6 mo-8 y, 1 or 2 doses of October and November have chronic cardiovascular, split virus only, at least for those more pulmonary, or renal diseases, 1 mo apart; 9-12 y, susceptible to flu chronic metabolic diseases, 1 dose of split virus complications, and hemoglobinopathies, only; Ͼ12 yrs, 1 dose November and immunosuppression, and of whole or split December for all others those receiving long-term virus aspirin therapy (risk of Reye syndrome) MMR (measles, Children SC 2 doses: 12-15 mo and Second dose may be mumps, rubella) 4-6 y administered during any visit, provided at least 4 wk have elapsed since the first dose; second dose should be given by 11 to 12 y

Table III. Cont’d

Vaccine Target population Route Dosage Comments Poliomyelitis Children SC Sequential series, 4 doses: Regimens with all IPV or 2 mo, IPV; 4 mo, IPV. all OPV are given in the Oral 6-18 mo, OPV; 4-6 y, same time frame; all OPV IPV doses are indicated for immunosuppressed patients or contacts; all OPV dosing is accepted in certain circumstances only. Rotavirus Infants Oral 3 doses: 2, 4, and 6 mo Vaccine is currently suspended for investigation regarding the association with intussuception. Streptococcus All children aged 2-23 mo, and SC or IM 4 doses: 2, 4, 6, and 12-15 pneumoniae recommended for certain mo children aged 24-59 mo Varicella zoster Children SC 1 dose at ages 12 mo to Do not give to children 13 y; 2 doses (4-8 wk younger than 12 mo. apart) in susceptible persons Ն13 y

IM, Intramuscular; HBsAg, hepatitis B surface antigen; IPV, inactivated polio vaccine; OPV, oral polio vaccine; SC, subcutaneous. *A combination vaccine (Twinrix), now available, contains Havrix (Hepatitis A) and Engerix-B (Hepatitis B). It thus reduces the number of vaccinations from 5 to 3. antibodies 1 month after the first dose, and 99% to areas of high endemicity for hepatitis A. It is also 100% of recipients are protected 1 month after the recommended for persons with chronic liver dis- second dose.67-72 When studied in placebo-con- eases due to causes other than hepatitis A, persons trolled clinical trials in Thailand (which has high engaging in high-risk sexual activity, residents of a rates of hepatitis A), 2 doses of the inactivated vac- community experiencing an outbreak of hepatitis A, cine were 94% effective in protecting against hepa- and users of illicit injectable drugs. In addition, the titis A infection.73 A similar study in New York chil- hepatitis A vaccine currently is recommended for dren showed 100% efficacy after a single dose of routine pediatric use in some states and regions. vaccine.74 Adverse effects with hepatitis A vaccination gen- Because of limited long-term data about this vac- erally are mild, and no serious side effects have been cine, the duration of immunity has yet to be deter- attributed to the vaccine in clinical trials.73 Other mined. In one study of a 3-dose series in adults, than soreness at the injection site, the most common detectable antibodies were documented in all sub- adverse effects include headache (14%) and malaise jects 4 years after immunization.75 According to ki- (7%) in adults and feeding problems (8%) and head- netic models of antibody concentration decline, pro- ache (4%) in children. tective levels of hepatitis A antibodies can be Hepatitis B virus. Prior to the development of expected to persist for 20 years76 and perhaps up to the hepatitis B vaccine, an estimated 200,000- 30 years.77 A separate mathematical evaluation of 300,000 persons worldwide were being infected long-term immunity after a primary dose and with the hepatitis B virus (HBV) annually.79 Immu- booster dose for hepatitis A has calculated that pro- nization for hepatitis B became a reality in 1981 tective antibody levels should persist for 24 to 47 when the plasma-derived vaccine was licensed in years.78 It is unknown whether vaccine-induced im- the United States. This vaccine was highly effective munity will persist beyond the loss of detectable in inducing immunity but was associated with sev- antibody levels, as occurs with hepatitis B immuni- eral drawbacks. The supply of suitable carrier zation, but this phenomenon has been suggested to plasma necessary to make the vaccine was not suf- occur.78 ficient for large-scale production. Also, despite the The hepatitis A vaccine is recommended for per- chemical treatment of plasma products for safety, sons at least 2 years of age living in or traveling to there was some concern about the risk, albeit small, 504 Wu et al JAM ACAD DERMATOL APRIL 2004

of HIV transmission.80 Both of these issues were chronic liver disease due to causes other than hep- addressed in 1986, when the yeast recombinant hepatitis B, prisoners, users of illicit injectable drugs, atitis B vaccine was licensed. This particular vaccine and police and fire department personnel who ren- has been a major breakthrough for the field of med- der first aid) and all children aged 0-18 years. Be- icine. It was the first licensed recombinant viral vac- cause of the current widespread use in children, a cine prototype, as well as the first effective viral thimerosal-free vaccine was recently approved by vaccine for a sexually transmitted disease. This vac- the FDA. Thimerosal is a preservative that contains cine is produced by means of recombinant DNA mercury, which has prompted the limitation of its technology, which involves insertion of the gene for use in children.99 In persons in whom vaccine-in- hepatitis B surface antigen (HBsAg) into the yeast duced protection is less complete, such as in hemo- Saccharomyces cerevisiae (baker’s yeast). Clinical dialysis patients, the need for a booster dose should studies in high-risk homosexual men demonstrated be assessed by means of annual antibody testing. three-dose vaccine efficacy of 82% to 93% in pre- Adverse effects after hepatitis B vaccination are venting acute hepatitis B.81,82 Overall, approximately generally mild and well tolerated. Most commonly 5% of immunocompetent adults fail to develop sig- reported is fatigue (15%), followed by headache nificant antibody titers after hepatitis B vaccination. (9%) and fever (1%-9%).100,101 A postmarketing clin- Nearly 99% of children respond to vaccination,83 ical surveillance of 4.5 million doses of hepatitis B while only 50% to 70% of those over age 60 acquire vaccine over 5 years revealed no serious or severe immunity.84,85 Variables associated with a lower like- reactions attributable to the vaccine.102 Several iso- lihood of seroconversion include immunosuppres- lated reports since that time have described the rare sion, renal failure, prematurity with low birth occurrence of adverse effects such as thrombocyto- weight, age older than 40 years, obesity, and smok- penic purpura,103-105 vasculitis,106,107 rheumatoid ar- ing.86-88 Because of the decreased rates of serocon- thritis,108 lichen planus,109 and lichenoid reaction.110 version in specific populations, additional research However, it appears that these conditions do not is focused on methods of increasing immunogenic- occur at a higher rate than in the unvaccinated pop- ity to hepatitis B vaccines. Alternative delivery sys- ulation. Large-scale hepatitis B vaccination programs tems, such as adenoviruses and vaccinia vectors, are have been unable to establish any association be- under evaluation. Clinical trials are currently inves- tween the vaccine and severe adverse effects other tigating the addition of adjuvants to the current re- than rare episodes of anaphylaxis.101,111 combinant vaccine in order to increase the host On May 11, 2001, the FDA licensed a new com- immune response.89,90 Several different types of vac- bination vaccine that protects people at least 18 cines also in development include DNA vaccines91 years of age against hepatitis A virus and hepatitis B and Pre-S vaccines, which incorporate the surface virus. This vaccine, Twinrix, combines 2 already proteins of the hepatitis B virus.92-94 approved vaccines, Havrix and Engerix-B, so that The duration of immunity afforded by vaccination persons at high risk for exposure to both viruses can merits further long-term studies, but according to be immunized against both at the same time. The present data, long-term efficacy is expected.88 Anti- combination reduces the number of injections from body levels decline rapidly in the first year after 5 to 3. This vaccine is given at the same schedule vaccination and then level off to a slow pace of that is used for the hepatitis B vaccine, administered decline.95 The loss of detectable antibodies to hepat months 0, 1, and 6. The adverse effects of this atitis B years after vaccination does not necessarily vaccine are similar in type and frequency to those of indicate a lack of immunity. The majority of persons the monovalent hepatitis A and hepatitis B vaccines. are protected by immunologic memory in B lym- The data from 11 clinical trials indicate that 99.9% of phocytes, which mount an anamnestic response to vaccinees developed seroconversion for antibodies natural infection.96 Rare cases of hepatitis B infection against hepatitis A virus and 98.5% antibodies in previously vaccinated patients have been de- against HBsAg, with persistence up to 4 years scribed.97,98 These patients generally have subclini- (GlaxoSmithKline Biologicals, unpublished data, cal disease, and none has developed chronic infec- 2001). tion or serious complications.88 In 2002, the FDA approved DTaP-HepB-IPV (Pe- The regimen for immunization includes 3 doses, diarix, SmithKline Beecham Biologicals, Rixensart, given at months 0, 1, and 6. Hepatitis B vaccination Belgium), a combined diphtheria and tetanus tox- is recommended for adults at risk (ie, persons living oids and acellular pertussis adsorbed (DTaP), in or traveling to areas of high endemicity of hepa- hepatitis B (HepB) (recombinant), and inactivated titis B, health care personnel, morticians, persons poliovirus vaccine (IPV). After 3 doses of DTaP- engaging in high-risk sexual activity, persons with HepB-IPV, the immunologic responses were similar JAM ACAD DERMATOL Wu et al 505 VOLUME 50, NUMBER 4

to those following 3 doses of separately administered vaccines for diphtheria, tetanus, 3 pertussis antigens, hepatitis B, and poliovirus types 1, 2, and 3.112,113 However, there are no immunologic data regarding simultaneous administration of DTaP- HepB-IPV and both Haemophilus influenzae type b (Hib) conjugate vaccine and pneumococcal conju- 114 gate vaccine. The rates of most solicited local and Fig 2. Herpes-zoster in the distribution of dermatome systemic adverse events, with the exception of fever, L2. after administration of DTaP-HepB-IPV were similar to rates that followed separate administration of US- 113,115 licensed vaccines. Furthermore, administration appears that the Oka vaccine reduces the rate of of DTaP-HepB-IPV together with Hib vaccine was varicella in children participating in the clinical trials associated with higher rates of fever in comparison by 65% to 90%.122 Additional studies in the United 112,116 with separately administered vaccines. States have shown that the Oka vaccine induces The FDA has approved Pediarix for use in infants humoral and cell-mediated immunity in healthy chil- aged 2, 4, and 6 months. The Advisory Committee dren,127-129 both of which have been shown to per- on Immunization Practices recommends that for in- sist for at least 8 years.130 Delayed-type hypersensi- fants who are born to women who are HBsAg- tivity skin reactions to varicella-zoster virus antigens positive or whose HBsAg status is unknown, a birth have also been shown to occur for at least 10 years dose of single-antigen vaccine is preferred, but the after vaccination.131 Case series have also shown birth dose can then be followed by 3 doses of Pe- that vaccinated persons have less severe varicella diarix at ages 2, 4, and 6 months.117 The recom- (Ͻ50 lesions, no fever, and shorter duration of ill- mended period between doses is 6-8 weeks, prefer- ness) than those unvaccinated.132,133 Recent data in- ably 8 weeks,114 and the third dose of Pediarix dicate that the varicella vaccine effectiveness was should be given at least 16 weeks after the first dose Ͼ95% for preventing disease and 100% for prevent- and at least 8 weeks after the second dose but not ing moderate or severe disease in susceptible con- before age 6 months. It should not be given to any tacts when given within 36 hours of exposure.134 infant aged Ͻ6 weeks or any person aged Ն7 Studies of adolescents and adults have shown years.117 that 2 doses administered 4-8 weeks apart were Varicella-zoster virus (Fig 2). Prior to the necessary to produce seroconversion rates and an- widespread availability of varicella vaccine, yearly tibody responses similar to those obtained in healthy US figures for varicella disease included approxi- children.135 Vaccination is recommended for suscep- mately 4 million cases, 11,000 hospitalizations, and tible adults, particularly those in high-risk situations 100 deaths.118 The currently available varicella vac- (eg, health-care personnel). The vaccine is recom- cine in the United States is a live attenuated Oka mended for all children who have no history of strain vaccine approved in 1995. The vaccine is very chickenpox and is required for all who attend school safe and effective.119-121 Clinical trials began more in most states. Clinical studies of the use of vaccina- than 20 years earlier in Japan, after the vaccine was tion in immunosuppressed children and adoles- developed by means of attenuation of virus isolated cents, particularly in those with acute lymphocytic from the vesicular fluid of a healthy boy (with the leukemia, have been performed.136-138 Results indi- surname Oka) who had natural varicella infection.122 cated that vaccination is safe for those who are at These initial studies showed a 90% seroconversion least 1 year away from induction chemotherapy if rate 4 weeks after vaccination with few clinical re- the current chemotherapy is halted around the time actions.123 Follow-up studies showed that the vac- of vaccination and the patient’s lymphocyte counts cine protected against chickenpox for at least 17 to are Ͼ700/mm3. The immune response in these per- 19 years, and all of the subjects had persistent anti- sons is lower than that of healthy recipients, thus bodies and delayed-type skin reactions to the vari- requiring the administration of 2 doses separated by cella-zoster antigen.124 In the United States, a dou- 3 months. Transmission of varicella from these vac- ble-blind, placebo-controlled study of the Oka cinees may occur if a vaccine-associated rash devel- vaccine in 914 children revealed an efficacy of 100% ops, although the risk of transmission is about one at 9 months.125 After a 7-year follow-up, 95% of the fourth that of natural varicella (20%-25% vs 87%). vaccinated subjects remained free of clinical disease Another study of hematopoietic-cell transplant re- with chickenpox.126 In comparison with the disease cipients, without a history of zoster, showed that rates of unvaccinated children in the United States, it zoster developed in only 13% of those who had 506 Wu et al JAM ACAD DERMATOL APRIL 2004

received the inactivated varicella vaccine but in 30% The Oka vaccine should be given as a single dose of those who were not vaccinated.140 These data to children 12 months to 12 years of age. Persons suggest that the varicella vaccine may boost immu- over the age of 13 should receive 2 doses, 4-8 weeks nity and prevent zoster. apart. The duration of protection is unknown at this Waning cellular immunity is strongly correlated time, and the need for a booster immunization is with the development of herpes zoster.141-143 Levin uncertain. It has been observed that vaccinees who et al144 studied the immune response of elderly per- are exposed to natural varicella have a boost in sons who received the live attenuated vaccine and antibody levels. However, it is postulated that in a found that approximately 10% to 15% of the vacci- highly vaccinated population, a lack of exposure to nees failed to develop increased immunity. Overall, natural varicella may result in waning immunity for however, the calculated half-life of the enhanced some. immunity in this study was 54 months. The long- The Oka vaccine is generally well tolerated. In term duration of the booster effect had a positive both adults and children, the most common side correlation with the dose of the administered vac- effect is mild tenderness, erythema, or induration at cine. In a follow-up study 6 years after vaccination, the injection site (19.3% to 24.4%). Fever occurred in Levin et al145 found that the varicella-zoster virus- 10.2% to 14.7% of clinical trial subjects, and a gen- responding T-cell frequency was still significantly eralized varicella-like rash developed in 3.8% to improved over initial baseline measurements, as 5.5%. A localized varicella-like rash at the injection well as expected measurements for this age cohort. site may also occur. The likelihood of transmission In this vaccinated population, the frequency of her- of the vaccine virus from a healthy vaccinee is low pes zoster was within the range of expected inci- but may be more likely if a rash develops after dents for this age cohort. However, in all of the cases vaccination, especially in those who are immuno- of herpes zoster in the study, the number of lesions compromised hosts. One case of transmission from a vaccinated child to a susceptible mother has been was small, the associated pain was minimal, and reported in the United States, but it is suspected that postherpetic neuralgia did not occur. These findings the child may have been concurrently infected with suggest that vaccination in the elderly may be able to natural wild-type varicella. Persons who undergo attenuate the course of herpes zoster.146 vaccination should avoid close association with sus- Multiple studies have reported a modified varicel- ceptible high-risk individuals for up to 6 weeks, if la-like syndrome in some vaccinated children after possible. This vaccination is also contraindicated in exposure to the natural wild-type varicella vi- pregnant women or in any woman planning to be- rus.126,132,147 The average yearly rate of modified come pregnant within 3 months, since vaccination varicella-like syndrome varies from 0 to 2.72% involves use of a live attenuated virus and natural among children who have been vaccinated with the varicella is known to cause fetal harm. U.S.-licensed Oka strain vaccine. These children typically develop a milder form of disease with fewer Bacteria than 50 lesions. Most children do not have associ- Anthrax. Interest in Bacillus anthracis was ated fever, and only 50% of them develop vesicular raised after the deliberate contamination of mail 148 lesions. None of the cases has been associated with spores after the September 11, 2001, attacks on with systemic or serious disease. It has been noted the United States. This aerobic or facultative anaer- that more complete and long-lasting protection from obic gram-positive rod forms highly resistant endo- varicella is associated with a stronger antibody re- spores under extreme conditions. The spores cause sponse to vaccination.132 human disease by means of direct contact, ingestion, It is known that immunization with the Oka strain or inhalation. Cutaneous anthrax occurs when a vaccine can lead to latent infection. In children, the break in the skin allows spores to enter. The incu- incidence of primary varicella is between 18 and 77 bation time is usually 2-3 days but can occur as soon per 1 million person years of follow-up.149 Herpes as 12 hours or as late as 2 weeks after exposure.153 zoster can develop later, either from this vaccine- Initially, a papule forms, and within 24 hours, a ring type virus or from natural wild-type varicella-zoster of vesicles follows. These lesions ulcerate and be- virus.150,151 There have been several reports of mild come black, necrotic, and edematous. Mortality is herpes zoster in previously healthy children who about 20% in untreated cases. had received the varicella vaccine. The incidence is The toxins of B anthracis come from 2 genes, less than that seen in children with prior chicken- pX01 and pX02.154,155 The gene pX01 encodes pro- pox,152 such that vaccinated children may perhaps tective antigen (PA), lethal factor, and edema factor, have a decreased risk for herpes zoster. which make up the anthrax toxin. The latter 2 com- JAM ACAD DERMATOL Wu et al 507 VOLUME 50, NUMBER 4

bine with the PA to form lethal toxin and edema signed for rapid induction of immunity,167 but a toxin. Edema toxin causes unregulated adenylate recent study showed that increasing the interval be- cyclase activity, which leads to production of un- tween the first 2 injections enhances the level of physiologically high concentrations of cyclic aden- AVA-induced antibodies to PA.168 Furthermore, a osine monophosphate.156 This event causes massive schedule of injections at 6, 12, and 18 months is not edema and organ failure. Plasmid pX02 encodes the well defined. The long-term protective efficacy in poly-␥-linked D-glutamic acid (PGA) capsule, which human beings is unknown. In animal studies, the prevents the antiphagocytic activity of macro- protective efficacy may last up to 2 years after 2 phages.157 Strains of B anthracis that lack pX02 are inoculations.169,170 Finally, AVA contains other cellu- avirulent. lar elements that contribute to the relatively high rate As early as 1881, Pasteur demonstrated the pro- of local and systemic adverse reactions.166 The most tective efficacy of the first anthrax vaccine when he common adverse effects included injection-site hy- injected sheep with heat-attenuated B anthracis.In persensitivity, edema, pain, headache, arthralgia, as- the 1930s, widespread vaccination with attenuated thenia, and pruritus. In 20% of recipients, mild cu- strains such as the Sterne strain significantly de- taneous reactions included erythema, edema, and creased the incidence of anthrax in domesticated induration. In Ͻ1% of recipients, systemic reactions animals in industrialized countries. In the United included fever, chills, nausea, and body aches.160 States, the licensed human vaccine (anthrax vaccine Spores and PGA have also been studied as pos- adsorbed [AVA], newly renamed BioThrax) is a cul- sible targets for immunization. PA antibodies have ture supernatant of a toxigenic, nonencapsulated B been found to have unexpected sporicidal proper- anthracis strain, V770-NP1-R, derived from the ties in vivo. PA antibodies both enhance phagocy- Sterne strain.158 A similar culture supernatant– tosis of spores by macrophages and suppress ger- derived human vaccine (PL 1511/0058) is produced mination.171 Active immunization of guinea pigs and in the United Kingdom.159 mice with formalin-inactivated spores also confers A 1950s study of wool sorters immunized with a immunity to infection.172,173 vaccine similar to AVA, coupled with long experi- Encapsulated B anthracis strains are virulent in ence with AVA and the United Kingdom vaccine, mice, regardless of whether they produce toxin.174 have shown that a critical level of serum antibodies PGA is the major virulence factor in mice, and vac- to the PA confers immunity to anthrax.160,161 After cines based on PA show reduced efficacy in those regular immunizations the previous year, staff of the animals.172 It may be easier to demonstrate a role for Government Wool Disinfection Station in Liverpool anti-PGA antibodies in protective immunity with the were free of the disease with a total protective effi- use of mice. However, there is no definitive test of cacy of 92.5%.162 Laboratory animals and cattle also whether anticapsular antibodies contribute to hu- are protected by AVA from both cutaneous and man immunity to B anthracis. Furthermore, it will inhalational B anthracis challenges.163,164 be difficult to extrapolate conclusions about capsu- The CDC recommends anthrax vaccinations for lar antibodies from mouse anthrax infection to hu- persons engaged in the production of quantities or man anthrax infection, given that the contributions concentrations of B anthracis cultures, those en- of PGA and PA to pathogenesis differ substantially gaged in activities with a high potential for aerosol between mice and humans. exposure, persons in the military, and other select Live vaccines are potential candidates for admin- populations for which a calculable risk can be as- istration as an oral, single dose. They consist of sessed.165 Preexposure vaccinations currently are organisms in which the gene encoding the vaccine not recommended for emergency first responders, has been introduced. After delivery, the microorgan- medical practitioners, and private citizens. ism either colonizes the mucosal surface or causes a Although efficacious and safe,166 AVA has multi- limited infection during which the vaccine candidate ple limitations. First, standardization of AVA is based is expressed and presented to the immune system. on the protection of guinea pigs challenged intracu- Two live vector systems have been described for taneously with B anthracis spores.164 PA is not mea- PA.173,175 The main disadvantage of live vaccines is sured in the vaccine, and there is no standardized the need to culture and store the organism prior to assay of PA antibodies in animals or humans vacci- use. nated with AVA. Second, the schedule of AVA ad- By contrast, DNA vaccines are extremely simple ministration (subcutaneous injections at 0, 2, and 4 and cost-effective. They can be defined broadly as weeks and boosters at 6, 12, and 18 months with plasmid DNA expression vectors that result in ex- recommended annual boosters to maintain immu- pression of an antigen in situ leading to the induc- nity) is likely suboptimal. This schedule was de- tion of antigen-specific immunity.176 DNA-based 508 Wu et al JAM ACAD DERMATOL APRIL 2004

against OspC after Lyme disease is unlikely to protect against a heterologous infection. However, cross-strain protection would be expected with an immune response directed against the spirochete’s OspA in the tick gut.186 In 1990, a mouse model of Lyme disease was developed. Shortly afterward, a recombinant OspA (rOspA) vaccine was shown to be protective against syringe-inoculated infection.187,188 Both passive immunization and active immunization were shown to Fig 3. Erythema migrans of the inguinal region, a symp- be protective. The rOspA vaccine was then shown to tom of Lyme disease. be protective against naturally occurring tick-transmitted infection.189-191 The effectiveness of rOspA vaccine initially was surprising because organisms vaccines have multiple advantages over conven- isolated from infected animals do not express OspA tional vaccines. Unlike subunit vaccines, which re- until naturally occurring late infections. It was dis- quire extensive purification, DNA is relatively cheap covered that the vaccine acts primarily in the tick to produce. The vaccines are heat-stable and are midgut rather than in the vaccinated host.192 As a amenable to genetic manipulation. DNA vaccines feeding tick ingests a blood meal, the ingested blood based on PA have been constructed and have been has circulating anti-OspA antibodies that destroy B shown to be capable of inducing PA immune re- burgdorferi in the midgut of the tick. This finding is sponses177 and of protecting mice against lethal significant because it suggests that a high level of toxin.178 circulating antibodies has to be maintained in the In the short term, improved anthrax vaccines will host to protect against infection at the time of a bite focus on PA. The National Institute of Allergy and by an infected tick. Infectious Diseases has an accelerated program for The rOspA vaccine was also shown to be effec- vaccine development to make 25 million doses of a tive in protecting dogs and rhesus monkeys against recombinant PA vaccine available within 2 years.179 Lyme disease.193,194 On the basis of these promising Lyme disease (Fig 3). Lyme disease is the most results, human immunogenicity, efficacy, and safety commonly diagnosed vector-borne disease in the trials were performed to evaluate recombinant, lipi- United States. Since 1982 the annual incidence of dated OspA vaccine (LYMErix) of B burgdorferi Lyme disease has increased more than 25-fold.180 sensu stricto. The rOspA protein is expressed in Between 1993 and 1997, an average of 12,451 new Escherichia coli and purified. LYMErix was found to cases were reported each year to the CDC. Lyme be immunogenic and safe in phases I and II clinical disease is a tick-borne zoonosis caused by an infec- trials.195,196 In a randomized, controlled clinical tion with the spirochete Borrelia burgdorferi. phase III trial,197 10,936 people were recruited from B burgdorferi has several outer surface proteins. 31 sites in Lyme-endemic areas. Each subject re- In naturally acquired infections, animals and hu- ceived 3 doses of vaccine (30 ␮g) or placebo on a 0-, mans mount an immune response against the spiro- 1-, and 12-month schedule and timed so that each chete’s flagellin (41 kd) and the 23-kd outer-surface subject received the initial vaccination several weeks protein (OspC).181 However, in culture, the domi- before B burgdorferi transmission season. These nant outer-surface protein expressed is OspA, a subjects were followed for clinical manifestations of 31-kd lipoprotein.182,183 Experiments have shown Lyme disease or adverse events for 20 months. that OspA is expressed abundantly by B burgdorferi Vaccine efficacy in protecting against sympto- in the midgut of infected ticks.183 When the tick matic infection (ie, the presence of erythema mi- attaches itself to a host, the spirochetes undergo a grans or objective neurologic, musculoskeletal, or substantial antigenic change during their migration cardiovascular manifestations) was 49% after 2 doses to the tick’s salivary gland, where OspA expression and 76% after 3 doses. The efficacy in protecting is decreased and OspC expression is increased.184,185 against asymptomatic infection (no recognized This temperature-sensitive ability is likely an ac- symptoms) was 83% after 2 doses and 100% after 3 quired protective mechanism that enables B burg- doses. All subjects had laboratory-confirmed infec- dorferi to become established in warm-blooded an- tion by means of cultural isolation, polymerase imals. OspA is uniform across different isolates in chain reaction positivity, or seroconversion. A sub- the United States, but OspC is highly variable among set of subjects had serologic testing for immunoge- different regions. An immune response directed nicity to correlate to protection. Protective immunity JAM ACAD DERMATOL Wu et al 509 VOLUME 50, NUMBER 4

was achieved after 2 doses, but antibody levels de- play in areas of high or moderate risk and in travel- clined rapidly, resulting in protective levels for less ers to areas of high or moderate risk with prolonged than a full year. With 3 doses, a significant anam- and frequent exposures to infected ticks. nestic response developed with maintenance of pro- Several specific issues surround the safety of tective antibody levels throughout the following ex- Lyme vaccines.202 The first is a theoretical concern posure season. that OspA-based vaccine could induce inflammatory The most common adverse event was soreness at arthritis in genetically susceptible persons through the injection site (24.1% of vaccine recipients versus an autoimmune mechanism. The second issue is the 7.6% of placebo recipients). Other side effects in- question of cross-strain protection; will the current cluded arthralgia, myalgias, flulike symptoms, and vaccine protect against all strains of B burgdorferi in fever and chills, but all were uncommon (less than the United States? The third is concern that booster 3.2%). The vaccine was found to be safe in subjects doses will be required to maintain adequate circu- with a history of Lyme disease. However, there was lating antibody levels, but the need for and safety of a greater incidence of musculoskeletal symptoms booster doses is not known. The fourth issue is within the first 30 days after vaccination in subjects whether the vaccine might alter the clinical course of previously afflicted with Lyme disease than in sub- infection if antibody levels fall below the level jects without Lyme disease (20% versus 13%).198 Af- needed for complete protection. Another concern is ter the first 30 days since vaccination, there was no whether alternative vaccine schedules might allow significant difference between vaccine and placebo the development of protective immunity in less than recipients with a history of Lyme disease (33% ver- 1 year. The final concern is the lack of information sus 35%).197 about the safety and immunogenicity of the vaccine The Pasteur Merieux Connaught vaccine, Imu- in children. Lyme, was studied in a similar phase III trial involv- Although the vaccine appeared safe and effective, ing 10,305 adult subjects.199 The immunogen is also it was taken off the market in early 2003 because of recombinant OspA lipoprotein, but unlike the LY- a lack of general use in the medical community. MErix vaccine, it does not have an aluminum adju- Haemophilus influenzae. The early 1980s saw vant. Subjects received 3 doses of 30 ␮g of vaccine the introduction of the first vaccine for Hib, which or placebo on a 0-, 1-, and 12-month schedule. At 12 consisted of polyribosyl ribitol phosphate (PRP), the months, 7,515 subjects received booster doses. The capsular polysaccharide of Hib. A large field trial primary end point was the total number of new performed in Finland showed that antibody re- clinical cases of Lyme disease, confirmed by means sponse to plain PRP vaccine correlated with preven- of serology. The efficacy of vaccine was 68% after 2 tion of invasive Hib disease.203 One month after doses of vaccine in the first year of study and 92% in vaccination, an antibody concentration of 1 g/mL in those who received the third dose of vaccine in the serum was associated with long-term protection second year. Local injection site reactions were more from disease.204 common in the vaccine group during the first week; In December 1987, the first Hib conjugate vac- otherwise, there was no difference between the vaccine, PRP-D (PRP conjugated to diphtheria toxoid; cine and placebo groups in the occurrence of late ProHIBIT, Aventis Pasteur) was licensed in the adverse reactions. United States. The PRP-D vaccine was found to pre- An analysis of the cost per quality-adjusted life- vent Hib disease in Finnish infants immunized dur- year gains with vaccination showed use of the Lyme ing the first 6 months of life.205,206 However, a study vaccination to be economically attractive only in of native Alaskan infants immunized at 2, 4, and 6 persons whose seasonal risk for Lyme disease ex- months showed no significant protection,207 and the ceeds 1%.200 In areas with a seasonal attack rate of FDA rejected the application to license PRP-D for 0.5%, the cost per quality-adjusted life-year gained use in infants.208 In 1987 the FDA approved PRP-D was $145,200. Areas with annual attack rates of 2.5% for use only in children older than 18 months.209 to 10% have been reported,201 but large endemic Two subsequent Hib conjugate vaccines were areas, such as those in which the 2 large Lyme licensed in the United States for use with infants disease vaccine trials were done, had annual attack beginning at 2 months of age: HbOC (Hib [PRP] rates of about 1%. In 1998, the LYMErix vaccine was oligosaccharides conjugated to CRM197, a cross-re- approved by the FDA for use in persons aged 15 to acting, mutant, nontoxic diphtheria toxin; HibTITER, 70 years on a 0-, 1-, and 12-month schedule. The Wyeth Laboratories) and PRP-OMP (PRP conjugated CDC recommends use of the Lyme disease vaccine to an outer-membrane protein complex; PedvaxHib, in persons aged 15-70 years who reside, work, or Merck Sharp and Dohme).210,211 Three randomized, 510 Wu et al JAM ACAD DERMATOL APRIL 2004

W135, but there currently is none against serogroup B. Thirty years ago, the first successful capsular polysaccharide vaccines against groups A and C were developed for epidemics of meningitis among U.S. military recruits.228-230 Studies performed in the United States, Africa, and Europe showed that these vaccines were safe and induced bactericidal antibodies in older children and adults.231-234 However, most polysaccharide vaccines are poor immunogens Fig 4. Disseminated meningococcal disease with second- in infants and do not elicit immunologic memory in ary disseminated intravascular coagulation resulting in ec- people of any age. Group A polysaccharide is im- chymoses and purpura fulminans. munogenic in children Ͻ2 years of age, but protective immunity after 1 dose lasts a short duration, and even after repeated injections, booster responses are placebo-controlled trials conducted in infants immu- low.235-238 Furthermore, repeated vaccination with nized beginning at 2 months of age showed the group C polysaccharide vaccine causes immune hy- efficacy of these vaccines.212-214 Further, these 2 vac- poresponsiveness, which may cause difficulties for cines were found to be significantly more immuno- patients who need long-term protection.239-241 genic in infants than PRP-D.211,215,216 As with Hib vaccines, meningococcal conjugate In 1993, the FDA approved 2 more Hib conjugate vaccines were developed and found to induce long- vaccines, PRP-T (PRP conjugated to tetanus toxoid) term protection and to be safe and immunogenic in vaccine (ActHIB, Aventis Pasteur) and a combined young infants.242 In November 1999, meningococcal diphtheria and tetanus toxoids and whole-cell per- group C conjugate vaccine entered routine immuni- tussis vaccine (DTP) and Haemophilus b conjugate zation in the United Kingdom. Infants received 3 vaccine (Tetramune, Lederle-Praxis Biologicals).217 doses of vaccine at 2, 3, and 4 months of age as their Two studies showed that PRP-T has an immunoge- routine primary immunizations. Also, a catch-up nicity profile similar to that of HbOC vaccine in campaign between November 1999 and December infants immunized at 2, 4, and 6 months of age.218,219 2000 was targeted at all children of Ͼ4 months and The DTP-HbOC vaccine was also found to be safe Ͻ18 years of age. Prospective nationwide surveil- and more immunogenic than separate vaccination lance showed that confirmed cases of invasive with DTP and HbOC.220,221 group C disease fell overall by 85%, in both the Before Hib conjugate vaccines became available, primary immunized and the catch-up popula- Hib was the principal cause of bacterial meningitis tions.243 However, a concern about mass immuniza- and a major cause of other serious invasive diseases tion with meningococcal group C conjugate vaccine among children aged Ͻ5 years in the United is capsular group replacement by strains not con- States.222,223 In the prevaccine era, the incidence of tained in the vaccine.244,245 Capsule switching be- Hib invasive disease was 100 per 100,000 among tween B and C strains has been documented.244,246 children aged Ͻ5 years. In 1991 all infants at age 2 However, careful and extensive surveillance in the months were recommended to receive Hib conju- meningococcal group C conjugate vaccine study in gate vaccines, and by 1996 the incidence of Hib the United Kingdom showed no evidence of capsu- invasive disease among children aged Ͻ5 years had lar group replacement. declined by more than 99%.222,224 During 1998-2000, Multiple clinical trials have shown that bivalent A a total of 824 Hib invasive disease cases was re- plus C polysaccharide conjugate vaccines are well ported among children younger than 5 years, and tolerated and immunogenic in infants, toddlers, and rates were 1.4 per 100,000 children in 1998 and 1999 adults.238,247-249 The currently available formulation and 1.6 in 2000.225 The Hib conjugate vaccines have in the United States is the tetravalent A, C, Y, W-135 been equally efficacious in the rest of the world, as vaccine (Menomune-A, C, Y, W-135; Aventis Pas- well.226,227 teur). It is safe and has an efficacy of 85%,250 and it Neisseria meningitidis (Fig 4). The important could prevent more than 60% of cases in college determinant of virulence of Neisseria meningitidis is students.251 The current recommendation for the tet- the polysaccharide capsule. Mutants without capsu- ravalent vaccine is selective immunization based on lar expression are nonpathogenic, since they are risk factors for meningococcal disease, instead of killed by complement. There are licensed polysac- universal immunization in the pediatric charide vaccines against serogroups A, C, Y, and population.252,253 JAM ACAD DERMATOL Wu et al 511 VOLUME 50, NUMBER 4

INVESTIGATIONAL VACCINES Table IV. Infectious diseases with cutaneous Many of the vaccines currently under investiga- manifestations for which vaccines are under tion more than likely will expand the focus of im- development munization. All the vaccines available up to the end Prophylactic Therapeutic of the 20th century have been used solely to prevent disease. However, several new candidate vaccines HIV HIV HSV HSV are being developed and evaluated in the treatment HPV HPV of already acquired infections. Table IV lists the Cytomegalovirus Varicella-zoster virus predominant diseases for which candidate vaccines Respiratory syncytial virus are presently under investigation. Parainfluenza virus Hepatitis C Viruses Dengue fever HIV. As the AIDS epidemic persists and spreads Epstein-Barr virus unabated in much of the world, the search for an Anthrax effective HIV vaccine is becoming critical. In 1997 Lyme disease President Clinton challenged scientists to develop an Neisseria meningitidis serotype B effective HIV vaccine by the year 2007. Since clinical Nontypeable Haemophilus influenzae trials first began in 1987, at least 34 different HIV Rocky Mountain spotted fever candidate vaccines have begun phase I trials, and a Staphylococcus aureus handful of these have progressed to phase II tri- Staphylococcus epidermidis als.254 Seventy-four additional HIV vaccine candi- Streptococcus pyogenes dates are reported to be in research and develop- Pseudomonas aeruginosa ment or preclinical testing in animals, and this Francisella tularensis number probably has increased.254 The predomi- Brucella melitensis nant types of HIV vaccines under investigation are Leptospira interrogans listed in Table V. Thus far, only one AIDS vaccine Candida species Aspergillus species had advanced to phase III trials, the VaxGen AIDS Cryptococcus neoformans vaccine AIDSVax, which was evaluated in the Coccidioides immitis United States and in Thailand. Earlier research sug- Blastomyces dermatitidis gests that this recombinant gp120 vaccine stimulates Histoplasma capsulatum antibody production but may not induce cellular Leishmania immunity. HIV research has shown that the induction of cytotoxic T lymphocytes may be an important correlate for protective efficacy of HIV vaccines.255 However, the recombinant gp120 HIV insertion of HIV gp160 gene. The vaccine alone vaccine failed. In the 3-year study, of 5,009 volun- induced little antibody.254 However, when it was teers at 59 trial sites in the United States, Canada, the used as a primer and boosted with the recombinant Netherlands, and Puerto Rico, 5.7% of those who gp160 vaccine, results showed strong induction of were vaccinated developed HIV compared with cellular immunity and antibody responses.260 Phase 5.8% of those given placebo.256 I trials are under way for a recombinant vaccinia HIV Recombinant subunit HIV vaccines are geneti- primer followed by boosting with a recombinant cally engineered from HIV surface envelope pro- gp120 vaccine.254 teins, such as gp120 or gp160. Because they do not Because of concerns over shedding of the vac- contain live virus or DNA, there is no risk of causing cinia virus and possible disseminated disease in im- infection. A therapeutic trial was carried out with munosuppressed persons, more attention has been gp160 subunit immunization every 3 months for 3 focused on canarypox and adenovirus vectors, years in HIV-positive persons, in addition to antiret- which can infect humans but cannot replicate. Rep- roviral therapy.257 Results demonstrated a modest lication in humans continues long enough to pro- effect on CD4 counts but no clinical benefit. These duce the necessary HIV proteins before abortion of results were consistent with similar, earlier the cycle.261 Early results have shown that recombi- studies.258,259 nant canarypox vector vaccines can induce humoral Recombinant live-virus vector vaccines involve and cellular immune responses, including cytotoxic the use of virus carriers that are genetically engi- lymphocytes.262 The greatest interest for these vac- neered to express particular HIV genes. The first cine candidates lies in the prime and boost ap- candidate to be tested was a vaccinia vector with the proach. The canarypox vaccine primer induces a 512 Wu et al JAM ACAD DERMATOL APRIL 2004

Table V. Predominant types of HIV vaccines under units and compare the immune responses in investigation recipients. Use of the vesicular stomatitis virus as a vector to DNA plasmid: gp120, gp160, GagPol, Pol, techniques such as multiplasmids, interleukin-2 adjuvants, genetic express HIV protein has also shown promise. One adjuvants, conventional adjuvants, DNA priming, study involved vaccination of 7 rhesus monkeys microspheres, and in vivo electroporation with live attenuated vesicular stomatitis virus ex- Epitopes: CTL or HTL pressing Env and Gag, and the animals were chal- Live attenuated virus: HIV, simian-human lenged with simian-human immunodeficiency vi- immunodeficiency virus rus.268 Two years after the challenge, none of the Peptides: synthetic V3-peptides, Tat, lipopeptides animals has developed AIDS and 6 have no detect- Recombinant live vector: adeno-associated viruses, able virus.269 Another study involved evaluation of replication-defective adenovirus serotype 5 vector, immune responses of animals vaccinated either in- alphaviruses, canarypox and other avian and mammalian tranasally or intramuscularly with the vesicular sto- poxviruses, herpes simplex virus type-1, picornaviruses, 269 rhabdoviruses, vaccinia, modified vaccinia virus Ankara matitis virus vector expressing Env and Gag. After vector, vesicular stomatitis virus, bacterial vectors a challenge with simian and human immunodefi- Recombinant subunit: rgp120, rgp160, Env ciency virus, the animals vaccinated intranasally had Retroviral vectors: recombinant murine retrovirus a slight loss of CD4 T lymphocytes. However, the RNA optimized constructs: pGag, pEnv animals vaccinated intramuscularly had a significant Self-replicating RNA: replicon particles based on decrease in CD4 T lymphocytes, which returned to Venezuelan equine encephalitis virus 70% of baseline. The virus load was undetectable in Virus-like particles (VLP): p170/p24:Ty VLP both groups. Whole inactivated virus: envelope depleted whole DNA vaccines are another promising prospect for inactivated HIV-1 HIV immunization. With this approach, purified CTL, Cytotoxic T lymphocyte; HTL, helper T lymphocyte. DNA that encodes for particular immunogenic antigens is injected. These antigens are presented to the host immune system in their native form and are strong cellular immunity, followed by a recombinant processed in a way similar to that for a natural viral subunit vaccine that boosts the antibody reinfection.262,270 Therapeutic immunization with a sponse.261 The combination of both vaccines in- plasmid/gp160 and gagϩ pol DNA vaccine in HIV- duces a stronger immune response than either one positive chimpanzees revealed a significant de- alone.255,263 Recent results from a phase II trial crease in viral load and a boost in the immune showed that 93% of subjects who received the com- response.270 Studies in seronegative primates dem- bination of vaccines developed neutralizing anti- onstrated the induction of neutralizing antibodies bodies.264 Also, almost one-third of the recipients and cytotoxic T-lymphocyte responses, but the vac- developed a cytotoxic lymphocyte response. Addi- cine did not protect against infection.254 A phase I tional studies have investigated canarypox vectors clinical trial of 2 DNA vaccine candidates is currently expressing gp160 or gp120/gag/pol HIV-1 antigens in progress.254 given along with recombinant gp160 or gp120 sub- Several other approaches to HIV vaccine devel- unit vaccines.265 In a comparison of data from dif- opment are under investigation. Live attenuated vi- ferent trials of several candidate canarypox vector rus vaccines are known to generate a broad and HIV vaccines, more than half of the recipients de- durable immune response, but they have not been veloped durable, HIV-specific cytotoxic T-lympho- tested in humans owing to potential safety concerns cyte responses.266 Researchers suggest that a with live HIV virus.254 Whole-inactivated vaccines broader recombinant vector vaccine would proba- are generally thought to be safer than live attenuated bly increase the percentage of responders.266 ones. However, inactivation of the virus often leads A trial in Uganda of the effect of a canarypox to a vaccine that is less potent or immunogenic. vector vaccine alone commenced in February Studies of whole-killed virus vaccines in chimpan- 1999.267 The vaccine, called Alvac vCP205, contains zees thus far have not been able to demonstrate 3 HIV genes in a weakened version of canarypox protection from HIV infection.254 In addition, there is virus. The particular genes come from clade B vi- concern that inadvertently incomplete inactivation ruses, which are the predominant subtype of HIV could lead to HIV infection of vaccine recipients. found in the United States and Europe. However, Virus-like particles (VLP) are a safer option, since the majority of HIV infections that occur in Uganda they consist of a noninfectious HIV “look-alike” that are due to clades A and D. This study will first does not contain the HIV genome. One such candi- evaluate the cross-reactivity among these viral sub- date, known as p17/p24:TY, has reached the stage JAM ACAD DERMATOL Wu et al 513 VOLUME 50, NUMBER 4

of clinical trials. Early results have shown that this vaccine leads to low levels of HIV binding antibodies and T-cell memory responses but induces very little cytotoxic T-lymphocyte activity.254 Other VLP candidates are under development. Among the many important controversies that exist in HIV vaccine development is whether neutralizing antibodies as typically measured are relevant to clinical protection. HSV (Fig 5). The search for a vaccine for herpes simplex virus (HSV 1 and 2) spans 9 decades. In the 1920s, untreated vesicular fluid from herpes lesions was injected into patients in an attempt to induce immunity.254 This method, to say the least, did not withstand the test of time. Inactivated whole virus vaccines were developed in the 1930s and were made from HSV-infected animal tissue, such as rab- bit brain.271 Despite the many advances made with inactivated virus vaccines through the years, none of the candidates proved to be sufficiently immunogenic. With increasing technology, several different approaches for HSV vaccines are currently in development and under evaluation. Fig 5. Herpes simplex type 2 infection of the buttocks. Two separate recombinant subunit vaccines have been investigated in phase III trials. One such candidate developed by Chiron contained HSV-2 sur- genes have shown promising results for the preven- face glycoproteins B and D and the adjuvant MF59. tion of infection.278,279 These vaccines are able to The development of this vaccine was halted prema- express only 1 or 2 viral antigens but can induce turely because results demonstrated overall lack of cell-mediated immunity without the need for potent efficacy for both preventive and therapeutic adjuvants. One such candidate that encodes glyco- use.272,273 A second recombinant vaccine was devel- protein D2 is currently in phase I clinical trials, and oped by SmithKline Beecham and contains the gly- several others are in preclinical development. coprotein D and the adjuvant monophosphoryl lipid Live attenuated HSV vaccines have been rather A immunostimulant.274 Results of clinical trials with difficult to develop, as viruses that are the safest and this candidate indicate that it has a clinical efficacy of most attenuated tend to lack immunogenicity. Re- 73% in protecting women who are serologically neg- search in the past has shown that stable attenuation ative for both HSV-1 and HSV-2 from acquiring of HSV was not achieved after passage in cell cul- HSV-2 disease.275 Another approach combines the ture. After immunization, the vaccine strain would safety profile of a killed vaccine with the immuno- then have the potential to revert to its virulent state genic potential of a live virus vaccine.276 The dis- and cause disease. A genetically engineered HSV abled infectious single-cycle vaccine lacks the gly- mutant vaccine was found to be safe and effective in coprotein H gene necessary for virus entry into cells. animal studies280 but in humans was overly attenu- After a single replication cycle, the virus is unable to ated and lacked sufficient immunogenicity.281 New spread to surrounding cells and thus remains non- genetically engineered strains are currently under infectious. Studies in guinea pigs showed encourag- development. ing results for both preventive and therapeutic treat- HPV (Fig 6). Certain types of HPV are associated ment.276,277 Although phase I studies showed the with the development of cervical cancer. Thus the candidate to be safe and well tolerated, phase II search for a prophylactic or therapeutic HPV vaccine trials showed that the vaccine failed as therapy. has been an important endeavor. Although more Trials are also planned to evaluate the efficacy in than 30 types of HPV are known to be sexually preventing infection in seronegative partners in dis- transmissible, the major types associated with ma- cordant couples.254 lignancy (16, 18, 31, 33, 45, 52, 58) and condylomata DNA vaccines are also in development for HSV (6 and 11) are relatively few in number, allowing for immunization. Animal studies that involve inocula- more focused strategies for immunization against tions of plasmid DNA carrying the desired viral these specific types. Vaccine development has been 514 Wu et al JAM ACAD DERMATOL APRIL 2004

der way, one involving HLA-A*0201 binding HPV16-E7 peptides, to assess the possible therapeutic implications these vaccines may offer.157 Other investigational approaches to HPV immunization include DNA vaccines,288 bacterial vectors,289-291 and dendritic cells pulsed with HPV epitopes.292 In 1 study, the cost-effectiveness of vaccinating adolescent girls who are at high risk of HPV infection was evaluated.293 Relative to current practice, a vaccine with a 75% probability of immunity against Fig 6. High-grade cervical dysplasia secondary to HPV- HPV infection resulted in a life-expectancy gain of 16. 2.8 days or 4.0 quality-adjusted days at a cost of $246 (incremental cost-effectiveness of $22,755 per qual- hampered in the past because of the inability to ity-adjusted life year). If all 12-year-old girls in the culture HPV. However, an in vitro culture system for United States (approximated at 1,988,600) were vac- HPV has recently been developed, furthering the cinated, more than 224,255 cases of HPV, 3,317 prospect for advances in this field.254 cases of cervical cancer, and 1,340 deaths from cer- VLP are produced by means of recombinant DNA vical cancer would be prevented. technology and are designed to self-assemble into conformations that resemble natural HPV. These Fungi vaccines contain no viral DNA and thus carry no risk The idea of an antifungal vaccine has been inves- of infection or oncogenic exposure. VLP have been tigated for more than 40 years.294 Development of an designed for all of the major HPV subtypes, and effective fungal vaccine is difficult because fungi, clinical trials are currently under way for HPV-11 L1 like other eukaryotic organisms, are orders of mag- 295 VLP,282 HPV-6 L1 VLP,283 and HPV-16 L1 VLP.284 A nitude more complex than bacteria or viruses. recent double-blind, placebo-controlled study The main obstacle of vaccine development is the showed that persons who were HPV-16 negative isolation of the smallest possible immunogenic sub- and received the HPV-16 vaccine had a significantly stance from multiple proteins and carbohydrates reduced incidence of both HPV-16 infections and that safely confers lasting immunity against infec- related cervical intraepithelial neoplasia at a median tion. A second major challenge is the lack of scien- follow-up of 17 months.285 tific knowledge about natural fungal immunity and Fusion protein vaccines are currently under eval- the relative contributions of the innate, acquired uation for the immunotherapy of cervical cancer and humoral and cellular systems.296,297 Currently, there genital warts. TA-HPV is a live recombinant vaccinia is no FDA-approved fungal vaccine for clinical use. virus that has been engineered to express the E6 and Attenuated low-virulence strains of Candida spp E7 protein genes for HPV 16 and 18 as a treatment have been used in experimental animal models with for cervical cancer.254 This method also involves some success.298-300 Other preparations, such as in- utilization of the viral vector approach, with vaccinia activated whole cells of the fungus, secretory and as a vehicle. Viral vector vaccines can be polyvalent cell surface–located molecules, and major cytoplas- and have the potential to produce immunity similar mic and cell wall enzymes, have been used with to that induced by live attenuated vaccines. A phase varying levels of success.301-304 I-II clinical trial of TA-HPV286 has shown encourag- The challenge in developing a candida vaccine is ing results, and further studies are under way. to purify antigens associated with invasive forms, TA-GW is a recombinant fusion protein vaccine con- not colonized forms. In one report, heat-killed wild- sisting of HPV-6 L2 and E7 proteins and is under type Candida albicans was combined with a novel investigation for the treatment of genital warts. A adjuvant from a Vibrio cholerae enterotoxin to aug- phase IIa clinical trial showed the vaccine to be ment the immune response.305 The vaccine was immunogenic, with encouraging clinical re- given intranasally to mice, and there was a response sponses.287 A third protein vaccine, TA-CIN, is in of induced cellular and humoral immunity by anti- preclinical development for the treatment of cervical body titers and a footpad delayed hypersensitivity in dysplasia.254 response to cutaneous antigen inoculation. There Peptide-based vaccines have been shown to be was a 90% survival rate among vaccinated mice, protective against HPV-induced tumors in mice, al- compared with 0 among the control animals, when though the T-cell repertoires in mice and humans they were challenged with a moderate inoculum of differ. Two early-stage human clinical trials are un- live, virulent organisms. JAM ACAD DERMATOL Wu et al 515 VOLUME 50, NUMBER 4

Table VI. Immunoglobulins: indications for administration

Infectious Disease Approved Indication Cytomegalovirus Cytomegalovirus prophylaxis in seronegative renal transplant recipients of a kidney from a cytomegalovirus-positive donor Hepatitis A Within 2 weeks of exposure in susceptible persons Hepatitis B Hepatitis B exposure in susceptible persons, first dose as soon as possible and the second within a month Measles Within 6 days of exposure in susceptible persons Rabies Rabies exposure in previously unvaccinated persons Respiratory syncytial virus Prophylaxis in high-risk infants (e.g., those with bronchopulmonary dysplasia, prematurity, or chronic lung disease) Tetanus Single dose after exposure; some recommend an injection around the site of infection Vaccinia For complications of vaccinia vaccination Varicella Within 96 hours of exposure for susceptible persons exposed to varicella who have a high risk for complications (e.g., immunocompromised patients and neonates) Other uses for intravenous immunoglobulin Primary immunodeficiencies (ataxia telangiectasia, agammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency, etc.), Guillain-Barre´ syndrome with ascending paralysis, immune thrombocytopenic purpura, bone marrow transplantation, Kawasaki disease, chronic B-cell lymphocytic leukemia, and in children with AIDS who are hypogammaglobulinemic or have had 2 or more serious bacterial infections, parvovirus B19 infection, failure to make specific antibodies after immunization, or enterovirus infection

In another trial, researchers examined the immu- Protozoa nogenicity of a specific candida antigen, mannan, Leishmaniasis (Fig 7). The World Health Orga- which is a carbohydrate associated with the cell wall nization considers leishmaniasis to be one of the during adhesion to host macrophages. Poorly immu- most significant parasitic diseases, with about 350 nogenic by itself, when encapsulated within a lipo- million people at risk of contracting it. The best some, it is effective. It has a short shelf life and option in controlling leishmaniasis is considered to requires multiple dosing.306 The same researchers be vaccination.312,313 Numerous antigens have been conjugated mannan to bovine albumin and with 2 tested with variable success against cutaneous leish- doses of vaccine, and survival improved from 0 at 20 maniasis in in vitro and mouse models,314 but there days in controls to 80% at 65 days in vaccinated currently are no commercially available effective animals. The vaccine also showed transferable pro- vaccines. The general opinion is that a vaccine tective immunity to na¨ıve animals.307 against leishmaniasis is feasible.314 Vaccines have A conjugate vaccine of cryptococcal capsular glu- the additional advantage of avoiding the problems curonoxylomannan covalently linked to tetanus tox- of drug resistance, which has been an increasing oid confers 70%-80% protection in mice by stimulat- problem in the control of leishmaniasis. ing both cellular and humoral immunity.308 Passive Since cured individuals are protected from further immunization with monoclonal antibodies against disease, vaccine development mainly has been fo- Cryptococcus neoformans has been successfully em- cused on cutaneous leishmaniasis. The develop- ployed in a murine model of disseminated dis- ment of a Leishmania vaccine has been hampered ease.309 by several factors, including the antigenic diversity, A new strategy is the use of vaccines to neutralize the complex life cycle, the use of experimental an- fungal virulence factors. Fungal phospholipases imal models not representative of human disease, have been found to be important mediators of fun- and the lack of sufficient financial support to de- gal infection.310 ␤-Blockers, which have antiphos- velop a vaccine for the population of third-world pholipase activity, have been used successfully in nations. combination with fluconazole to increase survival in Recently, the UNDP/World Bank/WHO Special mice with disseminated candidiasis.311 Programme for Research and Training in Tropical 516 Wu et al JAM ACAD DERMATOL APRIL 2004

nase (LACK) conferred protection to mice against infection with L major.320 Although the amino acid sequence of the LACK antigen was highly con- served, the efﬁcacy of this vaccine antigen against strains other than L major could not be shown. DNA vaccination with a L donovani LACK DNA vaccine

induced a strong parasite-specificTH1 immune response (interferon-␥ but not interleukin-4 production) and primed for an in vivo T-cell response to inoculated parasites in one study. However, it did not induce protection against cutaneous or systemic L donovani challenge in mice.321 DNA vaccination holds enormous promise for the Fig 7. Cutaneous leishmaniasis in a Brazilian patient. future of vaccine development against infectious agents, especially in developing countries. Such vaccines are attractive because they ensure correct fold- Diseases has organized a comparative study of sev- ing of the antigen, generate appropriate immune eral leading recombinant antigens to test candidate responses, are simple to produce, and do not re- antigens as potential vaccine candidates.315 The quire adjuvants, all of which may make them stable 314 study involved use of recombinant antigens from and affordable. DNA vaccines are also most likely 322 Leishmania major, L braziliensis, and L mexicana to confer long-term cellular immunity. Before expressed in Escherichia coli, either as a single re- DNA vaccines can be studied in clinical trials, it is combinant protein or as a mixture. The trial con- important that safety issues, such as the induction of sisted of testing the antigens for human peripheral autoimmune disease and the integration of the vac- blood mononuclear cell proliferation and conduct- cine DNA in the human genome, be appropriately 323,324 ing challenge experiments in immunized mice. addressed. Experiments of peripheral blood mononuclear Traditional molecular biologic methods work on cell stimulation showed that most antigens induced one gene at a time. Because of the limited output of some interferon-␥ production and proliferative re- such methods, the whole picture of gene function is sponses. This finding suggests that the selected an- difficult to obtain. With the recently developed mi- tigens have some degree of immunogenicity in hu- croarray technology, DNA molecules representing mans. However, none of the antigens induced many genes are placed in thousands of discrete significant protection in the mouse challenge exper- spots on a microscope slide. This technique allows iments. Because of these conflicting results, it is scientists to look at many genes at once and to difficult to draw any definitive conclusions. The use- determine which ones are expressed in a particular fulness of these antigens as a human vaccine still cell type. remains unknown. In 1994 the Leishmania Genome Network was DNA vaccination may be a new approach where launched in Rio de Janeiro, Brazil, and was aimed at conventional vaccines have failed.316,317 In DNA vac- sequencing the genome of the reference strain Leish- 325 cination, plasmid DNA containing the gene that en- mania major Friedlin. It is expected that microar- codes the vaccine candidate is introduced into the ray technology, together with the Leishmania ge- tissue through intramuscular injection or particle nome project, will allow the identification of many bombardment. The DNA is taken up by cells and new drug and vaccine targets. From initial studies, translocated to the nucleus, where it is transcribed more than 100 unknown genes were identified and 315 into RNA and then translated in the cytoplasm. Al- are now being tested as new vaccine candidates. though the uptake and expression in DNA are extremely low, the antigen is expressed in enough IMMUNOGLOBULINS quantity to induce a specific and potent immune Table VI lists the current immunoglobulins that response and to confer future protection.318 are used for infectious diseases. Immunoglobulins The effectiveness of DNA vaccines against infec- are proteins made by B lymphocytes and plasma tious diseases has been demonstrated in several an- cells as part of the humoral portion of the immune imal models, including a murine model for leish- system. Commercial sterile preparations are made maniasis in which a GP63-based DNA vaccine was from pooled human plasma of several thousand studied.319 Vaccination with DNA encoding Leish- donors and consist of purified immunoglobulin G mania homologue of receptors for activated C ki- along with small amounts of other globulins. These JAM ACAD DERMATOL Wu et al 517 VOLUME 50, NUMBER 4

preparations were first used to treat immune defi- ment was also indicated for travelers who plan to ciency diseases in 1952, with the discovery of Bru- stay in areas with poor sanitation, but the hepatitis A ton’s agammaglobulinemia.326 Early preparations vaccine is now the preferred method for hepatitis A were associated with frequent side effects when prevention in travelers.336 they were given intravenously and thus required Hepatitis B immune globulin is given with hepa- frequent and painful intramuscular administration. titis B vaccine in certain situations as part of the In 1981 an improved preparation of immunoglobu- recommended postexposure prophylaxis regimen. lin was licensed for intravenous use (IVIG). FDA- The following susceptible persons who were ex- approved indications include the following 6 condi- posed to hepatitis B virus should receive hepatitis B tions: primary immunodeficiencies, immune- hyperimmune globulin in addition to immunization: mediated thrombocytopenia, Kawasaki disease, persons with acute exposure to HbsAg-positive recent bone marrow transplantation (in persons at blood, infants with perinatal exposure to HBsAg- least 20 years of age), chronic B-cell lymphocytic positive mothers, persons with sexual exposure to leukemia, and pediatric HIV-1 infection.327 IVIG is HBsAg-positive partners, and infants with an also used in clinical practice for numerous other HBsAg-positive primary caregiver. Hepatitis hyper- conditions, such as multiple sclerosis. Intravenous immune globulin has been evaluated for the pro- preparations are manufactured by several different phylactic treatment of HBsAg-positive liver trans- companies, and owing to differences in the produc- plant recipients. High-dose, long-term treatment has tion process and donor populations, the products led to increased survival and decreased serologic 328 available may vary considerably. recurrence in a number of studies.337,338 However, The intramuscular form of immunoglobulin is still maintenance treatment is required for the preven- available and is approved for the prophylaxis of tion of recurrence, and long-term treatment is ex- hepatitis A and measles. Several immunoglobulin pensive.339 preparations with high titers to individual viruses are Varicella-zoster immune globulin should be ad- also available for the prophylaxis of specific viral ministered to susceptible persons exposed to vari- infections. These hyperimmune globulins are avail- cella virus who have an increased risk for complica- able for rabies, varicella, cytomegalovirus, respira- tions (i.e., immunocompromised persons). The tory syncytial virus, and hepatitis B. postexposure prophylaxis should be administered IVIG has also been shown to be of potential benefit as soon as possible and no later than 96 hours after for HIV-infected children. This population frequently exposure.340 The protection lasts at least 3 weeks suffers from bacterial infections with common encap- after the injection. sulated bacteria, whereas infected adults more fre- Adverse reactions to any of the immunoglobulin quently develop opportunistic infections.329 Several small studies with IVIG have shown decreased bacte- preparations are rare. The incidence of systemic side rial infections and sepsis, as well as improved survival effects is generally less than 5%, and these reactions in HIV-positive children.330-332 Another study of HIV- are typically mild and self-limited. Fever, chills, infected children who were undergoing treatment with headache, backache, nausea, vomiting, chest tight- zidovudine showed a benefit with the use of IVIG, but ness, myalgias, and dyspnea have all been reported. only in those subjects not receiving trimethoprim-sul- With intravenous preparations, slowing of the infu- famethoxazole as antibiotic prophylaxis.333 The exact sion rate can be of benefit in alleviating the side role of IVIG in this situation remains unclear. effects. Hydrocortisone and antihistamines are also Intramuscular immunoglobulin can be given for useful. Anaphylactic reactions may also occur in the prevention of measles in susceptible individuals immunoglobulin A–deficient patients receiving (those with no previous infection or immunization). IVIG, but this complication is rare.341 From 1985 to Its use is indicated for exposed persons with an 1998, acute renal failure has been described in 120 increased risk of complications from disease, such as IVIG recipients worldwide.327 Acute renal failure ap- immunocompromised patients or children less than pears most closely associated with IVIG prepara- 1 year old. This treatment should be given within 6 tions with high sucrose content. The majority of days of exposure. The second indication for intra- affected patients developed renal failure within 7 muscular immunoglobulin is the prophylaxis of hep- days of IVIG administration, and 40% required dial- atitis A. The protective effect is of most value if given ysis owing to the degree of failure. Although this prior to or immediately after exposure, and at least complication remains infrequent, it is associated within 2 weeks of exposure. If given within several with significant morbidity and mortality. Other un- days of exposure, the immunoglobulin prevents in- common adverse effects include encephalopathy fection in 80% to 95% of patients.334,335 This treat- and thromboembolism. 518 Wu et al JAM ACAD DERMATOL APRIL 2004

Because these biologic products are derived from sidered. With recent current events, the use of human plasma, viral contamination poses a poten- weapons of mass destruction, specifically smallpox tial, though small, risk. In 1994 the association of 2 and anthrax, is now a realistic and potential biologic different IVIG preparations with hepatitis C contam- threat. A smallpox vaccination program has now ination led to numerous cases of acute hepatitis C been initiated by the United States in preparation for infection (more than 100 cases in the United States). the possibility of terrorist attacks and in protecting The manufacturers added a solvent-detergent treat- persons in the front lines of a biologic attack. These ment for viral inactivation, and users of the products individuals include military personnel, medical pro- no longer are considered to be at risk for hepatitis fessionals, and emergency personnel and response C.342 All current IVIG preparations come from teams who would be first on the scene in a smallpox donors who are screened for hepatitis B and C, emergency. A similar situation exists for poliomyeli- HIV, and elevated levels of liver enzymes. Also, tis, which is expected to be eradicated worldwide in the majority of manufacturers include a viral inac- the near future. The cost savings for an HIV vaccine tivation step in the production process. No cases would also be phenomenal, considering the long- of HIV transmission have been reported with term treatment and numerous complications in- IVIG. volved with this chronic infection. Immunization has successfully led to the reduc- CONCLUSION tion in incidence of numerous diseases. Careful de- It is clear that vaccination is one of the greatest velopment and clinical evaluation have provided achievements in the history of mankind. Immuniza- safe and effective vaccines with few adverse effects. tion should be used in conjunction with public Many reported adverse reactions after vaccination health measures such as sanitation, blood product may be coincidental and have no proven direct screening, safe sex techniques, vector control, di- relationship with the vaccine in question. Although etary education, and exercise promotion. Although serious side effects may rarely occur from vaccines, immunization is considered widely as a major suc- a much greater risk for morbidity and mortality re- cess, there are the public health challenges of im- sults from the failure to become immunized. One plementing vaccine programs and allaying un- vaccine, however, was recently removed from the founded fears of the public about immunization side market owing to safety issues. Rotashield was a live, effects. Vaccine-preventable infectious diseases still oral, tetravalent rotavirus vaccine that was associ- remain major causes of morbidity and mortality in ated with several cases of intussusception and is the world. Many children in the world still die from considered to be causal.349 Most associations be- measles, tetanus, and pertussis,343 and influenza- tween vaccines and adverse events are not, how- related pneumonia and sepsis are among the top 10 ever, shown to be causal. For example, the MMR causes of death in the United States and in the vaccine was reported recently not to have a causal world.344,345 Despite the data that show efficacy of relationship to autism.350-352 Likewise, a causal rela- vaccinations, there is a small movement of antivac- tionship between the hepatitis B vaccine and a va- cination activists who may be partly contributing to riety of autoimmune diseases has been disproved. the lower rates of adult immunization.346,347 This vaccine does not increase the risk of multiple The implementation of routine immunizations sclerosis353 nor does it cause a relapse of preexisting not only has a significant impact on the overall multiple sclerosis.354 A claim that the rising rates of incidence of disease but also markedly decreases the diabetes mellitus in children may be due to indirect and indirect costs associated with health care. creased exposure to vaccination has been rigor- For instance, a 1994 study of the cost-effectiveness ously refuted.355,356 Nevertheless, suspected rela- of a varicella vaccination program in the United tionships between vaccines and adverse events States showed savings of $384 million dollars per need to be reported to the Vaccine Adverse Event year.348 The cost reduction with varicella is mostly Reporting System (800-822-7967) so that the ex- due to a decrease in time lost from work by care- cellent safety record of vaccines can be main- givers, although this savings is significant. Vaccines tained. for more serious diseases that often require hospi- The technology of vaccine development has pro- talization, such as respiratory syncytial virus in in- gressed dramatically in the last decade. While more fants, will likely result in a more beneficial cost- conventional methods have consisted of whole- effective profile. Historically, the cost savings of the killed or live attenuated viruses, more recent ad- eradication of smallpox, a disease that killed mil- vances include genetically engineered vectors and lions of people, approaches infinity when the mil- VLP, among many others. Anticipated vaccine de- lions more that would have been affected are con- velopments in the future show exciting promise in JAM ACAD DERMATOL Wu et al 519 VOLUME 50, NUMBER 4

several areas, such as immunization with plants. 19. Arita I. Duration of immunity after smallpox vaccination: a Potatoes, tomatoes, and bananas are currently un- study on vaccination policy against smallpox bioterrorism in Japan. Jpn J Infect Dis 2002;55:112-6. dergoing genetic engineering to express immuniz- 20. Breman J, Henderson D. Diagnosis and management of small- ing antigens against infections such as hepatitis B pox. N Engl J Med 2002;346:1300-8. virus and Norwalk virus.357,358 This form of vaccina- 21. CDC. Update: cardiac-related events during the civilian small- tion would offer a convenient, painless, and inex- pox vaccination program—United States, 2003. MMWR Morb pensive approach to widespread control of disease Mortal Wkly Rep 2003;52:492-6. 22. Cono J, Casey CG, Bell DM, CDC. Smallpox vaccination and ad- and thus would be accessible to developing coun- verse reactions. Guidance for clinicians. MMWR Recomm Rep tries. 2003;52:1-28. It is anticipated that the future will bring safe and 23. Meadows KP, Tyring SK, Pavia AT, Rallis TM. Resolution of recal- effective vaccines for a variety of infectious diseases. citrant molluscum contagiosum virus lesions in human immu- Although few vaccines are available for the therapy nodeﬁciency virus–infected patients treated with cidofovir. Arch Dermatol 1997;133:987-90. of infectious diseases, our concept of vaccines is 24. Wharton M, Cochi S, Williams W. Measles, mumps, and rubella now being expanded with ongoing clinical trials of vaccines. Infect Dis Clin North Am 1990;4:47-73. therapeutic vaccines. 25. CDC. Measles, mumps, and rubella: vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps—recommendations of the Ad- REFERENCES visory Committee on Immunization Practices (ACIP). MMWR 1. CDC. Ten great public health achievements: United States, Morb Mortal Wkly Rep 1998;47:1-57. 1900-1999. MMWR Morb Mortal Wkly Rep 1999;48:241-3. 26. Preblud SR. Some issues relating to rubella vaccine. JAMA 2. CDC. Achievements in public health, 1900-1999: impact of vac- 1985;254:253-6. cines universally recommended for children—United States, 27. James JM, Burks AW, Roberson PK, Sampson HA. Safe adminis- 1990-1998. MMWR Morb Mortal Wkly Rep 1999;48:243-8. tration of the measles vaccine to children allergic to eggs. 3. Bonanni P. Demographic impact of vaccination: a review. Vac- N Engl J Med 1995;332:1262-6. cine 1999;17(Suppl 3):S120-5. 28. Gellin BG, Katz SL. Putting a stop to a serial killer: measles. J In- 4. Wright PF, Kim-Farley RJ, de Quadros CA, Robertson SE. Strat- fect Dis 1994;170(Suppl 1):S1-2. egies for the global eradication of poliomyelitis by the year 29. Hope-Simpson RE. Infectiousness of communicable diseases 2000. N Engl J Med 1991;325:1774-9. in the household (measles, chicken pox, and mumps). Lancet 5. Brundtland GH. State of the world’s vaccines and immuniza- 1952;2:549-54. tions. JAMA 2002;288:2532. 30. CDC. Measles eradication: recommendations from a meeting 6. CDC. Measles update: measles activity through week 52 (end- cosponsored by the World Health Organization, the Pan Amer- ing Dec 28, 2002). National Immunization Program 2003;3:1-4. ican Health Organization, and CDC. MMWR Morb Mortal Wkly Rep 1997;46:1-20. 7. Heyward W, MacQueen K, Goldenthal K. HIV vaccine develop- 31. CDC. Measles: United States, 1999. MMWR Morb Mortal Wkly ment and evaluation: realistic expectations. AIDS Res Hum Ret- Rep 2000;49:557-60. roviruses 1998;14(Suppl 3):S205-10. 32. CDC. Measles: United States, 2000. MMWR Morb Mortal Wkly 8. Henderson DA, Moss B. Smallpox and vaccinia. In: Plotkin SA, Rep 2002;51:120-3. Orenstein WA, editors. Vaccines. 3rd ed. Philadelphia: WB 33. CDC. Measles: United States, 2002. MMWR Morb Mortal Wkly Saunders; 1999. p. 74-97. Rep 2003;50:i-xxiv, 1-136. 9. Is smallpox history? Lancet 1999;353:1539. 34. Murray C, Lopez A. Mortality by cause for eight regions of the 10. LeDuc JW, Becher J. Current status of smallpox vaccine. Emerg world: global burden of disease study. Lancet 1997;349:1269- Infect Dis 1999;5:593-4. 76. 11. Roizman B, Joklik W, Fields B, Moss B. The destruction of small- 35. Krause PJ, Cherry JD, Carney JM, Nalditch MJ, O’Connor K. Mea- pox virus stocks in national repositories: a grave mistake and a sles-speciﬁc lymphocyte reactivity and serum antibody in sub- bad precedent. Infect Agents Dis 1994;3:215-7. jects with different measles histories. Am J Dis Child 1980;134: 12. Joklik W. The remaining smallpox virus stocks are too valuable 567-71. to be destroyed. Scientist 1996;10:11. 36. Watson JC, Pearson JA, Markowitz LE, Baughman AL, Erdman 13. Breman JG, Henderson DA. Poxvirus dilemmas: monkeypox, DD, Bellini WJ, et al. An evaluation of measles revaccination smallpox, and biologic terrorism. N Engl J Med 1998;339:556-9. among school-entry-aged children. Pediatrics 1996;97:613-8. 14. Smallpox eradication: destruction of variola virus stocks. Paper 37. Davis RM, Whitman ED, Orenstein WA, Preblud SR, Markowitz presented at: World Health Assembly, May 24, 1999. LE, Hinman AR. A persistent outbreak of measles despite ap- 15. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox propriate control measures. Am J Epidemiol 1987;126:438-49. and its eradication. Geneva (Switzerland): World Health Orga- 38. Krugman S. Further-attenuated measles vaccine: characteris- nization; 1988. tics and use. Rev Infect Dis 1983;5:477-81. 16. Lane JM, Goldstein J. Evaluation of 21st-century risks of small- 39. Mathias RG, Meekison WG, Arcand TA, Schechter MT. The role pox vaccination and policy options. Ann Intern Med 2003;138: of secondary vaccine failures in measles outbreaks. Am J Public 488-93. Health 1989;79:475-8. 17. CDC. Smallpox response plan and guidelines (version 3.0). At- 40. Reyes MA, de Borrero MF, Roa J, Bergonzoli G, Saravia NG. Mea- lanta (GA): U.S. Department of Health and Human Services; sles vaccine failure after documented seroconversion. Pediatr 2002. Infect Dis J 1987;6:848-51. 18. Bicknell W, James K. The new cell culture smallpox vaccine 41. Pelota H, Heinonen OP. Frequency of true adverse reactions to should be offered to the general population. Rev Med Virol measles-mumps-rubella vaccine. A double-blind placebo-con- 2003;13:5-15. trolled trial in twins. Lancet 1986;1:939-42. 520 Wu et al JAM ACAD DERMATOL APRIL 2004

42. CDC. Measles: United States, 1988. MMWR Morb Mortal Wkly 66. Preblud S, Serdula M, Frank JJ, Brandling-Bennet A, Hinman A. Rep 1989;38:601-5. Rubella vaccination in the United States: a ten-year review. Epi- 43. Modlin JF, Jabbour JT, Witte JJ, Halsey NA. Epidemiologic stud- demiol Rev 1980;2:171-94. ies of measles, measles vaccine, and subacute sclerosing pan- 67. Balcarek KB, Bagley MR, Pass RF, Schiff ER, Krause DS. Safety encephalitis. Pediatrics 1977;59:505-12. and immunogenicity of an inactivated hepatitis A vaccine in 44. CDC. Subacute sclerosing panencephalitis surveillance: United preschool children. J Infect Dis 1995;171(Suppl 1):S70-2. States. MMWR Morb Mortal Wkly Rep 1982;31:585-8. 68. Clemens R, Safary A, Hepburn A, Roche C, Stanbury WJ, Andre´ 45. Dyken PR. Subacute sclerosing panencephalitis, current status. FE. Clinical experience with an inactivated hepatitis A vaccine. Neurol Clin 1985;3:179-96. J Infect Dis 1995;171(Suppl 1):S44-9. 46. Hilleman MR, Buynak EB, Weibel RE, Stokes J. Live, attenuated 69. Horng YC, Chang MH, Lee CY, Safary A, Andre´ FE, Chen DS. mumps vaccine. N Engl J Med 1968;278:227-32. Safety and immunogenicity of hepatitis A vaccine in healthy 47. Weibel RE, Stokes J Jr, Buynak EB, Whitman JEJ, Hilleman MR. children. Pediatr Infect Dis J 1993;12:359-62. Live attenuated mumps: virus vaccine. 3. Clinical and serologic 70. Westblom TU, Gudipati S, DeRousse C, Midkiff BR, Belshe RB. aspects in a field evaluation. N Engl J Med 1967;276:245-51. Safety and immunogenicity of an inactivated hepatitis A vac- 48. Sugg WC, Finger JA, Levine RH, Pagano JS. Field evaluation of cine: effect of dose and vaccination schedule. J Infect Dis 1994; live virus mumps vaccine. J Pediatr 1968;72:461-6. 169:996-1001. 49. Chaiken BP, Williams NM, Preblud SR, Parkin W, Altman R. The 71. Block SL, Hedrick JA, Tyler RD, Smith RA, Calandra G, Patterson effect of a school entry law on mumps activity in a school dis- C, et al. Safety, tolerability and immunogenicity of a formalin- trict. JAMA 1987;257:2455-8. inactivated hepatitis A vaccine (VAQTA) in rural Kentucky chil- 50. Kim-Farley R, Bart S, Stetler H, Orenstein WA, Bart K, Sullivan dren. Pediatr Infect Dis J 1993;12:976-80. KM, et al. Clinical mumps vaccine efficacy. Am J Epidemiol 72. Werzberger A, Mensch B, Kuter B, Brown L, Lewis J, Sitrin R, et al. 1985;121:593-7. A controlled trial of a formalin-inactivated hepatitis A vaccine 51. Sullivan KM, Halpin TJ, Marks JS, Kim-Farley R. Effectiveness of in healthy children. N Engl J Med 1992;327:453-7. mumps vaccine in a school outbreak. Am J Dis Child 1985;139: 73. Innis BL, Snitbhan R, Kunasol P, Laorakpongse T, Poopatanak- 909-12. ool W, Kozik CA, et al. Protection against hepatitis A by an in- 52. Wharton M, Cochi SL, Hutcheson RH, Bitowish JM, Schaffner W. activated vaccine. JAMA 1994;271:1328-34. A large outbreak of mumps in the post vaccine era. J Infect Dis 74. CDC. Prevention of hepatitis A through active or passive immu- 1988;158:1253-60. nization: recommendations of the Advisory Committee on Im- 53. Hersh BS, Fine PE, Kent WK, Cochi SL, Kahn LH, Zell ER, et al. munization Practices (ACIP). MMWR Morb Mortal Wkly Rep Mumps outbreak in a highly vaccinated population. J Pediatr 1996;45:1-30. 1991;119:187-93. 75. Wiens BL, Bohidar NR, Pigeon JG, Egan J, Hurni W, Brown L, et 54. CDC. Mumps surveillance: United States, 1988-1993. MMWR al. Duration of protection from clinical hepatitis A disease after Morb Mortal Wkly Rep 1995;44(S-3):1-14. vaccination with VAQTA. J Med Virol 1996;49:235-41. 55. Weibel RE, Buynak EB, McLean AA, Hilleman MR. Persistence of 76. Damme PV, Thoelen S, Cramm M, Groote KD, Safary A, Meheus antibody after administration of monovalent and combined A. Inactivated hepatitis A vaccine: reactogenicity, immunoge- live attenuated measles, mumps, and rubella virus vaccines. nicity, and long-term antibody persistence. J Med Virol 1994; Pediatrics 1978;61:5-11. 44:446-51. 56. Chang TW, DesRosiers S, Weinstein L. Clinical and serologic 77. Wiedermann G, Kundi M, Ambrosch F, Safary A, D’Hondt E, studies of an outbreak of rubella in a vaccinated population. Delem A. Inactivated hepatitis A vaccine: long term antibody N Engl J Med 1970;283:246-8. 57. Bakshi SS, Cooper LZ. Rubella and mumps vaccines. Pediatr persistence. Vaccine 1997;15:612-5. Clin North Am 1990;37:651-68. 78. Nalin DR, Kuter BJ, Brown L, Patterson C, Calandra GB, Werz- 58. Plotkin SA, Farquhar JD, Ogra PL. Immunologic properties of berger A, et al. Worldwide experience with the CR326F-derived RA 27-3 rubella virus vaccine. A comparison with strains pres- inactivated hepatitis A virus vaccine in pediatric and adult pop- ently licensed in the United States. JAMA 1973;225:585-90. ulations: an overview. J Hepatol 1993;18(Suppl 2):S51-5. 59. Gershon AA, Frey HM, Borkowsky W, Steinberg S. Live attenu- 79. Armstrong GL, Mast EE, Wojczynski M, Margolis HS. Childhood ated rubella virus vaccine: comparison of responses to HPV-77- hepatitis B virus infections in the United States before hepatitis DE5 and RA 27/3 strains. Am J Med Sci 1980;279:95-7. B immunization. Pediatrics 2001;108:1123-8. 60. Hilleman M, Weibel R, Buynak E, Stokes JJ, Whitman JJ. Live 80. Douglas RG. The heritage of hepatitis B vaccine. JAMA 1996; attenuated mumps-virus vaccine: 4. Protective efficacy as 276:1796-8. measured in a field evaluation. N Engl J Med 1967;276:252-8. 81. Francis DP, Hadler SC, Thompson SE, Maynard JE, Ostrow DG, 61. Chu SY, Bernier RH, Stewart JA, Herrmann KL, Greenspan JR, Altman N, et al. The prevention of hepatitis B with vaccine. Henderson AK, et al. Rubella antibody persistence after immu- Report of the Centers for Disease Control multicenter efficacy nization: sixteen-year follow-up in the Hawaiian islands. JAMA trial among homosexual men. Ann Intern Med 1982;97:362-6. 1988;259:3133-6. 82. Szmuness W, Stevens CE, Harley EJ, Zang EA, Oleszko WR, Wil- 62. O’Shea S, Best JM, Banatvala JE, Marshall WC, Dudgeon JA. Ru- liam DC, et al. Hepatitis B vaccine: demonstration of efficacy in bella vaccination: persistence of antibodies for up to 16 years. a controlled trial in a high-risk population in the United States. Br Med J (Clin Res Ed) 1982;285:253-5. N Engl J Med 1980;303:833-41. 63. Kimberlin DW. Rubella immunization. Pediatr Ann 83. Katkov WN, Dienstag JL. Hepatitis vaccines. Gastroenterol Clin 1997;26:366-70. North Am 1995;24:147-59. 64. Freestone DS, Prydie J, Smith SG, Laurence G. Vaccination of 84. Denis F, Mounier M, Hessel L, Michel JP, Gualde N, Dubois F, et adults with Wistar RA 27/3 rubella vaccine. J Hyg (Lond) 1971; al. Hepatitis B vaccination in the elderly. J Infect Dis 1984;149: 69:471-7. 1019. 65. Polk BF, Modlin JF, White JA, DeGirolami PC. A controlled com- 85. Heyward WL, Bender TR, McMahon BJ, Hall DB, Francis DP, parison of joint reactions among women receiving one of two Lanier AP, et al. The control of hepatitis B virus infection with rubella vaccines. Am J Epidemiol 1982;115:19-25. vaccine in Yupik Eskimos. Demonstration of safety, immuno- JAM ACAD DERMATOL Wu et al 521 VOLUME 50, NUMBER 4

genicity, and efficacy under field conditions. Am J Epidemiol 105. Poullin P, Gabriel B. Thrombocytopenic purpura after recombi- 1985;121:914-23. nant hepatitis B vaccine. Lancet 1994;334:1293. 86. Roome AJ, Walsh SJ, Cartter ML, Hadler JL. Hepatitis B vaccine 106. Hello CL, Cohen P, Bousser MG, Letellier P, Guillevin L. Sus- responsiveness in Connecticut public safety personnel. JAMA pected hepatitis B vaccination related vasculitis. J Rheumatol 1993;270:2931-4. 1999;26:191-4. 87. Wood RC, MacDonald KL, White KE, Hedberg CW, Hanson M, 107. Allen MB, Cockwell P, Page RL. Pulmonary and cutaneous vas- Osterholm MT. Risk factors for lack of detectable antibody fol- culitis following hepatitis B vaccination. Thorax 1993;48:580-1. lowing hepatitis B vaccination of Minnesota health care work- 108. Pope JE, Stevens A, Howson W, Bell DA. The development of ers. JAMA 1993;270:2935-9. rheumatoid arthritis after recombinant hepatitis B vaccination. 88. Zimmerman RK, Ruben FL, Ahwesh ER. Hepatitis B virus infec- J Rheumatol 1998;25:1687-93. tion, hepatitis B vaccine, and hepatitis B immune globulin. J 109. Rebora A, Rongioletti F, Drago F, Parodi A. Lichen planus as a Fam Pract 1997;45:295-315. side effect of HBV vaccination. Dermatology 1999;198:1-2. 89. Thoelen S, Damme PV, Mathei C, Leroux-Roels G, Desombere I, 110. Saywell CA, Wittal RA, Kossard S. Lichenoid reaction to hepati- Safary A, et al. Safety and immunogenicity of a hepatitis B vac- tis B vaccination. Australas J Dermatol 1997;38:152-4. cine formulated with a novel adjuvant system. Vaccine 1998; 111. Chen DS. Control of hepatitis B in Asia: mass immunization 16:708-14. program in Taiwan. In: Hollinger FB, Lemon SM, Margolis HS, 90. Heineman TC, Clements-Mann NL, Poland GA, Jacobson RM, editors. Viral hepatitis and liver disease. Baltimore: Williams & Izu AE, Sakamoto D, et al. A randomized, controlled study in Wilkins; 1991. p. 716-9. adults of the immunogenicity of a novel hepatitis B vaccine 112. Yeh SH, Ward JI, Partridge S, Marcy SM, Lee H, Jing J, et al. Safety containing MF59 adjuvant. Vaccine 1999;17:2769-78. 91. Jilg W. Novel hepatitis B vaccines. Vaccine 1998;16(suppl): immunogenicity of a pentavalent diphtheria, tetanus, pertus- S65-8. sis, hepatitis B and polio combination vaccine in infants. Pedi- 92. Hourvitz A, Mosseri R, Solomon A, Yehezkelli Y, Atsmon J, atr Infect Dis J 2001;20:973-80. Danon YL, et al. Reactogenicity and immunogenicity of a new 113. Partridge S, Yeh SH. Clinical evaluation of a DTaP-HepB-IPV recombinant hepatitis B vaccine containing Pre S antigens: a combined vaccine. Am J Manag Care 2003;9:S13-22. preliminary report. J Viral Hepat 1996;3:37-42. 114. Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertus- 93. Yap I, Guan R, Chan SH. Recombinant DNA hepatitis B vaccine sis Adsorbed, Hepatitis B (Recombinant) and Inactivates Polio- containing Pre-S components of the HBV coat protein: a pre- virus Vaccine Combined] prescribing information. Rixensart liminary study on immunogenicity. Vaccine 1992;10:439-42. [Belgium]: SmithKline Beecham Biologicals; 2002. 94. Bertino JS, Tirrell P, Greenberg RN, Keyserling HL, Poland GA, 115. CDC. FDA licensure of diphtheria and tetanus toxoids and acel- Gump D, et al. A comparative trial of standard or high-dose S lular pertussis adsorbed, hepatitis B (recombinant), and polio- subunit recombinant hepatitis B vaccine versus a vaccine con- virus vaccine combined (Pediarix) for use in infants. MMWR taining S subunit, Pre-S1, and Pre-S2 particles for revaccination Morb Mortal Wkly Rep 2003;52:203-4. of healthy adult nonresponders. J Infect Dis 1997;175:678-81. 116. Zepp F, Schuind A, Meyer C, Sanger R, Kaufhold A, Willems P. 95. Jilg W, Schmidt M, Deinhardt F. Persistence of specific antibod- Safety and reactogenicity of a novel DTPa-HBV-IPV combined ies after hepatitis B vaccination. J Hepatol 1988;6:201-7. vaccine given along with commercial Hib vaccines in compar- 96. Stevens CE, Taylor FE, Tong MJ, et al. Hepatitis B vaccine: an ison with separate concomitant administration of DTPa, Hib, overview. In: Vyas GN, Dienstag JL, Hoofnagle JH, editors. Viral and OPV vaccines in infants. Pediatrics 2002;109:e58. hepatitis and liver disease. Orlando: Grune & Stratton; 1984. p. 117. CDC. FDA licensure of diphtheria and tetanus toxoids and acel- 275-91. lular pertussis adsorbed, hepatitis B (recombinant), and polio- 97. Hadler S, Francis D, Maynard J, Thompson S, Judson F, Echen- virus vaccine combined (Pediarix) for use in infants. Erratum in: berg D, et al. Long-term immunogenicity and efficacy of hep- MMWR Morb Mortal Wkly Rep 2003;52:379. atitis B vaccine in homosexual men. N Engl J Med 1986;315: 118. CDC. Prevention of varicella: updated recommendations of the 209-14. Advisory Committee on Immunization Practices (ACIP). MMWR 98. Stevens C, Toy P, Taylor P, Lee T, Yip H. Prospects for control of Morb Mortal Wkly Rep 1999;48:1-5. hepatitis B virus infection: implications of childhood vaccina- 119. Arvin AM. Varicella vaccine: the first six years. N Engl J Med tion and long-term protection. Pediatrics 1992;90:170-3. 2001;344:1007-9. 99. CDC. Notice to readers: availability of hepatitis B vaccine that 120. Vazquez M, LaRussa PS, Gershon AA, Steinberg SO, Freudig- does not contain thimerosal as a preservative. MMWR Morb man K, Shapiro ED. The effectiveness of the varicella vaccine in Mortal Wkly Rep 1999;48:780-2. clinical practice. N Engl J Med 2001;344:955-60. 100. Andre F, Safary A. Summary of clinical findings on Engerix-B, a 121. Wise RP, Salive ME, Braun MM, Mootrey GT, Seward JF, Rider LG, genetically engineered yeast derived hepatitis B vaccine. Post- et al. Postlicensure safety surveillance for varicella vaccine. grad Med J 1987;63(Suppl 2):169-78. 101. CDC. Update: vaccine side effects, adverse reactions, contrain- JAMA 2000;284:1271-9. dications and precautions—recommendations of the Advi- 122. White C. Varicella-zoster virus vaccine. Clin Infect Dis 1997;24: sory Committee on Immunization Practices (ACIP). MMWR 753-63. Morb Mortal Wkly Rep 1996;45:1-35. 123. Takahashi M. Clinical overview of varicella vaccine: develop- 102. Andre FE. Overview of 5-year clinical experience with a yeast- ment and early studies. Pediatrics 1986;78:736-41. derived hepatitis B vaccine. Vaccine 1990;8(suppl):74-8. 124. Asano Y, Suga S, Yoshikawa T, Kobayashi I, Yazaki T, Shibata M, 103. Neau D, Bonnet F, Michaud M, Perel Y, Longy-Boursier M, Rag- et al. Experience and reason: twenty-year follow-up of protec- naud JM, et al. Immune thrombocytopenic purpura after re- tive immunity of the Oka strain live varicella vaccine. Pediatrics combinant hepatitis B vaccine: retrospective study of seven 1994;94:524-6. cases. Scand J Infect Dis 1998;30:115-8. 125. Weibel R, Neff B, Kuter B, Guess H, Rothenberger C, Fitzgerald 104. Ronchi F, Cecchi P, Falcioni F, Marsciani A, Minak G, Muratori G, A, et al. Live attenuated varicella virus vaccine. Efficacy trial in et al. Thrombocytopenic purpura as adverse reaction to re- healthy children. N Engl J Med 1984;310:1409-15. combinant hepatitis B vaccine. Arch Dis Child 1998;78:273-4. 126. Kuter B, Weibel R, Guess H, Matthews H, Morton D, Neff B, et al. 522 Wu et al JAM ACAD DERMATOL APRIL 2004

Oka/Merck varicella vaccine in healthy children: final report of 144. Levin M, Murray M, Zerbe G, White C, Hayward A. Immune re- a 2-year efficacy study and 7-year follow-up studies. Vaccine sponses of elderly persons 4 years after receiving a live atten- 1991;9:643-7. uated varicella vaccine. J Infect Dis 1994;170:522-6. 127. Watson BM, Keller PM, Ellis RW, Starr SE. Cell-mediated im- 145. Levin MJ, Barber D, Goldblatt E, Jones M, LaFleur B, Chan C, et mune responses after immunization of healthy seronegative al. Use of a live attenuated varicella vaccine to boost varicella- children with varicella vaccine: kinetics and specificity. J Infect specific immune responses in seropositive people 55 years of Dis 1990;162:794-9. age and older: duration of booster effect. J Infect Dis 1998; 128. White C, Kuter B, Hildebrand C, Isganitis K, Matthews H, Miller 178(Suppl 1):S109-12. W, et al. Varicella vaccine (Varivax) in healthy children and ad- 146. Levin JM. Use of varicella vaccines to prevent herpes zoster in olescents: results from clinical trials, 1987 to 1989. Pediatrics older individuals. Arch Virol Suppl 2001;39:151-60. 1991;87:604-10. 147. Clements DA, Armstrong CB, Ursano AM, Moggio MM, Walter 129. Watson B, Boardman C, Laufer D, Piercy S, Tustin N, Olaleye D, EB, Wilfert CM. Over five-year follow-up of Oka/Merck varicella et al. Humoral and cell-mediated immune responses in healthy vaccine recipients in 465 infants and adolescents. Pediatr In- children after one or two doses of varicella vaccine. Clin Infect fect Dis J 1995;14:874-9. Dis 1995;20:316-9. 148. Bernstein HH, Rothstein EP, Watson BM, Reisinger KS, Blatter 130. Watson B, Gupta R, Randall T, Starr S. Persistence of cell-medi- MM, Wellman CO, et al. Clinical survey of natural varicella com- ated and humoral immune responses in healthy children im- pared with breakthrough varicella after immunization with live munized with live attenuated varicella vaccine. J Infect Dis attenuated Oka/Merck varicella vaccine. Pediatrics 1994;169:197-9. 1993;92:833-7. 131. Asano Y, Nagai T, Miyata T, Yazaki T, Ito S, Yamanishi K, et al. 149. Guess HA, Broughton DD, Melton LJ, Kurland LT. Epidemiology Long-term protective immunity of recipients of the OKA strain of herpes zoster in children and adolescents: a population- of live varicella vaccine. Pediatrics 1985;75:667-71. based study. Pediatrics 1985;76:512-7. 132. White C, Kuter B, Ngai A, Hildebrand C, Isganitis K, Patterson C, 150. Hammerschlag MR, Gershon A, Steinberg S, Clarke L, Gelb L. et al. Modified cases of chickenpox after varicella vaccination: Herpes zoster in an adult recipient of live attenuated varicella correlation of protection with antibody response. Pediatr In- vaccine. J Infect Dis 1989;160:535-7. fect Dis J 1992;11:19-23. 151. Gelb LD, Dohner DE, Gershon AA, Steinberg SP, Waner JL, Ta- 133. Watson B, Piercy S, Plotkin S, Starr S. Modified chickenpox in kahashi M, et al. Molecular epidemiology of live, attenuated children immunized with the Oka/Merck varicella vaccine. Pe- varicella virus vaccine in children and in normal adults. J Infect diatrics 1993;91:17-22. Dis 1987;155:633-40. 134. Watson B, Seward J, Yang A, Witte P, Lutz J, Chan C, et al. Post- 152. White CJ. Clinical trials of varicella vaccine in healthy children. exposure effectiveness of varicella vaccine. Pediatrics Infect Dis Clin North Am 1996;10:595-608. 2000;105:84-8. 153. Leppla S, Robbins J, Schneerson R, Shiloach J. Development 135. Kuter BJ, Ngai A, Patterson CM, Staehle BO, Cho I, Matthews H, of an improved vaccine for anthrax. J Clin Invest 2002;110: et al. Safety, tolerability, and immunogenicity of two regimens 141-4. of Oka/Merck varicella vaccine (Varivax) in healthy adolescents 154. Green BD, Battisti L, Koehler TM, Thorne CB, Ivins BE. Demon- and adults: Oka/Merck Varicella Vaccine Study Group. Vaccine stration of a capsule plasmid in Bacillus anthracis. Infect Immun 1995;13:967-72. 1985;49:291-7. 136. Hardy I, Gershon AA, Steinberg SP, LaRussa P. The incidence 155. Uchida I, Hashimoto K, Terakado N. Virulence and immunoge- of zoster after immunization with live attenuated varicella nicity in experimental animals of Bacillus anthracis strains har- vaccine. A study in children with leukemia. The Varicella bouring or lacking 110 MDa and 60 MDa plasmids. J Gen Mi- Vaccine Collaborative Study Group. N Engl J Med 1991;325: crobiol 1986;132:557-9. 1545-50. 156. Leppla SH. The bifactorial Bacillus anthracis lethal and oedema 137. Heller L, Berglund G, Ahstro¨m L, Hellstrand K, Wahren B. Early toxins. In: Alouf JE, Freer JH, editors. Comprehensive source- results of a trial of the Oka-strain varicella vaccine in children book of bacterial protein toxins. London: Academic Press, with leukaemia or other malignancies in Sweden. Postgrad 1999. p. 243-63. Med J 1985;61(Suppl 4):79-83. 157. Makino S, Uchida I, Terakado N, Sasakawa C, Yoshikawa M. Mo- 138. Gershon A, Steinberg S, Gelb L, Galasso G, Borkowsky W, La- lecular characterization and protein analysis of the cap region, Russa P, et al. Live attenuated varicella vaccine: efficacy for chil- which is essential for encapsulation in Bacillus anthracis. J Bac- dren with leukemia in remission. JAMA 1984;252:355-62. teriol 1989;171:722-30. 139. Tsolia M, Gershon AA, Steinberg SP, Gelb L. Live attenuated 158. Puziss M. Large-scale production of protective antigen of Ba- varicella vaccine: evidence that the virus is attenuated and the cillus anthracis in anaerobic cultures. Appl Microbiol 1963;11: importance of skin lesions in transmission of varicella-zoster 330-4. virus. National Institute of Allergy and Infectious Diseases Vari- 159. Hambleton P, Carman JA, Melling J. Anthrax: the disease in cella Vaccine Collaborative Study Group. J Pediatr 1990;116: relation to vaccines. Vaccine 1984;2:125-32. 184-9. 160. Brachman PS. Field evaluation of a human anthrax vaccine. 140. Hata A, Asanuma H, Rinki M, Sharp M, Wong RM, K KB, et al. Use Am J Public Health 1962;52:632-45. of an inactivated varicella vaccine in recipients of hematopoi- 161. FDA. Biological products: bacterial vaccines and toxoids; im- etic-cell transplants. N Engl J Med 2002;347:26-34. plementation of efficacy review. Proposed rule. Federal Regis- 141. Miller A. Selective decline in cellular immune response to vari- ter 50:1002-117. cella-zoster in the elderly. Neurology 1980;30:582-7. 162. Ministry of Labor (United Kingdom). Report of the Committee 142. Burke BL, Steele RW, Beard OW. Immune responses to varicella- of Inquiry on Anthrax. London: Her Majesty’s Stationery Office, zoster in the aged. Arch Intern Med 1982;142:291-3. 1959. p. 83. 143. Hayward A, Levin M, Wolf W, Angelova G. Varicella-zoster virus- 163. Wright GG, Green TW, Kanode RG. Studies on immunity in an- specific immunity after herpes zoster. J Infect Dis 1991;163: thrax. Immunizing activity of alum-precipitated protective an- 873-5. tigen. J Immunol 1954;73:387-91. JAM ACAD DERMATOL Wu et al 523 VOLUME 50, NUMBER 4

164. Fellows PF, Linscott MK, Ivins BE, Pitt ML, Rossi CA, Gibbs PH, et 182. Fikrig E, Feng W, Aversa J, Schoen RT, Flavell RA. Differential al. Efficacy of a human anthrax vaccine in guinea pigs, rabbits, expression of Borrelia burgdorferi genes during erythema mi- and rhesus macaques against challenge by Bacillus anthracis grans and Lyme arthritis. J Infect Dis 1998;178:1198-201. isolates of diverse geographical origin. Vaccine 183. Schwan TG, Piesman J, Golde WT, Dolan MC, Rosa PA. Induc- 2001;19:3241-7. tion of an outer surface protein on Borrelia burgdorferi during 165. CDC. Biosafety in microbiological and biomedical laboratories. tick feeding. Proc Natl Acad Sci USA 1995;92:2909-13. 4th ed. Washington, DC: US Department of Health and Human 184. da Silva AM, Telford SR, Brunet L, Barthold S, Fikrig E. Borrelia Services; 2000. p. 88-9. burgdorferi OspA is an arthropod-specific transmission-block- 166. Is it safe? Does it work? In: Joellenbeck LM, Zwanziger LL, Durch ing Lyme disease vaccine. J Exp Med 1996;183:271-5. JS, Strom BL, editors. The anthrax vaccine. Washington, DC: 185. da Silva AM, Zeidner N, Zhang Y, Dolan M, Piesman J, Fikrig E. National Academy Press; 2002. p. 265. Influence of outer surface protein A antibody on Borrelia burg- 167. Puziss M, Wright GG. Studies on immunity in anthrax. Gel-ad- dorferi within feeding ticks. Infect Immun 1999;67:30-5. sorbed protective antigen for immunization of man. J Bacteriol 186. Probert WS, Crawford M, Cadiz RB, LeFebvre RB. Immunization 1963;85:230-6. with outer surface protein (Osp) A, but not OspC, provides 168. Pittman PR, Mangiafico JA, Rossi CA, Cannon TL, Gibbs PH, cross-protection of mice challenged with North American iso- Parker GW, et al. Anthrax vaccine: increasing intervals between lates of Borrelia burgdorferi. J Infect Dis 1997;175:400-5. the first two doses enhances antibody response in humans. 187. Fikrig E, Barthold S, Kantor F, Flavell R. Long-term protection of Vaccine 2000;19:213-6. mice from Lyme disease by vaccination with OspA. Infect Im- 169. Turnbull PC, Broster MG, Carman J, Manchee RJ, Melling J. De- mun 1992;60:773-7. velopment of antibodies to protective antigen and lethal fac- 188. Fikrig E, Barthold SW, Kantor FS, Flavell RA. Protection of mice tor components of anthrax toxin in humans and guinea pigs against the Lyme disease agent by immunizing with recombi- and their relevance to protective immunity. Infect Immun nant OspA. Science 1990;250:553-6. 1986;52:356-63. 189. Gern L, Hu CM, Voet P, Hauser P, Lobet Y. Immunization with a 170. Ivins BE, Pitt ML, Fellows PF, Farchaus JW, Benner GE, Waag DM, polyvalent OspA vaccine protects mice against Ixodes ricinus et al. Comparative efficacy of experimental anthrax vaccine tick bites infected by Borrelia burgdorferi ss, Borrelia garinii and Borrelia afzelii. Vaccine 1997;15:1551-7. candidates against inhalation anthrax in rhesus macaques. 190. Golde WT, Burkot TR, Piesman J, Dolan MC, Capiau C, Hauser P, Vaccine 1998;16:1141-8. et al. The Lyme disease vaccine candidate outer surface pro- 171. Welkos S, Little S, Friedlander A, Fritz D, Fellows P. The role of tein A (OspA) in a formulation compatible with human use antibodies to Bacillus anthracis and anthrax toxin components protects mice against natural tick transmission of B. burgdor- in inhibiting the early stages of infection by anthrax spores. feri. Vaccine 1995;13:435-41. Microbiology 2001;147:1677-85. 191. Telford SR, Kantor FS, Lobet Y, Barthold SW, Spielman A, Flavell 172. Brossier F, Levy M, Mock M. Anthrax spores make an essen- RA, et al. Efficacy of human Lyme disease vaccine formulations tial contribution to vaccine efficacy. Infect Immun 2002;70: in a mouse model. J Infect Dis 1995;171:1368-70. 661-4. 192. Fikrig E, Telford SR, Barthold SW, Kantor FS, Spielman A, Flavell 173. Cohen S, Mendelson I, Altboum Z, Kobiler D, Elhanany E, Bino T, RA. Elimination of Borrelia burgdorferi from vector ticks feeding et al. Attenuated nontoxinogenic and nonencapsulated re- on OspA-immunized mice. Proc Natl Acad Sci USA 1992;89: combinant Bacillus anthracis spore vaccines protect against 5418-21. anthrax. Infect Immun 2000;68:4549-58. 193. Chang YF, Appel MJ, Jacobson RH, Shin SJ, Harpending P, 174. Welkos SL, Vietri NJ, Gibbs PH. Non-toxigenic derivatives of the Straubinger R, et al. Recombinant OspA protects dogs against Ames strain of Bacillus anthracis are fully virulent for mice: role infection and disease caused by Borrelia burgdorferi. Infect Im- of plasmid pX02 and chromosome in strain-dependent viru- mun 1995;63:3543-49. lence. Microb Pathog 1993;14:381-8. 194. Van Hoecke C, Comberbach M, De Grave D, Desmons P, Fu D, 175. Barnard JP, Friedlander AM. Vaccination against anthrax with Hauser P, et al. The outer surface protein A (OspA) vaccine attenuated recombinant strains of Bacillus anthracis that pro- against Lyme disease: efficacy in the rhesus monkey. Vaccine duced protective antigen. Infect Immun 1999;67:562-7. 1997;15:1872-87. 176. Hassett DE, Whitton JL. DNA immunization. Trends Microbiol 195. Van Hoecke CV, Comberbach M, De Grave D, Desmons P, Fu D, 1996;4:307-12. Hauser P, et al. Evaluation of the safety, reactogenicity and im- 177. Williamson ED, Beedham RJ, Bennett AM, Miller J, Baillie LW. munologenicity of three recombinant outer surface protein Presentation of protective antigen to the mouse immune sys- (OspA) lyme vaccines in healthy adults. Vaccine tem: immune sequelae. J Appl Microbiol 1999;87:315-7. 1996;14:1620-6. 178. Gu ML, Leppla SH, Klinman DM. Protection against anthrax by 196. Hoecke CV, Lebacq E, Beran J, Parenti D. Alternative vaccina- vaccination with a DNA plasmid encoding anthrax protective tion schedules (0, 1, and 6 months versus 0, 1, and 12 months) antigen. Vaccine 1999;17:340-4. for a recombinant OspA Lyme disease vaccine. Clin Infect Dis 179. Development and testing of vaccines against anthrax. Request 1994;28:1260-4. for proposal. Bethesda (MD): National Institute of Allergy and 197. Steere AC, Sikand VK, Meurice F, Parenti DL, Fikrig E, Schoen RT, Infectious Diseases; 2002. et al. Vaccination against Lyme disease with recombinant Bor- 180. Advisory Committee on Immunization Practices (CDC). Rec- relia burgdorferi outer-surface lipoprotein A with adjuvant. ommendations for the use of Lyme disease vaccine. MMWR N Engl J Med 1998;339:209-15. Morb Mortal Wkly Rep 1999;48:1-25. 198. Schoen RT, Meurice F, Brunet C, Cretella S, Krause DS, Craft JE, 181. Montgomery RR, Malawista SE, Feen KJ, Bockenstedt LK. Direct et al. Safety and immunogenicity of an outer surface protein A demonstration of antigenic substitution of Borrelia burgdorferi vaccine in subjects with previous Lyme disease. J Infect Dis ex vivo: exploration of the paradox of the early immune re- 1995;172:1324-9. sponse to outer surface proteins A and C in Lyme disease. J Exp 199. Sigal LH, Zahradnik JM, Lavin P, Patella SJ, Bryant G, Haselby R, Med 1996;183:261-9. et al. A vaccine consisting of recombinant Borrelia burgdorferi 524 Wu et al JAM ACAD DERMATOL APRIL 2004

outer-surface protein A to prevent Lyme disease. N Engl J Med 218. Holmes SJ, Fritzell B, Guito KP, Esbenshade JF, Blatter MM, Re- 1998;339:216-22. isinger KS, et al. Immunogenicity of Haemophilus influenzae 200. Shadick NA, Liang MH, Phillips CB, Fossel K, Kuntz KM. The cost- type b polysaccharide-tetanus toxoid conjugate vaccine in in- effectiveness of vaccination against Lyme disease. Arch Intern fants. Am J Dis Child 1993;147:832-6. Med 2001;161:554-61. 219. Fritzell B, Plotkin S. Efficacy and safety of a Haemophilus influ- 201. Lastavica CC, Wilson ML, Berardi VP, Spielman A, Deblinger RD. enzae type b capsular polysaccharide-tetanus protein conju- Rapid emergence of a focal epidemic of Lyme disease in gate vaccine. J Pediatr 1992;121:355-62. coastal Massachusetts. N Engl J Med 1989;320:133-7. 220. Paradiso PR, Hogerman DA, Madore DV, Keyserling H, King J, 202. Rahn DW. Lyme vaccine: issues and controversies. Infect Dis Reisinger KS, et al. Safety and immunogenicity of a com- Clin North Am 2001;15:171-87. bined diphtheria, tetanus, pertussis and Haemophilus influ- 203. Peltola H, Kaÿhty H, Sivonen A, Ma¨kela¨ PH. Haemophilus influenzae type b vaccine in young infants. Pediatrics 1993;92: enzae type b capsular polysaccharide vaccine in children: a 827-32. double-blind field study of 100,000 vaccinees 3 months to 5 221. Huang LM, Chang PF, Lee PI, Chiu HH, Tsai SY, Lee CY. Immu- years of age in Finland. Pediatrics 1977;60:730-7. nogenicity and safety of Haemophilus influenzae type b con- 204. Kaÿhty H, Peltola H, Karanko V, Ma¨kela¨ PH. The protective level jugate vaccine (HibTiter) and a combination vaccine of of serum antibodies to the capsular polysaccharide of Hae- diphtheria, tetanus, pertussis and HibTITER (Tetramune) in mophilus influenzae type b. J Infect Dis 1983;147:1100. two-month-old infants. J Microbiol Immunol Infect 1998;31: 205. Eskola J, Peltola H, Takala AK, Kayhty H, Hakulinen M, Karanko 180-6. V, et al. Efficacy of Haemophilus influenzae type b polysaccha- 222. Adams WG, Deaver KA, Cochi SL, Plikaytis BD, Zell ER, ride diphtheria toxoid conjugate vaccine in infancy. N Engl Broome CV, et al. Decline of childhood Haemophilus influen- J Med 1987;317:717-22. zae type b (Hib) disease in the Hib vaccine era. JAMA 1993; 206. Eskola J, Peltola H, Kaÿhty H, Takala AK, Ma¨kela¨ PH. Finnish 269:221-6. efficacy trials with Haemophilus influenzae type b vaccines. J In- 223. Ward JI, Zangwill KM. Haemophilus influenzae vaccines. In: Plot- fect Dis 1992;165(Suppl 1):S137-8. kin SA, Orenstein WA, editors. Vaccines. 3rd ed. Philadelphia: 207. Ward J, Brenneman G, Letson GW, Heyward WL. Limited effi- WB Saunders; 1999. p. 183-221. cacy of a Haemophilus influenzae type b conjugate vaccine in 224. CDC. Progress toward elimination of Haemophilus influen- Alaska Native infants. The Alaska H. influenzae Vaccine Study zae type b disease among infants and children: United Group. N Engl J Med 1990;323:1393-401. States, 1987-1997. MMWR Morb Mortal Wkly Rep 1998;47: 208. Granoff DM. Assessing efficacy of Haemophilus influenzae type 993-8. b combination vaccines. Clin Infect Dis 2001;33(Suppl 4):S278- 225. CDC. Progress toward elimination of Haemophilus influenzae 87. type b invasive disease among infants and children: United 209. CDC. Haemophilus influenzae type b vaccine. MMWR Morb States, 1998-2000. MMWR Morb Mortal Wkly Rep Mortal Wkly Rep 1988;36:832. 2002;51:234-7. 210. CDC. Food and Drug Administration approval of use of a Hae- 226. Booy R, Heath PT, Slack MP, Begg N, Moxon ER. Vaccine failures mophilus b conjugate vaccine for infants. MMWR Morb Mortal after primary immunisation with Haemophilus influenzae Wkly Rep 1990;39:925-6. type-b conjugate vaccine without booster. Lancet 1997;349: 211. CDC. Haemophilus b conjugate vaccines for prevention of Hae- 1197-202. mophilus influenzae type b disease among infants and children 227. Dagan R, Fraser D, Greif Z, Keller N, Kaufstein M, Shazberg G, et two months of age and older: recommendations of the Immu- al. A nationwide prospective surveillance study in Israel to doc- nization Practices Advisory Committee (ACIP). MMWR Morb ument pediatric invasive infections, with an emphasis on Hae- Mortal Wkly Rep 1991;40:1-7. mophilus influenzae type b infections. Israeli Pediatric Bactere- 212. Black SB, Shinefield HR, Fireman B, Hiatt R. Safety, immunoge- mia and Meningitis Group. Pediatr Infect Dis J 1998;17(Suppl nicity, and efficacy in infancy of oligosaccharide conjugate 9):S198-203. Haemophilus influenzae type b vaccine in a United States pop- 228. Gotschlich EC, Goldschneider I, Artenstein MS. Human immu- ulation: possible implications for optimal use. J Infect Dis 1992; nity to the meningococcus IV. Immunogenicity of group A and 165(Suppl 1):S139-43. group C meningococcal polysaccharides. J Exp Med 1969;129: 213. Black S, Shinefield H, Fireman B, Hiatt R, Polen M, Vittinghoff E. 1367-84. Efficacy in infancy of oligosaccharide conjugate Haemophilus 229. Artenstein MS, Gold R, Zimmerly JG, Wyle FA, Schneider H, Har- influenzae type b vaccine in a United States population of kins C. Prevention of meningococcal disease by group C poly- 61,080 children. Pediatr Infect Dis J 1991;10:97-104. saccharide vaccine. N Engl J Med 1970;282:417-20. 214. Santosham M, Wolff M, Reid R, Hohenboken M, Bateman M, 230. Liu TY, Gotschlich EC, Jonssen EK, Wysocki JR. Studies on the Goepp J, et al. The efficacy in Navajo infants of a conjugate meningococcal polysaccharides. I. Composition and chemical vaccine consisting of Haemophilus influenzae type b polysac- properties of the group A polysaccharide. J Biol Chem 1971; charide and Neisseria meningitidis outer-membrane protein 246:2849-58. complex. N Engl J Med 1991;324:1767-72. 231. Makela PH, Peltola H, Kayhty H, Jousimies H, Pettay O, Ruoslahti 215. Daum RS, Granoff DM. Lessons from the evaluation of immu- E, et al. Polysaccharide vaccines of group A Neisseria meningi- nogenicity. In: Ellis RW, Granoff DM, editors. Development and tidis and Haemophilus influenzae type b: a field trial in Finland. clinical uses of Haemophilus b conjugate vaccine. New York: J Infect Dis 1977;136(suppl):S43-50. Marcel Dekker; 1994. p. 291-312. 232. Wahdan MH, Rizk F, el-Akkad AM, el-Ghoroury AA, Hablas R, 216. Decker MD, Edwards KM, Bradley R, Palmer P. Comparative trial Girgis NI, et al. A controlled field trial of a serogroup A menin- in infants of four conjugate Haemophilus influenzae type b vac- gococcal polysaccharide vaccine. Bull World Health Organ cines. J Pediatr 1992;120:184-9. 1973;48:667-73. 217. CDC. FDA approval of use of a new Haemophilus b conjugate 233. Wahdan M, Sallam S, Hassan M, Gawad AA, Rakha A, Sippel J, et vaccine and a combined diphtheria-tetanus-pertussis and al. A second controlled field trial of a serogroup A meningococ- Haemophilus b conjugate vaccine for infants and children. cal polysaccharide vaccine in Alexandria. Bull World Health Or- MMWR Morb Mortal Wkly Rep 1993;42:296-8. gan 1977;55:645-51. JAM ACAD DERMATOL Wu et al 525 VOLUME 50, NUMBER 4

234. Sanborn WR, Bencic Z, Cvjetanovic B, Gotschlich EC, Pollock meningococcal diseases and college students: recommenda- TM, Sippel JE. Trial of a serogroup A meningococcus polysac- tions of the Advisory Committee on Immunization Practices charide vaccine in Nigeria. Prog Immunobiol Stand (ACIP). MMWR Morb Mortal Wkly Rep 2000;49:13-20. 1972;5:497-505. 253. Pediatrics AAo. Meningococcal infections. In: Pickering L, edi- 235. Gold R, Lepow ML, Goldschneider I, Draper TL, Gotschlich EC. tor. Red book. Report of the Committee on Infectious Diseases. Clinical evaluation of group A and group C meningococcal 25th ed. Elk Grove Village (IL): American Academy of Pediatrics; polysaccharide vaccines in infants. J Clin Invest 1975;56:1536- 2000. 47. 254. The Jordan report: accelerated development of vaccines. Be- 236. Gold R, Lepow M, Goldschneider I, Draper T, Gotschlich E. thesda (MD): National Institute of Allergy and Infectious Dis- Antibody responses of human infants to three doses of eases, 1998. group A Neisseria meningitidis polysaccharide vaccine ad- 255. Evans TG, Keefer MC, Weinhold KJ, Wolff M, Montefiori D, Gorse ministered at two, four, and six months of age. J Infect Dis GJ, et al. A canarypox vaccine expressing multiple human im- 1978;138:731-5. munodeficiency virus type 1 genes given alone or with Rgp120 237. Reingold AL, Broome CV, Hightower AW, Ajello GW, Bolan GA, elicits broad and durable CD8ϩ cytotoxic T lymphocyte re- Adamsbaum C, et al. Age-specific differences in duration of sponses in seronegative volunteers. J Infect Dis clinical protection after vaccination with meningococcal poly- 1999;180:290-8. saccharide A vaccine. Lancet 1985;2:114-8. 256. McCarthy M. HIV vaccine fails in phase 3 trial. Lancet 2003;361: 238. Campagne G, Garba A, Fabre P, Schuchat A, Ryall R, Boulanger 755-6. D, et al. Safety and immunogenicity of three doses of a Neisse- 257. Sandsto¨m E, Wahren B. Therapeutic immunisation with recom- ϩ ria meningitidis A C diphtheria conjugate vaccine in infants binant gp160 in HIV-1 infection: a randomised double-blind from Niger. Pediatr Infect Dis J 2000;19:144-50. placebo-controlled trial. Nordic VAC-04 Study Group. Lancet 239. Lepow ML, Goldschneider I, Gold R, Randolph M, Gotschlich 1999;353:1735-42. EC. Persistence of antibody following immunization of chil- 258. Birx DL, Davis C, Ruiz N, et al. Results of a phase II double-blind dren with groups A and C meningococcal polysaccharide vac- multicenter, placebo controlled HIV therapeutic vaccine trial cines. Pediatrics 1977;60:673-80. [abstract]. International Conference on AIDS. Vancouver, July 240. Granoff D, Gupta R, Belshe R, Anderson E. Induction of immu- 1996. Abstract 175. nologic refractoriness in adults by meningococcal C polysac- 259. Tsoukas CM, Raboud J, Bernard NF, et al. Immunization of pa- charide vaccination. J Infect Dis 1998;178:870-4. tients with HIV infection: a study of the effect of VaxSyn, a re- 241. MacDonald NE, Halperin SA, Law BJ, Forrest B, Danzig LE, combinant HIV envelope subunit vaccine, on progression of Granoff DM. Induction of immunologic memory by conju- immune deficiency. AIDS Res Hum Retroviruses 1998;14:483- gated vs plain meningococcal C polysaccharide vaccine in 90. toddlers: a randomized controlled trial. JAMA 260. Graham BS, Matthews TJ, Belshe RB, Clements ML, Dolin R, 1998;280:1685-9. Wright PF, et al. Augmentation of human immunodeficiency 242. Jodar L, Feavers IM, Salisbury D, Granoff DM. Development of virus type 1 neutralizing antibody by priming with gp160 re- vaccines against meningococcal disease. Lancet combinant vaccinia and boosting with rgp160 in vaccinia-na- 2002;359:1499-508. ¨veı adults. J Infect Dis 1993;167:533-7. 243. Ramsay ME, Andrews N, Kaczmarski EB, Miller E. Efficacy of me- 261. Frey SE. HIV vaccines. Infect Dis Clin North Am 1999;13:95- ningococcal serogroup C conjugate vaccine in teenagers and 112. toddlers in England. Lancet 2001;357:195-6. 262. Oxford JS, Addawe M, Lambkin R. AIDS vaccine develop- 244. Swartley JS, Marfin AA, Edupuganti S, Liu LJ, Cieslak P, Perkins B, et al. Capsule switching of Neisseria meningitidis. Proc Natl ment: let a thousand flowers bloom. J Clin Pathol 1998;51:725- Acad Sci USA 1997;94:271-6. 30. 245. Maiden MC, Spratt BG. Meningococcal conjugate vaccines: 263. Clements-Mann ML, Weinhold K, Matthews TJ, Graham BS, new opportunities and new challenges. Lancet Gorse GJ, Keefer MC, et al. Immune responses to human immu- 1999;354:615-6. nodeficiency virus (HIV) type 1 induced by canarypox express- 246. Vogel U, Claus H, Frosch M. Rapid serogroup switching in Neis- ing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both seria meningitidis. N Engl J Med 2000;342:219-20. vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation 247. Anderson EL, Bowers T, Mink CM, Kennedy DJ, Belshe RB, Hara- Group. J Infect Dis 1998;177:1230-46. keh H, et al. Safety and immunogenicity of meningococcal A 264. Belshe RB, Stevens C, Gorse G, et al. Phase II evaluation of a live and C polysaccharide conjugate vaccine in adults. Infect Im- recombinant canarypox (AVLAC) vector HIV-1 vaccine with or mun 1994;62:3391-5. without gp120 subunit HIV-1 vaccine [abstract]. International 248. Lieberman JM, Chiu SS, Wong VK, Partidge S, Chang SJ, Chiu Society for Sexually Transmitted Diseases Research; July 11-14, CY, et al. Safety and immunogenicity of a serogroup A/C Neis- 1999; Denver, CO. Abstract 227. seria meningitidis oligosaccharide-protein conjugate vaccine 265. Ferrari G, Humphrey W, McElrath MJ, Excler JL, Duliege AM, in young children. JAMA 1996;275:1499-503. Clements ML, et al. Clad B-based HIV-1 vaccines elicit cross- 249. Fairley CK, Begg N, Borrow R, Fox AJ, Jones DM, Cartwright K. clade cytotoxic T lymphocyte reactivities in uninfected volun- Conjugate meningococcal serogroup A and C vaccine: reacto- teers. Proc Natl Acad Sci USA 1997;94:1396-401. genicity and immunogenicity in United Kingdom infants. J In- 266. Evans T, Corey L, Clements-Mann ML, et al. CD8ϩCTL induced fect Dis 1996;174:1360-3. in AIDS Vaccine Evaluation Group phase I trials using canary- 250. Rosenstein N, Levine O, Taylor JP. Efficacy of meningococcal pox vectors (ALVAC) encoding multiple HIV gene products vaccine and barriers to vaccination. JAMA 1998;279:435-9. (vCP125, vCP205, vCP300) given with or without subunit 251. Meningococcal disease prevention and control strategies for boost. Paper presented at: World AIDS Conference; June 28- practice-based physicians (addendum: recommendations for July 3, 1998; Geneva, Switzerland. college students). Committee on Infectious Diseases. Pediat- 267. Doepel LK. NIAID opens first AIDS vaccine trial in Africa. NIAID rics 2000;106:1500-4. News. National Institute of Allergy and Infectious Diseases, 252. CDC. Prevention and control of meningococcal disease and February 8, 1999. 526 Wu et al JAM ACAD DERMATOL APRIL 2004

268. Rose NF, Marx PA, Luckay A, Nixon DF, Moretto WJ, Donahoe sented at: International Papillomavirus Conference; January SM, et al. An effective AIDS vaccine based on live attenuated 9-15, 1999; Charleston [SC]. vesicular stomatitis virus recombinants. Cell 2001;106:539- 284. Silva DD, Nieland J, Greenstone H, Schiller J, Kast W. Chimeric 49. papillomavirus virus-like particles induce antigen-specific 269. Stephenson J. In HIV vaccine efforts, new strategies and pa- therapeutic immunity against tumours expressing the HPV-16 tience are needed in equal measure. JAMA 2002;288:2671-2. E7 protein. Paper presented at: International Papillomavirus 270. Boyer JD, Ugen KE, Wang B, Agadjanyan M, Gilbert L, Bagarazzi Conference; January 9-15, 1999; Charleston [SC]. ML, et al. Protection of chimpanzees from high-dose heterolo- 285. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, gous HIV-1 challenge by DNA vaccination. Nature Med 1997;3: et al. A controlled trial of a human papillomavirus type 16 vac- 526-32. cine. N Engl J Med 2002;347:1645-51. 271. Frank SB. Formulized herpes virus therapy and neutralizing 286. Borysiewicz LK, Fiander A, Nimako M, Man S, Wilkinson GW, substance in herpes simplex. J Invest Dermatol 1938;1:267- Westmoreland D, et al. A recombinant vaccinia virus encod- 82. ing human papillomavirus types 16 and 18, E6 and E7 pro- 272. Straus S, Wald A, Kost R, McKenzie R, Langenberg A, Hohman P, teins as immunotherapy for cervical cancer. Lancet 1996; et al. Immunotherapy of recurrent genital herpes with recom- 347:1523-7. binant herpes simplex virus type 2 glycoproteins D and B: re- 287. Lacey CJ, Monteiro EF, Thompson HS, et al. A phase IIa study of sults of a placebo-controlled vaccine trial. J Infect Dis 1997;176: a therapeutic vaccine for genital warts. Paper presented at: 1129-134. Medical Society for the Study of Venereal Disease; July 1997; 273. Corey L, Langenberg AG, Ashley R, Sekulovich RE, Izu AE, Doug- Oxford, England. las JM, et al. Recombinant glycoprotein vaccine for the preven- 288. Duggan-Keen MF, Brown MD, Stacey SN, Stern PL. Papilloma- tion of genital HSV-2 infection: two randomized controlled tri- virus vaccines. Front Biosci 1998;3:1192-208. als. JAMA 1999;282:331-40. 289. Nardelli-Haefliger D, Roden RB, Benyacoub J, Sahli R, Kraehen- 274. Leroux-Roels G, Moreau E, Desombere I, et al. Safety, hu- buhl JP, Schiller JT, et al. Human papillomavirus type 16 virus- moral and cellular immune responses of three different like particles expressed in attenuated Salmonella typhimurium doses of glycoprotein D(gD2t) in herpes simplex vaccine elicit mucosal and systemic neutralizing antibodies in mice. with aluminum and MPL. Paper presented at: Interscience Infect Immun 1997;65:3328-36. 290. Jensen ER, Selvakumar R, Shen H, Ahmed R, Wettstein FO, Conference on Antimicrobial Agents and Chemotherapy; Miller JF. Recombinant Listeria monocytogenes vaccination 1997; New Orleans. eliminates papillomavirus-induced tumors and prevents 275. Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Min- papilloma formation from viral DNA. J Virol 1997;71:8467- del A, Sacks S, et al. GlaxoSmithKline Herpes Vaccine Efficacy 74. Study Group. Glycoprotein-D-adjuvant vaccine to prevent 291. Krul M, Tijhaar E, Kleijne J, Loon AV, Nievers M, Schipper H. genital herpes. N Engl J Med 2002;347:1652-61. Induction of an antibody response in mice against human pap- 276. Boursnell ME, Entwisle C, Blakely D, Roberts C, Duncan IA, illomavirus (HPV) type 16 after immunization with HPV recom- Chisholm SE, et al. A genetically inactivated herpes simplex binant Salmonella strains. Cancer Immunol Immunother 1996; virus type 2 (HSV-2) vaccine provides effective protection 43:44-8. against primary and recurrent HSV-2 disease. J Infect Dis 1997; 292. Ossevoort MA, Feltkemp MC, VanVeen KJ, Melief CJ, Kast 175:16-25. WM. Dendritic cells as carriers for a cytotoxic T-lymphocyte 277. McLean CS, Challanin DN, Duncan I, Boursnell ME, Jennings R, epitope-based peptide vaccine in protection against a hu- Inglis SC. Induction of a protective immune response by mu- man papillomavirus type 16-induced tumor. J Immunother cosal vaccination with a DISC HSV-1 vaccine. Vaccine 1996;14: 1995;18:86-94. 987-92. 293. Sanders GD, Taira AV. Cost effectiveness of a potential vac- 278. McClements WL, Armstrong ME, Keys RD, Liu MA. Immuniza- cine for human papillomavirus. Emerg Infect Dis 2003;9:37- tion with DNA vaccines encoding glycoprotein D or glycopro- 48. tein B, alone or in combination, induces protective immunity in 294. Kong YC, Levine HB. Experimentally induced immunity in the animal models of herpes simplex virus-2 disease. Proc Natl mycoses. Bacteriol Rev 1967;31:35-53. Acad Sci USA 1996;93:11414-20. 295. Neely MN, Ghannoum MA. The exciting new future of anti- 279. Rouse BT, Nair S, Rouse RJ, Yu Z, Kuklin N, Karem K, et al. DNA fungal therapy. Eur J Clin Microbiol Infect Dis 2000;19:897- vaccines and immunity to herpes simplex virus. Curr Top Mi- 914. crobiol Immunol 1998;226:69-78. 296. Casadevall A, Cassone A, Bistoni F, Cutler JE, Magliani W, 280. Meignier B, Longnecker R, Roizman R. In vivo behavior of ge- Murphy JW, et al. Antibody and/or cell-mediated immunity, netically engineered herpes simplex viruses R7017 and R 7020: protective mechanisms in fungal disease: an ongoing di- construction and evaluation in rodents. J Infect Dis 1988;58: lemma or an unnecessary dispute? Med Mycol 1998;36(Suppl 602-14. 1):95-105. 281. Cadoz M, Micoud M, Seigneurin JM. Phase I trial of R7020: a 297. Deepe GS. Prospects for the development of fungal vaccines. live-attenuated recombinant herpes simplex virus (HSV) can- Clin Microbiol Rev 1997;10:585-96. didate vaccine. Paper presented at: Interscience Conference 298. Bistoni F, Vecchiarelli A, Cenci E, Puccetti P, Marconi P, Cas- on Antimicrobial Agents and Chemotherapy; 1992; Anaheim sone A. Evidence for macrophage-mediated protection [CA]. againstlethalCandidaalbicansinfection.InfectImmun1986; 282. Reichman R, Balsley J, Carlin D, et al. Evaluation of the safety 51:668-74. and immunogenicity of a recombinant HPV-11 L1 virus like 299. Cassone A, Boccanera M, Adriani D, Santoni G, Bernardis FD. particle vaccine in healthy adult volunteers. Paper presented Rats clearing a vaginal infection by Candida albicans acquire at: International Papillomavirus Conference; January 9-15, specific, antibody-mediated resistance to vaginal reinfection. 1999; Charleston [SC]. Infect Immun 1995;63:2619-24. 283. Zhang LF, Zhou J, Shao C, et al. A phase 1 trial of HPV 6 B virus 300. Fidel PL, Sobel JD. Protective immunity in experimental Can- like particles as immunotherapy for genital warts. Paper pre- dida vaginitis. Res Immunol 1998;149:361-73. JAM ACAD DERMATOL Wu et al 527 VOLUME 50, NUMBER 4

301. Bernardis FD, Boccanera M, Adriani DA, Spreghini E, Santoni protective against experimental visceral leishmaniasis. Infect G, Cassone A. Protective role of antimannan and anti-aspar- Immun 2001;69:4719-25. tyl proteinase antibodies in an experimental model of Can- 322. Gurunathan S, Wu C, Freidag BL, Seder RA. DNA vaccines: a key dida albicans vaginitis in rats. Infect Immun 1997;65:3399- for inducing long-term cellular immunity. Curr Opin Immunol 409. 2000;12:442-7. 302. Han Y, Morrison RP, Cutler JE. A vaccine and monoclonal anti- 323. Klinman DM, Takeshita F, Kamstrup S, Takeshita S, Ishii K, Ichino bodies that enhance mouse resistance to Candida albicans M, et al. DNA vaccines: capacity to induce auto-immunity and vaginal infection. Infect Immun 1998;66:5771-76. tolerance. Dev Biol 2000;104:45-51. 303. Mencacci A, Torosantucci A, Spaccapelo R, Romani L, Bistoni F, 324. Mor G, Eliza M. Plasmid DNA vaccines. Immunology, tolerance Cassone A. A mannoprotein constituent of Candida albicans and autoimmunity. Mol Biotechnol 2001;19:245-50. that elicits different levels of delayed-type hypersensitivity, cy- 325. Ivens AC, Blackwell JM. The Leishmania genome comes of age. tokine production, and anticandidal protection in mice. Infect Parasitol Today 1999;15:225-31. Immun 1994;62:5353-60. 326. Dickler HB, Gelfand EW. Current perspectives on the use of 304. Mizutani S, Endo M, Ino-ve T, Kurosawa M, Uno Y, Saito H, et al. intravenous immunoglobulin. Adv Intern Med 1996;41:641-80. CD4-T-cell-mediated resistance to systemic candidiasis in- 327. CDC. Renal insufficiency and failure associated with immune duced by a membrane fraction of Candida albicans. Antimi- globulin intravenous therapy: United States, 1985-1998. crob Ag Chemother 2000;44:2653-8. MMWR Morb Mortal Wkly Rep 1999;48:518-21. 305. Cardenas-Freytag L, Cheng E, Mayeux P, Domer JE, Clements 328. Bean B. Antiviral therapy: current concepts and practices. Clin JD. Effectiveness of a vaccine composed of heat-killed Candida Microbiol Rev 1992;5:146-82. albicans and a novel mucosal adjuvant, LT(R192G), against sys- 329. Bernstein LJ, Krieger BZ, Novick B, Sicklick MJ, Rubinstein A. temic candidiasis. Infect Immun 1999;67:826-33. Bacterial infections in the acquired immunodeficiency syn- 306. Han Y, Cutler JE. Antibody response that protects against dis- drome of children. Pediatr Infect Dis J 1985;4:472-5. seminated candidiasis. Infect Immun 1995;63:2714-9. 330. Calvelli TA, Rubinstein A. Intravenous gamma-globulin in in- 307. Han Y, Ulrich MA, Cutler JE. Candida albicans mannan extract- fant acquired immunodeficiency syndrome. Pediatr Infect Dis J protein conjugates induce a protective immune response 1986;5(Suppl 3):S207-10. against experimental candidiasis. J Infect Dis 1999;179:1477- 331. Gupta A, Novick BE, Rubinstein A. Restoration of suppressor 84. T-cell functions in children with AIDS following intravenous 308. Devi SJ. Preclinical efficacy of a glucuronoxylomannan-tetanus gamma globulin treatment. Am J Dis Child 1986;140:143-6. toxoid conjugate vaccine of Cryptococcus neoformans in a mu- 332. Oleski JM, Connor EM, Bohila R, et al. Treatment of immunode- rine model. Vaccine 1996;14:841-4. ficiency virus antibody positive children with intravenous im- 309. Mukherjee J, Zuckier LS, Scharff MD, Casadevall A. Therapeutic munoglobulin. Vox Sang 1987;52:162-75. efficacy of monoclonal antibodies to Cryptococcus neoformans 333. Spector SA, Gelber RD, McGrath N, Wara D, Barzilai A, Abrams E, glucuronoxylomannan alone and in combination with am- et al. Controlled trial of intravenous immune globulin for the photericin B. Antimicrob Agents Chemother 1994;38:580-7. prevention of serious bacterial infections in children receiving 310. Ghannoum MA. Potential role of phospholipases in virulence zidovudine for advanced human immunodeficiency virus in- and fungal pathogenesis. Clin Microbiol Rev 2000;13:122-43. fection. N Engl J Med 1994;331:1181-7. 311. Hanel H, Kirsch R, Schmidts HL, Kottmann H. New systemati- 334. Hadler SC, Erben JJ, Matthews D, Starko K, Francis DP, Maynard cally active antimycotics from the beta-blocker category. My- JE. Effect of immunoglobulin on hepatitis A in day-care cen- coses 1995;38:251-64. ters. JAMA 1983;249:48-53. 312. Tesh RB. Control of zoonotic visceral leishmaniasis: is it time to change strategies? Am J Trop Med Hyg 1995;52:287-92. 335. Krugman S, Ward R, Giles JP, Jacobs AM. Infectious hepatitis. 313. Dye C. The logic of visceral leishmaniasis control. Am J Trop Studies on the effect of gamma globulin and on the incidence Med Hyg 1996;55:125-30. of inapparent infection. JAMA 1960;174:883-90. 314. Handman E. Leishmaniasis: current status of vaccine develop- 336. Woodson RD, Clinton JJ. Hepatitis prophylaxis abroad. JAMA ment. Clin Microbiol Rev 2001;14:229-43. 1976;209:1053-9. 315. Schallig HD, Oskam L. Molecular biological applications in the 337. Lauchart W, Muller R, Pichlmayr R. Immunoprophylaxis of hep- diagnosis and control of leishmaniasis and parasite identifica- atitis B viral reinfection in recipients of human liver allografts. tion. Trop Med Int Health 2002;7:641-51. Transplant Proc 1987;19:2387-9. 316. Ulmer JB, Sadoff JC, Liu MA. DNA vaccines. Curr Opin Immunol 338. Samuel D, Bismuth A, Mathieu D, Arulnaden JL, Reynes M, 1996;8:531-6. Benhamou JP, et al. Passive immunoprophylaxis after liver 317. Wahren B. Gene vaccines. Immunotechnology 1996;2:77-83. transplantationinHBsAg-positivepatients.Lancet1991;337: 318. Hassan UA, Abai AM, Harper DR, Wren BW, Morrow WJ. Nucleic 813-5. acid immunization: concepts and techniques associated with 339. Grellier L, Dusheiko GM. Hepatitis B virus and liver transplanta- third generation vaccines. J Immunol Methods 1999;229:1-22. tion: concepts in antiviral prophylaxis. J Viral Hepat 1997; 319. Walker PS, Scharton-Kersten T, Rowton ED, Hengge U, Bouloc 4(Suppl 1):111-6. A, Udey MC, et al. Genetic immunization with glycoprotein 63 340. CDC. Prevention of varicella: recommendations of the Advi- cDNA results in a T helper cell type 1 response and protection sory Committee on Immunization Practices (ACIP). MMWR in a murine model of leishmaniasis. Hum Gene Ther 1998;9: Morb Mortal Wkly Rep 1996;45:1-36. 1899-907. 341. Burks AW, Sampson HA, Buckley RH. Anaphylactic reactions 320. Gurunathan S, Sacks DL, Brown DR, Reiner SL, Charest H, after gamma globulin administration in patients with hypo- Glaichenhaus N, et al. Vaccination with DNA encoding the im- gammaglobulinemia. Detection of IgE antibodies to IgA. munodominant LACK parasite antigen confers protective im- N Engl J Med 1986;314:560-3. munity to mice infected with Leishmania major. J Exp Med 342. IVIG transmission of hepatitis C. FDA Med Bull 1994;24:3-4. 1997;186:1137-47. 343. Maldonado YA. Current controversies in vaccination: vaccine 321. Melby PC, Yang J, Zhao W, Perez LE, Cheng J. Leishmania dono- safety. JAMA 2002;288:3155-8. vani p36 (LACK) DNA vaccine is highly immunogenic but not 344. Murray CJ, Lopez AD. Global mortality, disability, and the con- 528 Wu et al JAM ACAD DERMATOL APRIL 2004

tribution of risk factors: Global Burden of Disease Study. Lancet 352. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, 1997;349:1436-42. Thorsen P, et al. A population-based study of measles, mumps, 345. National Center for Health Statistics. National vital statistics and rubella vaccination and autism. N Engl J Med 2002;347: system for numbers of death. Washington, DC: US Bureau of 1477-82. Census; 2001. 353. Ascherio A, Zhang SM, Hernan MA, Olek MJ, Coplan PM, 346. Davies P, Chapman S, Leask J. Antivaccination activists on the Brodovicz K, et al. Hepatitis B vaccination and the risk of multi- world wide web. Arch Dis Child 2002;87:22-5. ple sclerosis. N Engl J Med 2001;344:327-32. 347. Wolfe RM, Sharp LK, Lipsky MS. Content and design attributes 354. Confavreux C, Suissa S, Saddier P, Bourdes V, Vukusic S. Vacci- of antivaccination web sites. JAMA 2002;287:3245-8. nations and the risk of relapse in multiple sclerosis. Vaccines in 348. Lieu TA, Cochi SL, Black SB, Halloran ME, Shineﬁeld HR, Holmes Multiple Sclerosis Study Group. N Engl J Med 2001;344:319-26. SJ, et al. Cost-effectiveness of a routine varicella vaccination 355. Karvonen M, Cepaitis Z, Tuomilehto J. Association between program for US children. JAMA 1994;271:375-81. type 1 diabetes and Haemophilus inﬂuenzae type b vaccina- 349. Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, et al. Intussusception among infants given an tion: birth cohort study. BMJ 1999;318:1169-72. oral rotavirus vaccine. N Engl J Med 2001;344:564-72. 356. Graves PM, Barriga KJ, Norris JM, Hoffman MR, Yu L, Eisenbarth GS, 350. Dales L, Hammer SJ, Smith NJ. Time trends in autism and in et al. Lack of association between early childhood immunizations MMR immunization coverage in California. JAMA 2001;285: and beta-cell autoimmunity. Diabetes Care 1999;22:1694-7. 1183-5. 357. Tacket CO, Mason HS, Losonsky G, Clements JD, Levine MM, Arn- 351. Kaye JA, Melero-Montes MdM, Jick H. Mumps, measles, and tzen CJ. Immunogenicity in humans of a recombinant bacterial rubella vaccine and the incidence of autism recorded by antigen delivered in a transgenic potato. Nat Med 1998;4:607-9. general practitioners: a time trend analysis. BMJ 2001;322: 358. Arakawa T, Langridge WH. Plants are not just passive creatures! 460-3. Nat Med 1998;4:550-1.