INTRODUCTION

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The prevention of infection in patients with impaired immunity is paramount for the success of therapies for malignancy, autoimmune diseases, and AIDS. Vaccination is an attractive means to realize this end, but infections in patients with impaired immunity present a formidable challenge. The course of infections in these individuals can be more aggressive than in normal hosts; e.g., varicella infection, a benign disease of childhood, has a mortality rate of up to 10% in children with leukemia. Also, antimicrobial therapy can be less effective in individuals with impaired immunity, because the contribution of underlying host defense mechanisms is absent. Many infections in patients with impaired immunity are incurable despite the administration of microbicidal therapy; e.g., infections with the fungi Cryptococcus neoformans, Coccidiodes immitis, and Histoplasma capsulatum are difficult to cure in patients with AIDS. They can be suppressed with powerful antifungal drugs, but lifelong suppressive therapy is required to prevent relapses. Some infections in hosts with impaired immunity, e.g., those caused by Streptococcus pneumoniae, may be of similar severity to those with normal immunity, but they may be recurrent and necessitate frequent courses of antibiotic therapy. In this regard, the extensive use of antibiotics for treatment and prophylaxis in patients with impaired immunity may be playing a role in the emergence of drug-resistant organisms.

Many vaccines now under development target specific pathogens that cause infections in patients with impaired immunity. For example, a conjugate vaccine has been made against C. neoformans (73, 74), which is a pathogen almost exclusively in patients with impaired immunity. However, nearly all of the licensed vaccines in use today were developed for administration to individuals with normal immunity, and assessment of their immunogenicity was carried out exclusively in normal hosts. Therefore, there are many unresolved questions about the feasibility of using existing vaccines to prevent infectious diseases in patients with impaired immunity. This review summarizes the experience with licensed vaccines in various populations with underlying immune defects. Our goal was to assess the immunogenicity of commonly used vaccines in those with impaired immunity and to illustrate important issues, problems, and potential solutions related to the use of these agents in this patient population.

TERMINOLOGY

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Impaired Immunity

Although human populations have probably always included some individuals with immune disorders, the concept that patients with impaired immunity represent a specific group did not evolve until the late 20th century. Advances in the therapy of neoplastic diseases and the use of corticosteroids have led to the emergence of specific patient populations with chronically depressed immune function who are at high risk for both opportunistic and nonopportunistic infections. The human immunodeficiency virus (HIV) pandemic, which was recognized in 1981, has resulted in unprecedented numbers of patients who have developed severely impaired immune function. Armstrong has eloquently described the origins of various terms used to describe patients with impaired immunity, including compromised host, immunodeficiency, and immunocompromised host (17). We have chosen to use the phrase "individual with impaired immunity" because it encompasses a broad range of individuals who are at risk for infections as a result of immunological dysfunction.

"Impaired immunity" refers to any condition that decreases immune system function. The immune response is extraordinarily complex, and many aspects of immune system function remain poorly understood despite a century of intense study. In general, the immune system can be divided into two main arms: specific and nonspecific immunity. Specific immunity refers to the ability of the host to mount an immune response to discrete antigenic determinants of particular pathogens and/or vaccines. For example, an episode of mumps or vaccination with the mumps vaccine will elicit specific immunity to mumps that will not protect against other microbes. The immune system components responsible for specific immunity are B and T lymphocytes. Nonspecific immunity refers to complex humoral and cellular mechanisms by which the host can protect against microbial pathogens without the requirement for recognition of specific antigenic determinants. Some infections may be cleared by macrophages and neutrophils with the help of complement-derived opsonins without eliciting a measurable antibody or T-cell response. Nonspecific humoral mechanisms include complement and serum iron-binding proteins, and nonspecific antimicrobial effector cells include macrophages, neutrophils, NK cells, eosinophils, and platelets.

A problem in defining and understanding the host with impaired immunity is that the human population is outbred and genetically diverse. The genetic diversity of the human population contributes to variability in immune responses to pathogens and vaccines. In some instances, impaired responses to certain antigens result from genetic factors. In this regard, the affected individuals manifest impaired immunity to a specific pathogen or vaccine but are otherwise normal. For example, a subset of the human population will not respond to hepatitis B immunization despite having no apparent immune system defect that would predispose them to more severe infections, possibly because of their genetic background (see below). These individuals are not immunodeficient in the common use of this term but do have impaired immunity to hepatitis B surface antigen. The inability of certain individuals to respond to particular antigens and infections is a price of genetic diversity which provides survival insurance for the species. For the purposes of this review, the term "impaired immunity" will be used only to refer to conditions that predispose an individual to an increased risk of infection.

This review is concerned primarily with vaccines that are licensed for use in the United States. The decision to limit the scope as such was based on the fact that because the licensing process requires extensive studies, a significant amount of information on the efficacy and safety of each vaccine is available. Table 1 lists the currently licensed vaccines with their type and recommended route of administration.

All therapy including vaccine administration involves a risk-benefit decision. For most vaccines, the benefit greatly outweighs the risk, but these parameters are usually defined in the context of a normal host. Patients with impaired immunity are usually at greater risk from both infection and vaccination. For example, chickenpox is usually a benign disease of childhood caused by varicella virus, but it caused significant mortality in children with lymphoproliferative malignancies before antiviral therapy was available. The varicella vaccine is highly effective in normal children. In children with impaired immunity who are at great risk for severe varicella infections, the vaccine is less effective and has more severe side effects, but it is nevertheless still useful because it can reduce the morbidity and mortality associated with wild-type virus infection. Hence, vaccine efficacy in the patient with impaired immunity involves a risk-benefit assessment that is different from that for healthy populations. In general, pathogen inactivated, toxoid, and subunit vaccines pose little or no risk to individuals with impaired immunity, and the benefits of such vaccines far outweigh their risk. Conversely, most live vaccines are contraindicated in patients with impaired immunity. One notable exception is that the varicella vaccine is recommended for children with acute lymphocytic leukemia but not HIV infection or other malignancies (64).

The risk-benefit algorithm for vaccine use in patients with impaired immunity is dependent on the prevalence and severity of infection with the particular pathogen, the nature of the underlying host immune defect, and the efficacy and safety of the vaccine. For example, the worldwide eradication of smallpox indicates no benefit to continued use of vaccinia virus. For most vaccines, the risk-benefit algorithm is complex and involves choices between acceptable risk and expected benefits.

Many patients at high risk for vaccine-preventable infections are poor responders to immunization because of their underlying immune defect and/or the weak immunogenicity of some vaccines. An option for enhancing the immune response to some vaccines is to use adjuvants which can augment the immune response to an antigen. Vaccine adjuvants are a widely diverse group of reagents that include aluminum compounds, oil emulsions, plant products, bacterial products, biopolymers, and natural immunomodulators such as cytokines (for reviews, see references 117 and 201). A persistent problem in adjuvant development has been uncertainty as to their safety.

The only adjuvants currently approved for human use are aluminum compounds. The aluminum adjuvant, often referred to as Alum, is a complex mixture of aluminum compounds including aluminum phosphate and aluminum hydroxide (117). Aluminum compounds are effective in increasing antibody responses to some antigens but have little or no effect on cell-mediated immune responses (117). The mechanism of action of aluminum adjuvants appears to involve a combination of enhanced immunogenicity by serving as antigen depots (in particular for the toxoids) and effects on antigen-presenting cells (117). At present, other adjuvants, such as Quil (72), monophosphoryl lipid (124), and others (24, 117), are being investigated for human use.

In recent years, there has been considerable interest in the potential of cytokines to function as vaccine adjuvants (201). The use of cytokines is attractive because these peptides are natural products of the immune system that have the potential to modulate specific immune functions. The ability of cytokines to shift an immune response toward a cell-mediated or humoral response suggests their potential to enhance specific areas of immunity. Cytokines could be particularly useful adjuvants in patients with impaired immunity who have defects in activation of antigen-specific cells. At present, the use of cytokine adjuvants for vaccine efficacy is a research tool, and a considerable amount of basic and clinical research remains to be done before the efficacy of cytokines or other immunomodulators as vaccine adjuvants is established.

The potential of the adrenal hormone dihydroepiandrosterone sulfate (DHEAS) to function as an adjuvant in the elderly is being explored (15, 96). Available data suggest that DHEAS can augment the primary antibody responses of elderly mice (15, 96). Clinical information that is available from humans who were immunized with DHEAS and the 1994 to 1995 trivalent influenza vaccine suggest that the number of individuals who can generate primary antibody responses to new antigens is increased by DHEAS (15). A study of elderly mice demonstrated that DHEAS administration enhanced the immunogenicity of a polyvalent pneumococcal polysaccharide vaccine (96). Although the elderly manifest decreased antibody responses to many vaccines (172), we have not included this population in this review because their defects in antibody formation are heterogeneous, poorly understood, and a function of immunosenescence rather than primary or exogenously induced immune system dysfunction.

Although there is considerable interest in developing new adjuvants, the efficacy of these compounds in patients with impaired immunity is unknown. Since immune responses in normal and immunocompromised individuals may be qualitatively and quantitatively different, it is not certain that adjuvants developed for routine immunization of healthy populations will be effective in patients with impaired immunity. Hence, vaccine adjuvant development for the immunocompromised host may require different strategies from those used in healthy hosts.

Patients with impaired immunity may have qualitatively different antibody responses from normal hosts. One should not assume that a given antibody level has the same protective efficacy in patients with and without normal immunity. Antibody responses can differ in the amount, isotype, and affinity of the antibody generated in response to immunization. Another variable in the efficacy of antibody function is the status of cellular immunity. In mice infected with the fungus C. neoformans, CD4⁺ helper T cells are required for antibody-mediated protection (292). Similarly, cutaneous delayed-type hypersensitivity to an antigen may or may not correlate with a protective immune response to vaccination. Hence, an important caveat of vaccine use in patients with impaired immunity is a lack of efficacy data that document their ability to actually prevent disease.

LIVE VACCINES

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Adenovirus Vaccine

Oral vaccines containing live, nonattenuated virions are used for prevention of adenovirus type 4 and type 7 infections in military recruits (97). Adenovirus infection has been associated with self-limited acute respiratory disease in healthy hosts. However, several epidemics of adenovirus infection, resulting in significant morbidity, have occurred among military recruits during their time of basic training (97). Adenovirus-related respiratory illnesses in military recruits due to type 4 and 7 viruses have been controlled by the use of a live, enteric-coated vaccine (97). Release of the virus in the gastrointestinal tract results in local proliferation of the virus and elicits immunity which protects against subsequent respiratory infection. In healthy men, the adenovirus vaccines are safe and immunogenic (77, 260, 263, 264). Their efficacy and safety in individuals with impaired immunity is unknown since experience with these vaccines is limited largely to healthy individuals in military service. Adenovirus vaccine use is contraindicated in individuals who have impaired immunity or are pregnant. Routine adenovirus vaccine use is not recommended in civilian populations because a clear need for immunization has not been established (97).

The efficacy of the measles vaccine in many types of immunocompromised patients depends on the type of underlying disorder. A small study of attenuated measles virus vaccine administration to eight children with acute leukemia in remission revealed that seven (87%) produced antibody to measles virus with titers ranging from 2 to 128 by hemagglutination inhibition (265). Neutralizing antibody was measured in six of the eight children, and no cases of measles were reported in this small group (265). Among 20 recipients of allogeneic bone marrow transplant, the seroconversion rate following immunization with measles virus was 77% (171).

Malnutrition could contribute to poor measles vaccine responses in children in developing countries. Nevertheless, the measles vaccine can be immunogenic in the setting of malnutrition: 70 and 90% of vaccinated children with protein-calorie malnutrition had protective antibodies within 21 and 42 days, respectively, of vaccination with the live measles vaccine (281). Measles vaccination may have higher side effects in malnourished children and could have predisposed to fatal pneumonia in one child (281).

Measles vaccination is contraindicated in patients with disorders of cell-mediated immunity and in pregnant women. This recommendation dates to 1962 and is based on observations of abnormal antibody responses to vaccination in such persons and the possibility of disseminated infection from the attenuated measles virus strain (187). Several cases of disseminated infection following measles vaccination in children with impaired immunity have been described (33, 187, 190). However, these individuals are also at high risk for severe measles as a result of natural infection (40, 153). The risk-benefit assessment for the risk of vaccination versus the benefit of protection against natural infection in immunocompromised patients is unknown. The mortality rate from measles infection in children with HIV infection or cancer is 40 and 70%, respectively (143). The live attenuated measles vaccine appears to be significantly less immunogenic in children with HIV infection. A retrospective study of 18 New York City children with HIV infection who received the measles vaccine revealed serum antibody in only 3 (17%) (153). When eight children were vaccinated prospectively, antibody to measles was detected in only two (25%) (153). Recently, a review of cases of measles infection in HIV-infected patients suggested that those who were vaccinated had lower mortality rates, and the authors recommended a reassessment of the existing practice of avoiding vaccination in patients with impaired immunity (143). Two small studies suggest that measles vaccination is safe in children with leukemia in remission after chemotherapy (265) or in children who received bone marrow transplants at least 2 years earlier, had no graft-versus-host disease, and were not being treated with immunosuppressive drugs (171).

The measles vaccine (in the form of the MMR vaccine) is recommended for all asymptomatic patients with HIV infection (51). For symptomatic children with HIV infection, measles vaccination should be considered (51), recognizing that measles infection has been reported in children with HIV infection (53). Measles vaccination with MMR has been well tolerated by children with HIV infection (91, 185), but cases of measles have been reported after vaccination (153). Children with HIV infection on regular immune globulin therapy may not respond to the MMR vaccine because of passive transfer of virus-specific antibodies (51).

A concern specific to the use of the measles virus vaccine in immunocompromised patients is the potential for a worsening of immune function. Measles virus infection has been classically associated with susceptibility to other viral and bacterial infections as a result of a transient state of immunosuppression following infection. Immune suppression may follow vaccination with live attenuated measles vaccines. Skin test responses to antigens are depressed in children receiving live attenuated virus vaccine (86). The mechanism for the transient depression of immunity which can accompany measles vaccination is not well understood (125). The immunosuppressive effect of measles virus vaccine requires live virus, since immunization with killed measles virus had no measurable effect on host immunity (86). The measles vaccine produces significant leukopenia in many patients 7 to 13 days after vaccine administration, causing reductions in the numbers of lymphocytes, monocytes, neutrophils, and eosinophils (38). Interestingly, the vaccine has the most severe effect on eosinophil counts, which fall to zero at approximately 10 days postvaccination (38). Lymphocytes from children who received measles vaccine have depressed lymphocyte proliferative responses to many common antigens in vitro (86). This may account for the reduction in lymphocyte proliferative responses among healthy children receiving the MMR vaccine (194). Administration of measles vaccine to individuals who are seropositive for measles can suppress chemotactic factor production in response to a variety of antigens (125). Hence, live attenuated measles vaccine administration is associated with a series of abnormal immunological tests that measure cell-mediated immunity and probably reflect a period of transient immunosuppression.

The experience with high-titer measles vaccines in developing countries indicates problems that may have implications for measles vaccine use in immunocompromised hosts (1, 95, 127, 167). High-titer measles vaccines are designed to elicit high-titer responses in infants. The high-titer vaccines protected children against measles but were associated with a higher mortality from other infectious diseases (1, 95, 127, 167). The increase in mortality occurred in girls and not boys (1, 127). Its cause remains unknown (167, 236).

Mumps is a generalized viral illness of childhood which is usually characterized by parotitis. Mumps can be prevented by vaccination with an attenuated mumps strain, and such a vaccine has been available in the United States since 1967. Few studies have evaluated the efficacy of the live attenuated mumps vaccine in individuals with impaired immunity, but the available evidence suggests that this vaccine is often immunogenic in this population. In an early study, four Japanese children with acute leukemia in remission were immunized, and all produced a neutralizing-antibody response (265). Vaccination of six children on continuous ambulatory peritoneal dialysis with mumps vaccine revealed that all mounted immunoglobulin G (IgG) responses in serum, albeit lower than those in controls (126). However, another study in children on continuous ambulatory peritoneal dialysis revealed only a 50% response when the antibody level in serum was measured by ELISA (244). Other immunosuppressed states may result in lower vaccine response: of 10 children with HIV infection immunized with the MMR vaccine, only 4 had serum antibody detected by indirect immunofluorescence (91). In recipients of allogeneic bone marrow transplants (BMT), the efficacy of the mumps vaccine was 64% (171). Vaccination of HIV-infected children against mumps with the MMR vaccine has revealed no significant adverse effects, and vaccine use is recommended in this population (91, 185). Similarly, no adverse effects were noted among BMT recipients (171).

Rubella virus causes rubella or German measles, which is a self-limited viral infection of childhood characterized by fever, rash, and lymphadenopathy. Rubella infection in pregnancy can be devastating to the fetus, resulting in birth defects. A live attenuated strain of rubella virus has been licensed for vaccination against rubella in the United States since 1969. In BMT recipients vaccinated with rubella vaccine, the prevalence of seroconversion was 75% (171). Rubella vaccination can result in viremia and persistent infection in some individuals without apparent immune system defects. In 1981, the isolation of rubella virus 2 years after rubella vaccination in an apparently healthy woman was described (56). A follow-up study documented persistent rubella infection in six women with rubella vaccine-associated arthritis (57). An advisory panel concluded that there was a causal association between rubella vaccination with the RA27/3 strain and the occurrence of chronic arthritis in women (128). Whether individuals at risk for this unusual complication of rubella vaccine have a specific immune system defect or genetic predisposition is unknown. Vaccination with rubella virus is generally contraindicated in patients with impaired immunity. Erroneous administration of rubella vaccine to a boy with leukemia in remission resulted in a persistent infection accompanied by acute arthritis and arthralgia (98). However, vaccination with rubella virus had no adverse effects in 10 children with symptomatic HIV infection who were vaccinated with the MMR vaccine (91). Similarly, no adverse effects of rubella vaccination were observed among 20 patients recovering from BMT (171).

For the prevention of poliomyelitis there are two vaccines available: a live attenuated oral polio vaccine (OPV) and an inactivated polio vaccine (IPV). Both are highly effective. OPV produces a gastrointestinal infection that induces long-lasting immunity and has the added advantage of immunizing individuals in close contact with the vaccine recipient. IPV is administered by intramuscular injection and induces systemic immunity. OPV has, on rare occasions, been associated with paralytic episodes, and the frequency of such events is higher in adults and individuals with impaired immunity. Furthermore, the only cases of polio in the United States at present are vaccine associated. IPV is now recommended for primary immunization of those with impaired immunity, and OPV is only recommended for booster vaccinations (64).

Both OPV and IPV can elicit neutralizing antibody responses in children with HIV infection (26). The magnitudes of serum titers to poliovirus in HIV-positive and -negative children appear to be comparable (26). Children with AIDS can produce weaker responses to IPV vaccination than normal children do (25). A review of 138 cases of vaccine-associated paralytic poliomyelitis identified 13 cases in patients with impaired immunity (200). These patients all had either congenital immunodeficiency or acquired hypogammaglobulinemia, but none had been diagnosed with impaired immunity prior to vaccine administration (200). The risk of vaccine-associated poliomyelitis appears to be 10,000 times greater in patients with hypogammaglobulinemia than in normal individuals (291). Many well-documented cases of vaccine-related progressive poliomyelitis have been described in patients with immunodeficiencies (68, 82, 200, 239, 291). For some patients, immune system deficiencies have been diagnosed only when paralytic poliomyelitis developed as a consequence of vaccination. Feigin et al. in 1971 described a 7-year-old child who developed fatal paralytic poliomyelitis after immunization with OPV without a history of recurrent infections or adverse reactions to previously administered live viral vaccines (82). Vaccine-related poliomyelitis was described in a girl with cartilage-hair hypoplasia, a congenital cause of dwarfism, leading to the suggestion that live viral vaccines be avoided in children with dwarfism until an immunologic evaluation has been completed (239).

Several studies suggest that the OPV is well tolerated by patients with HIV infection. No adverse reactions were reported in eight Italian children with prenatal HIV infection to whom OPV was given (26). A retrospective study of 221 children with perinatal HIV infection in New York City who received OPV revealed no cases of paralytic disease or other adverse effects (185). Nevertheless, IPV is recommended for vaccination against poliomyelitis in all individuals with impaired immunity, including patients with HIV infection (51). IPV use eliminates any theoretical risk to the vaccinee and to close contacts who may also have impaired immunity. IPV appears to be well tolerated in HIV-infected children (26). Another study in which an enhanced IPV vaccine was given to children born to HIV-positive mothers revealed no significant side effects (25). The effect of IPV administration in adults with advanced HIV infection has been studied in a small number of patients who had preexisting antibody (182). Poliovirus antibody titers decreased in adult patients vaccinated with IPV, a finding that was attributed to a desensitization phenomenon analogous to that observed in the treatment of allergy by antigen immunization (182).

Chickenpox is usually a mild disease of childhood, which can be complicated by encephalitis, pneumonia, and superinfection of skin lesions. In patients with impaired immunity, chickenpox can produce severe infections with high mortality. A live attenuated strain of varicella virus (the Oka strain) is licensed for use in patients older than 1 year with no history of chickenpox (154). The Oka strain was isolated in Japan from a healthy child with chickenpox and attenuated by passage through a variety of human and animal cell lines (262). The vaccine underwent a tortuous development process in part because of the need to demonstrate efficacy and safety in the immunocompromised individuals who would benefit most from immunization (180). The Oka varicella virus strain was tested extensively in children with malignancies because this population is at high risk for severe chickenpox infections. A small early study suggested that administration of varicella vaccine to hospitalized children with a variety of illnesses was effective in preventing an outbreak of infection (19). Several large studies have shown that the vaccine is effective in individuals with and without impaired immunity. Among 86 healthy adults, the seroconversion rate after one dose was 58% and the rate after more than one dose was 92% (100). Administration of varicella vaccine to 437 children with leukemia in remission resulted in a seroconversion rate of 89% after one dose and 98% after two doses (99). After 5 years, 30% of children were seronegative and chickenpox was documented in 8% of vaccinated children (99). In children with acute lymphoblastic leukemia, the seroconversion rate after vaccine administration did not differ regardless of whether chemotherapy was being administered (16). Follow-up studies of leukemic children without breakthrough varicella revealed that more than 90% had antibodies in serum 8 to 10 years after vaccination. In children on chronic dialysis and with renal transplants, the antibody response was 76%, but for many children the appearance of antibody was delayed relative to the timing in normal hosts (293). Hence, the varicella vaccine is effective in individuals with and without malignancies, and immunity lasts for at least a decade.

Some authorities have suggested that use of the varicella vaccine be limited to immunocompromised patients at high risk for chickenpox (231). Safety issues with the varicella vaccine include communicability to household contacts, the development of chickenpox-like rashes in immunized individuals, and the possibility of long-term reactivation as shingles. The incidence of a chickenpox-like maculopapular rash after vaccination was 6 and 42% in children receiving and not receiving chemotherapy, respectively (100). The Oka strain can reactivate in immunocompromised hosts, but the rate of reactivation with zoster appears to be similar to that which follows natural infection (154). Hence, the varicella vaccine appears to be relatively safe in children with leukemia who are in remission. Vaccination of susceptible children with leukemia undergoing induction chemotherapy or experiencing a relapse is not recommended (100). A small study suggests that vaccination prior to chemotherapy may be safe and effective (59). The efficacy and safety of the varicella vaccine in children with HIV infection are being studied. Similarly, there is little information on safety in individuals with impaired immunity not related to malignancy or its treatment.

Yellow fever is caused by a flavivirus and can be prevented by vaccination with the live attenuated virus strain 17D (256a). The 17D vaccine was generated by serial passage of yellow fever virus in cell culture (256a). This vaccine has been used primarily in Africa and South America and is considered safe and effective (260). The vaccine elicits long-lasting immunity in the majority of recipients but should not be given before the age of 6 months because of the risk of vaccine-related encephalitis. There is little or no information on the efficacy or safety of the 17D vaccine in individuals with impaired immunity. Protein malnutrition has been associated with impaired antibody responses to the yellow fever virus vaccine (44). The response to 17D immunization has been reported to be enhanced by simultaneous administration of the Vi polysaccharide vaccine for typhoid fever (6). Despite the scarcity of literature reports indicating adverse effects in individuals with impaired immunity, administration of 17D to patients with immunodeficiency is contraindicated on hypothetical grounds (208). The safety of the 17D vaccine in pregnant women is also uncertain. A retrospective study of inadvertent vaccination in pregnancy revealed a case of congenital infection without apparent adverse effects to the fetus (266).

Vaccinia virus was used for the prevention of smallpox but was discontinued when worldwide eradication of the virus was declared. It remains a viable vaccine against smallpox and may conceivably find employment for the expression of microbial and tumor antigens (193). If live vaccinia virus derivatives are used as carriers of microbial or vaccine antigens, caution should be exercised in their use in immunocompromised patients. Vaccinia necrosum was a severe complication of vaccinia virus administration in patients with immunologic deficiencies; it was characterized by a progressive virus-induced tissue necrosis originating at the site of inoculation (78, 205). Vaccinia gangrenosum was frequently associated with agammaglobulinemia (78). Recently, a case of disseminated vaccinia infection was reported in a military recruit with unrecognized HIV infection who was vaccinated with vaccinia virus (220).

Typhoid fever is caused by S. typhi. Typhoid fever is endemic in most areas of the world, but in the United States most cases occur among international travellers (289). A live attenuated vaccine made from S. typhi Ty21a was licensed in 1989 (289). This vaccine is administered orally in four doses over 7 days. The concept behind the development of an oral live attenuated vaccine for typhoid fever was a large body of direct and circumstantial evidence that ingestion of live bacilli conferred immunity (290). In addition to Ty21a, a killed parenteral vaccine against S. typhi is available, but it appears to be less effective and has more side effects (289). Large-scale trials of the Ty21a vaccine in children in Chile and Egypt have shown 67 to 95% efficacy (276, 289, 290). The efficacy of this vaccine in patients with impaired immunity is unknown. The Ty21a attenuated strain was generated by chemical mutagenesis, and one of the mutants accumulates galactose precursors, which kill the bacteria in vivo. The inability of Ty21a to persist in vivo prevents stool shedding among individuals receiving a normal vaccine dose (289). These characteristics suggest a high safety profile, and there are no reports of disseminated or progressive infection among patients receiving this vaccine in large field trials. Ty21a, like all live attenuated agent vaccines, is contraindicated in individuals with impaired immunity (289). In a situation analogous to that of poliomyelitis, for which both live and killed vaccines are available, typhoid fever immunization with the killed parenteral vaccine may be preferable in patients with impaired immunity on theoretical grounds (289). The Vi polysaccharide vaccine, which is now licensed to prevent typhoid fever, is preferable for those with impaired immunity.

The bacillus Calmette-Guérin (BCG) vaccine is derived from an attenuated strain of Mycobacterium bovis and is used for the prevention of tuberculosis. The efficacy of BCG vaccine in populations at risk for M. tuberculosis infections is variable, and BCG vaccination is not currently recommended for routine use in the United States because of the low prevalence of tuberculosis in this country (52). Considering the difficulties encountered in establishing vaccine efficacy in normal populations, it is not surprising that there is no conclusive information for the efficacy of BCG vaccine in patients with impaired immunity. There is evidence that tuberculin skin tests after BCG vaccination in patients with HIV infection are weaker than in normal hosts, suggesting a lower vaccine efficacy in this population (52). BCG administration is contraindicated in patients with impaired immunity. The most serious complication of BCG administration is disseminated infection, which occurs at a rate of 0.06 to 1.56 cases per million doses of vaccine administered (52). Most deaths due to disseminated BCG infection have occurred in patients with impaired immunity. Several cases of disseminated BCG infection have been reported in patients with HIV infection (293). A comparison of the outcome of BCG vaccination in children from HIV-positive and -negative mothers in Haiti revealed a higher complication rate in children of HIV-positive mothers, but the reactions were usually mild and not life-threatening (203). BCG vaccination is not recommended for HIV-infected patients in the United States, but the World Health Organization does recommend vaccination of asymptomatic HIV-infected children who live in countries with a high prevalence of tuberculosis (52).

Use as adjunctive immunotherapy in patients with bladder cancer. Brief mention should be made of the use of the BCG vaccine for the therapy of bladder cancer (121, 250). Immunotherapy with live BCG vaccine delays the progression of superficial bladder cancer and reduces the mortality rate (121, 250). The mechanism of action of the vaccine is poorly understood, but it is generally believed that the antineoplastic effect is a result of an immune response to BCG (250). Complications of BCG therapy in these patients include fever, cystitis, and extravesical dissemination (250). Intravesical administration of BCG for bladder cancer is an effective immunotherapy involving the use of a live pathogen vaccine in an unconventional role.

Assessing the risks versus the benefits of live-pathogen vaccination in persons with impaired immunity results in a complex calculation, and there are often inadequate data for rigorous and objective problem solving. Table 2 summarizes the response rates of various groups of patients with impaired immunity to some live agents. The use of live-pathogen vaccines in patients with impaired immunity implies, to a certain extent, a contradiction in vaccine design and expected efficacy. Attenuated live-pathogen vaccines replicate in the host until an immune response develops that inhibits replication and prevents the disease associated with infection by wild-type pathogens. Unfortunately, the immune response necessary for checking the proliferation of an attenuated strain may not be adequate in patients with impaired immunity. Therefore, live-pathogen vaccines which elicit protective immunity in normal hosts are likely to always carry some risk in immunocompromised hosts. Furthermore, the immune system deficit of the host will determine the magnitude of the risk associated with a particular live vaccine, e.g., the attenuated live measles vaccine may pose little risk to HIV-infected children but a significant risk to children with lymphoproliferative disorders. A complicating factor is that the patients who are at the greatest risk for the negative sequelae of live-pathogen vaccines often experience the most severe courses of natural infection. The possibility that a live attenuated pathogen vaccine will reduce the baseline immune system function is another important consideration in patients with impaired immunity. Theoretically, the administration of a live vaccine could either enhance or decrease preexisting immunity (e.g., measles vaccination, as detailed above).

In malnourished populations, live-pathogen vaccines carry the parallel concerns that the immunologic response will be suboptimal because of malnutrition and that some vaccines could exacerbate the malnourished state. Kwashiorkor is associated with weak responses to immunization. However, immunization with live virus vaccines can also precipitate a negative nitrogen balance in nutrition. In 1961, Gandra and Scrimshaw reported a negative nitrogen balance in children who were given the live attenuated 17D yellow fever vaccine (93). The effect appeared to be the result of increased catabolism or tissue destruction associated with a subclinical infection by the attenuated yellow fever virus (93). In 1977, Kielmann demonstrated statistically significant reductions in weight in children younger than 6 months old who were given live-pathogen vaccines (BCG, smallpox, and polio) relative to matched nonimmunized controls (148). The weight loss was attributed to increased catabolism from vaccine-induced infection and was not observed with killed or toxoid vaccines such as diphtheria-pertussis-tetanus (148). These observations raise the concern that live-agent vaccination in malnourished children could result in a clinically significant deterioration of the nutritional state (148).

Live attenuated pathogen vaccines are always likely to carry some risks for hosts with impaired immunity, despite their efficacy. The experience with the varicella vaccine shows that it is possible to develop a relatively safe and effective live-agent vaccine for use primarily in patients with impaired immunity. However, the lengthy development and licensing process of the varicella vaccine (due in part to concerns about safety) also illustrates the difficulty that can be encountered in the development of live attenuated pathogen vaccines. For vaccines to be widely accepted in industrialized countries with low mortality rates due to infectious diseases, the risk of vaccination must be zero or close to zero. In the future, it is likely that some of the live vaccines presently in use will be replaced by subunit vaccines that do not carry the risk of infection in patients with impaired immunity.

SUBUNIT VACCINE

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Hepatitis B Vaccine

Hepatitis B virus (HBV) causes acute and chronic infections of the liver. Chronic HBV infection has been associated with a high risk for cirrhosis and primary hepatocellular carcinoma. HBV infection is transmitted through exposure to infected body fluids, and the modes of transmission include sexual contact, intravenous drug use, perinatal contact, and blood product transfusions. The first vaccines for prevention of HBV infection contained surface antigen (HBsAg) made by purifying noninfectious 22-nm viral protein particles from the plasma of individuals with chronic infection. In 1981, a plasma-derived vaccine was licensed in the United States. This vaccine was used throughout the 1980s but was replaced in 1989 with a vaccine composed of HBsAg made by expression in the yeast Saccharomyces cerevisiae (recombinant DNA vaccine). The antigen produced in yeast has the same amino acid sequence as the viral protein but is not glycosylated. Hence, the recombinant DNA vaccine is not identical to the plasma-derived product. Several comparative studies of the plasma-derived and recombinant HBsAg have shown that the plasma-derived vaccine was more immunogenic, especially in homosexual men at risk for HIV infection (206) and in patients with renal failure (247). In healthy medical students, the recombinant vaccine elicited antibody titers that were only one-fourth those elicited by the plasma-derived vaccine, and there was a higher proportion of nonresponders (162). The change in vaccine formulation introduces some uncertainty in comparing results from the early studies that used plasma-derived vaccine to those obtained with the presently available recombinant DNA vaccine.

A major impetus for the replacement of the plasma-derived vaccine was a theoretical concern that unrecognized infectious agents may exist in the human plasma preparation. The AIDS epidemic was recognized in the same year that the plasma-derived HBV vaccine was licensed, and the increased awareness of blood-borne pathogens heightened concern about the possibility of infectious-agent transmission by the use of plasma-derived products. Despite strong evidence that the plasma-derived vaccine was safe, this vaccine was phased out in favor of a theoretically safer but less immunogenic recombinant DNA vaccine.

The development of the HBV vaccine introduced several novelties in antiviral vaccine design. For the first time, a viral illness was prevented in humans by immunization with a viral protein subunit preparation. Since a major complication of hepatitis B infection is chronic hepatitis leading to cirrhosis and hepatocellular carcinoma, the HBV vaccine was also an anticancer vaccine. The early vaccine was made from the plasma of patients with chronic infectiona fact that hindered widespread acceptance and provided a source of theoretical fears about the possibility of contagion with other infectious diseases. The HBV vaccine was developed in the midst of the molecular biology revolution, which permitted its rapid replacement by a recombinant formulation. The design of the HBV vaccine relied on basic science knowledge gathered by studying the HBV and the course of infection and avoided the empiricism of attenuated live virus vaccines.

The HBV vaccine has been extensively studied for more than three decades, and the response to vaccination is dependent on many variables including the site of injection, host genetic background, concomitant diseases, and immune status of the host. Intramuscular injection is more likely to elicit antibody responses than is subcutaneous injection (267). Obesity has been associated with poor response to buttock injection with a short needle, presumably because of antigen deposition in the subcutaneous space (282). Poor responses have also been associated with advanced age (69, 282), leading to the recommendation that vaccination should be performed at an early age if possible (179). The mental state of the vaccine recipient is also a variable in efficacy of vaccination with HBV. A study of medical students showed that probability of mounting an antibody response to the first injection of HBV given on the third day of a 3-day examination series was inversely proportional to the level of anxiety and stress (107). Furthermore, the students with better social infrastructures demonstrated stronger immune responses by the time they received the third vaccine dose (107). Another study correlated the antibody titer at 7 months with psychological stress and reported that stress, coping styles, and loneliness had a negative impact on the antibody response (132). The effect of anxiety and psychological stress on vaccine response may be important in patients with impaired immunity, who are often chronically ill.

Despite optimal vaccination schedules, approximately 5 to 10% of healthy adults fail to make a high-level antibody response to HBV. A considerable body of evidence indicates that antibody responsiveness to HBV is under genetic control. A study in Taiwan demonstrated differences that appear to have a genetic basis between Han Chinese and people in aboriginal villages in immune response to HBV (129). Children of Han Chinese parents had significantly higher immune responses to HBV than did children of aboriginal parents, and those of mixed parentage had intermediate responses (129). Analysis of nonresponders to HBV has shown that genetic factors are important in determining the likelihood of mounting an antibody response after vaccination. In a small study of nonresponders among health care workers, there was a higher frequency of the HLA haplotypes DR7 and DR3 (66). Patients who are homozygotes for the HLA haplotypes B8-SC01-DR3 have been shown to mount lower responses to HBV in a small prospective study (5). In Japanese vaccinees who are nonresponders to HBV, other HLA haplotypes have been associated with suboptimal antibody responses (119). The response to HBV follows a dominant inheritance pattern in families (159). The mechanism by which nonresponders fail to make an antibody response is not well understood, but the defect does not appear to be an inability to present peptide in major histocompatibility complex class II molecules (71). Analysis of lymphocytes from nonresponders has shown depressed reactivity to pokeweed mitogen, which has been interpreted to suggest that the lack of response to HBV may reflect a larger number of suppressor T cells in these individuals (202). Many individuals who are nonresponders will respond to a second complete course of vaccination (179).

The immune response to HBV is greatly dependent on the immune status of the host and on the presence of concurrent medical conditions. Table 3 lists HBV vaccine efficacy in a variety of patient groups. Many conditions that affect the immune system are associated with significantly reduced antibody responses to the HBV vaccine (Table 3). However, not all patients with impaired immunity manifest the same type of response to the HBV vaccine. Chronic hemodialysis patients given HBV vaccine have consistently shown high rates of seroconversion to multiple-dose vaccine schedules, and the antibody response in this population has been associated with protection against infection (67, 70, 257). HIV-infected individuals consistently show weaker responses to HBV vaccine (147). Furthermore, HIV infection may be associated with a loss of previously acquired antibody responses to HBV vaccine administration (37). Therefore, larger doses are recommended in immunosuppressed adults and those on dialysis (64). However, at this time, few data support this practice.

The HBV vaccine consists of purified viral protein expressed in yeast. This vaccine carries no risk for viral infection and can be safely used in immunocompromised patients.

INACTIVATED VACCINES

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Toxoids

Toxoids are inactivated bacterial products that elicit strong immune responses. Two of the toxoids in current use, diphtheria and tetanus, are inactivated toxins. The third toxoid is an inactivated preparation of Bordetella pertussis. The discovery by von Behring that inactivated diphtheria toxin could produce protective immunity against diphtheria provided the basis for modern immunology and for the development of effective vaccines from inactivated agents or their components (192). These toxoids are strong immunogens that have been used extensively since their development in the early 20th century. At present, the diphtheria-pertussis-tetanus (DPT) vaccine is universally recommended in all patient groups (50). However, an acellular preparation of the pertussis component (aP) was introduced in 1992 for booster vaccinations. As of December 1996, the acellular pertussis vaccine is also recommended for primary vaccination (64). However, this vaccine has not been extensively evaluated in patients with impaired immunity (64).

In HIV-infected individuals, antibody responses to tetanus toxoid have been decreased in comparison to control subjects (156, 157, 207). The magnitude of the IgG response to tetanus in HIV-infected patients correlates with the CD4⁺ cell count (207). Although vaccination of HIV-infected individuals with tetanus toxoid has been reported to result in a transient increase in HIV-1 plasma viremia that did not correlate with CD4⁺ cell counts (254), another group reported that booster vaccination had no effect on plasma viremia (79). The significance of this phenomenon and its potential impact on the long-term prognosis in HIV-infected individuals is unknown. However, some conjugate vaccines, including one of the H. influenzae type b conjugates that is administered to HIV-infected infants and children, use tetanus toxoid as their carrier protein (see below). Tetanus toxoid is generally considered safe, but the relationship between vaccination with this agent and immune system activation in HIV-infected individuals suggests a need for caution and further study.

Diphtheria and tetanus toxoid vaccines are immunogenic in BMT recipients when they are administered 12 and 24 months after transplantation (172). Increased antibody responses of vaccinated recipients have been demonstrated when the bone marrow donors were also vaccinated (284). Children with malignancies generally respond to DPT vaccination (8, 161). Toxoids are adequately immunogenic in a variety of patients with impaired immunity, and DTaP is recommended in all children according to the guidelines of routine childhood immunization.

Human influenza infection is caused by influenza A and B viruses, which are single-stranded RNA viruses. The pathogenicity of the viruses is linked to their capacity to undergo antigenic variation. Influenza A viruses regularly undergo two kinds of antigenic mutation, which occur only rarely in influenza B viruses. Antigenic variation occurs as the result of antigenic drift, which is due to point mutations in the hemagglutinin (HA), or antigenic shift, which leads to the emergence of a new HA subtype. These processes establish new, antigenically distinct viral strains, which are less well recognized by preexisting antibodies. The consequence of this phenomenon for the host is that existing antibodies are less effective. Also, the new strains can stimulate heterologous (to the original strain) rather than homotypic antibodies, a phenomenon that is referred to as "original antigenic sin" (41, 88). The human antibody response to both of the major influenza virus antigens, HA and neuraminidase (NA), is predominantly IgG1 and IgG3 (218).

Serum antibody protects against influenza virus infection and facilitates recovery after infection (155, 217). The role of cell-mediated immunity in host defense against influenza viruses remains unclear. In one animal model of influenza infection, transfer of immune spleen cells to a susceptible recipient did not provide protection in the absence of antibody (274), but others have demonstrated that cytotoxic T cells are necessary and sufficient for recovery from influenza in nude mice (34). Passive antibody administration can protect normal or immunosuppressed animals from influenza virus infections (34, 273, 274), but IgA antibodies may prevent only pneumonia, not tracheobronchitis (34). Despite the proven role of antibody immunity in animal models, influenza virus infection is generally thought to be confined to the respiratory tract and viremia is usually not demonstrated (149). Passive antibody has been cited as ineffective in altering disease pathogenesis (149), but strain-specific antibodies with known biological function have not been studied in this capacity. Serum antibody provides primarily strain-specific protection against influenza viruses, but heterologous antibodies can protect against variants of the same subtype (antigenic drift) (186). The presence of secretory as well as serum antibody is optimal for protection, but the evaluation of vaccine immunogenicity is generally based upon measurements of antibody in serum. The amount of antibody that is needed for protection is unknown, but hemagglutination inhibition titers of greater than 40 are associated with protection (149). Hemagglutination inhibition titers of less than 20 are associated with less protection, and the elderly may require titers of greater than 40 for protection (35).

Influenza has plagued humanity for at least 500 years. The scientific progress that led to the introduction of inactivated influenza vaccines in the 1940s included the first isolation of the virus from humans in the 1930s and the cultivation of the virus in embryonated hen eggs in 1940 (35). These developments, in combination with the discovery of hemagglutination, provided the scientific and serologic basis for the production of influenza vaccines. The influenza vaccines currently manufactured in the United States are trivalent, consisting of two currently circulating influenza A subtypes and one influenza B strain. Viral preparations are inactivated with formalin, and split-virus preparations are then prepared by ether or detergent disruption. The vaccines are contaminated with egg products, and influenza vaccine is contraindicated in those with egg hypersensitivity. The major target groups for influenza vaccination are adults or children with underlying pulmonary or cardiac disease, nursing home residents, health care personnel, and other high-risk patients. Influenza vaccines must be administered yearly so that antibody responses can be elicited by preparations that contain prevalent subtypes. The problem of determining the long-term duration of vaccine-elicited protection in immunosuppressed individuals is not an issue for the presently available inactivated influenza vaccines, but antibody levels must be maintained throughout the influenza season to afford protection. Table 4 lists the response rates of various groups with impaired immunity to influenza vaccines.

The importance of influenza vaccination for patients with cancer may exceed that of other vaccines which prevent less common infections, because of the worldwide prevalence of influenza. Viral infections are associated with increased morbidity and mortality in patients with cancer (75), which makes this group a major target for influenza vaccination. Studies of influenza vaccination of patients with different cancers have generally reported decreased antibody responses in comparison to normal controls (81, 94, 113, 115, 173, 209, 240). The administration of whole bivalent influenza vaccine to patients with solid tumors and lymphoreticular neoplasms either at the time of administration of chemotherapy or at the nadir of blood counts resulted in a 71% seroconversion rate, in contrast to a 94% rate in normal controls (209). Those who were vaccinated at the time of chemotherapy had lower antibody titers, lower responses to antigens in the absence of preexisting immunity, and a fourfold increase in antibody titer 50% of the time (209). Those who were vaccinated at the nadir of their blood counts had equal antibody responses regardless of preexisting immunity, higher postvaccination antibody titers, and a 93% response rate (209). The poor response rates during antineoplastic therapy have been documented in a large number of patients (115). Additional factors that have been implicated in poor antibody responses to influenza vaccine in some groups are low initial antibody levels in patients with hematologic cancers (81, 113, 209), and low IgG levels in serum in patients with chronic lymphocytic leukemia (113). A major review of the studies that evaluated influenza vaccination in patients with cancer concluded that the overall response rate was 24 to 71% and that antineoplastic therapy was a major determinant of decreased antibody responses (115). The response of patients with solid tumors to influenza vaccine has been reported to be greater than the response of those with hematologic cancers (259). The antibody response of adults with lymphoma who were vaccinated during chemotherapy increased from 42 to 71% after a second dose of influenza vaccine (173). A similar booster regimen increased antibody responses in the elderly (38). Booster vaccinations are rational because the initial antibody responses can decline by 60 days after immunization (113).

Influenza vaccination of renal transplant recipients is safe (112, 123). The proportion of renal transplant patients who manifested a fourfold increase in antibody titer for each of three influenza antigens was 42, 58, and 48% 1 month after vaccination and 88, 100, and 93% 2 months after vaccination (112). Pediatric renal transplant recipients responded to the 1993 to 1994 trivalent influenza vaccine similarly to normal controls (92). However, decreased response rates were reported for transplant recipients in the 1970s (160, 258). Poor antibody responses in patients on cyclosporine therapy did not increase with booster vaccination (272), suggesting that immunosuppressive therapy itself can impair antibody responses to influenza vaccine irrespective of the underlying process (see above). An uncontrolled study of influenza vaccine safety in cardiac transplant recipients reported that there were no episodes of graft rejection and that 33 and 67% of the vaccinees responded with a twofold increase in titer to the influenza B and A antigens, respectively (151).

Administration of influenza vaccine to dialysis patients results in lower antibody levels than in normal individuals (123). Differences have been demonstrated in the production of antibodies against the individual components of a trivalent vaccine preparation, which resulted in protection against only one of three antigens (36). In this study, response rates to two of the antigens were only 25 and 27% and a significant booster effect was not observed upon administration of a second dose of vaccine. This phenomenon was interpreted to indicate a defect in primary rather than secondary immunity in the population of hemodialysis patients who were studied. However, others have suggested a role for booster vaccination in hemodialysis patients who manifest poor antibody responses (271). A cohort of 10 pediatric hemodialysis patients had response rates to the influenza A and B antigens that were similar to those of control subjects (92). In this study, the patients with chronic renal failure had lower antibody responses against influenza A antigens, but the differences were not statistically different.

Influenza vaccination of patients with systemic lupus erythematosus (SLE) has resulted in normal (42, 122) and impaired (222, 283) antibody responses. Decreased antibody responses to some influenza A virus antigens among subjects with SLE have correlated with corticosteroid administration (122), which suggests that administration of immunosuppressive therapy to patients with SLE can impair normal antibody responses to influenza virus antigens. Influenza vaccination of patients with stable SLE has not been associated with the precipitation of accelerated disease (42, 177, 222, 283).

Individuals who are infected with HIV, particularly children who have a high incidence of underlying cardiac and respiratory dysfunction, are at risk for the complications of viral respiratory infections. Influenza vaccination has been recommended in HIV-infected patients, but there has been concern about immune system activation of HIV-infected CD4⁺ cells by influenza vaccine. Several groups have reported increases in plasma viremia that follow the kinetics of the antibody response in influenza vaccine-vaccinated HIV-infected individuals (204, 255). Following influenza vaccination with a trivalent split-virus preparation, threefold or greater increases in plasma viremia were documented in 90% of HIV-infected individuals with more than 500 CD4⁺ cells (255). Although 30 to 90% of all subjects in this study manifested threefold or greater increases in plasma viremia following vaccination, only those with more than 500 CD4⁺ cells had a return to baseline viremia after 4 weeks. These individuals also had the greatest serologic response to vaccination, although the overall responses of the HIV-infected individuals in the study were lower than those of normal controls (255). Increases in HIV-1 plasma viremia following tetanus toxoid booster and pneumococcal polysaccharide administration have been reported by some (137, 254), but not others (79, 158). The effect of this phenomenon on disease progression and whether it is inhibited by antiretroviral therapy is unknown.

HIV-infected men who were vaccinated with influenza vaccine had a response rate of 73% to at least one influenza antigen, whereas the response rate of normal subjects was 93% (131). Protective titers of 40 or greater to all of the antigens postvaccination were manifested by fewer of the HIV-infected persons than by the normal subjects, but the difference was not statistically significant (131). The antibody response did not correlate with the CD4⁺ count in the HIV-infected subjects in this study, but others have shown an association between the CD4⁺ count and antibody responses to influenza vaccination (54, 156). Antibody titers to each antigen in a tetravalent split-virus vaccine were markedly decreased in HIV-infected subjects; those with fewer than 100 CD4⁺ cells did not respond, but those with higher CD4⁺ cell counts did manifest antibody responses (156). Furthermore, a booster dose did not increase antibody titers in this study (156). In HIV-infected children, antibody responses to a standard trivalent vaccine were correlated with CD4⁺ cell counts (54). Pre- and postimmunization titers were lower for the HIV-infected children than for the controls, but protective responses were observed for both influenza A virus strains, although children older than 9 years did not respond to H3N2 antigens (54). Higher antibody responses were observed in vaccine-naive children who received a two-dose regimen, suggesting that booster doses can increase the influenza virus antibody titers of these children (54). Immunization of HIV-infected children with a split-virus preparation resulted in a fourfold increase in antibody titers in 18.9% to A/Texas, in 26.4% to A/Shangdong, and in 26.4% to B/Panama (133). Immunization did not result in plasma viremia, but a low prevaccination CD4⁺/CD8⁺ ratio was associated with decreased antibody responses (133). Taking into consideration the impaired antibody responses of HIV-infected individuals to influenza vaccination and the possibility that vaccine-elicited immune activation will activate HIV-infected CD4⁺ cells and increase viral production, caution should be exercised regarding influenza vaccination in this population. Some have suggested that amantadine prophylaxis rather than vaccination should be considered (255), and others have recommended vaccination of close contacts to decrease the risk of influenza infection in HIV-infected people. However, it should be noted that the impact of potent antiretroviral therapy upon vaccine-elicited enhancement of viral load and the long term consequences of this phenomenon are presently unknown.

POLYSACCHARIDE VACCINES

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Overview

Several polysaccharide vaccines are available for the prevention of infections by encapsulated pathogens. The development and improvement of the existing capsular polysaccharide vaccines have paralleled our understanding of human antibody responses to T-independent antigens. T-independent antigens are categorized as type 1 or type 2 (191). The bacterium Brucella abortus and lipopolysaccharide are type 1 antigens; they stimulate B cells in the complete absence of T cells (191). Capsular polysaccharides of microorganisms are type 2 antigens; they can stimulate B cells without T-helper cells, although T cells do amplify and/or suppress host immune responses to these antigens (23, 191). In adult humans, T-cell-independent type 2 antibody responses are restricted largely to the IgG2 subclass and perhaps to specific idiotypes (2, 3, 215, 216, 246). T-cell-independent antigens do not elicit memory B cells, and T-cell-independent antibody responses cannot be boosted to produce secondary responses (191), although antibody responses may be long-lived (120). Neonatal B-cell unresponsiveness to bacterial polysaccharides is well known (114), but adults with normal immunologic function develop protective anti-polysaccharide antibodies to both natural infection with capsular pathogens and vaccination with bacterial polysaccharides.

Encapsulated microorganisms are surrounded by anti-phagocytic polysaccharide capsules, which are key virulence factors. Infants, young children, the elderly, and those with impaired B-cell function are at increased risk for infections with encapsulated bacterial pathogens. For infants, this is the result of a normal physiologic delay in the capacity of the human immune system to respond to bacterial polysaccharides (114). Neonates become susceptible to infection when transplacentally acquired maternal immunity wanes 3 to 6 months after birth (225). Susceptibility persists throughout early childhood until the development of naturally occurring immunity. The latter is derived from antibodies against cross-reactive, commensal, and colonizing organisms (225) and from maturation of the immunoglobulin repertoire. A report in the 1980s that patients who manifest decreased levels of IgG2 antibodies had poor antibody responses to polysaccharide vaccines (252) suggested that IgG2 is needed for protection against encapsulated pathogens. Patients with deficient antibody-mediated immunity due to primary immunodeficiencies or chemotherapy-induced defects have markedly increased susceptibility to encapsulated pathogens and poor antibody responses to immunization with bacterial polysaccharides. I