VACCINE EFFICACY DATA. INACTIVATED VACCINES. LIVE VACCINES. Immunization has its roots in the Latin word immune, which originally referred to an exception to taxation. Vaccination is the act of administering a vaccine. VACCINE EFFICACY DATA.. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. Vaccine. Am J Epidemiol. Vaccine. Vaccine. [Vaccine. Vaccine. [Vaccine. Vaccine. [Vaccine. Vaccine. [Vaccine. Vaccine. [Vaccine. Vaccine. [Vaccine. Vaccine. [Vaccine. Am J Epidemiol. [Am J Epidemiol. Vaccine. [Vaccine. The 1979 J. Burns Amberson lecture.

Use of Licensed Vaccines for Active Immunization of the Immunocompromised Host.. .. Journal List > Clin Microbiol Rev > v.11(1); Jan 1998 .. : Formats. Abstract. | . Full Text. | . PDF (241K). :. :. .. Clin Microbiol Rev. 1998 January; 11 (1) : 1?26. . PMCID: PMC121373 .. :. Copyright &x000a9; 1998, American Society for Microbiology.. . Use of Licensed Vaccines for Active Immunization of the Immunocompromised Host..

. Liise-anne Pirofski and Arturo Casadevall&x0002a;.. . Division of Infectious Diseases, Department of Medicine, and Department of Microbiology &x00026; Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.. . &x0002a;Corresponding author. Mailing address: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-4260.

Fax: (718) 430-8968. E-mail: casadeva/at/aecom.yu.edu . ... This article has been cited by other articles in PMC. ......  Other Sections? .. Abstract. TERMINOLOGY. LICENSED VACCINES. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. POLYSACCHARIDE VACCINES.

The latter part of the 20th century has witnessed an unprecedented rise in the number of individuals with impaired immunity. This is primarily attributable to the increased development and use of antineoplastic therapy for malignancies, organ and bone marrow transplantation, and the AIDS epidemic. Individuals with impaired immunity are often at increased risk for infections, and they can experience more severe and complicated courses of infection.

The efficacy of most licensed vaccines has been established in immunocompetent hosts. However, there is also considerable experience with most vaccines in those with impaired immunity.

VACCINE EFFICACY DATA.

SUBUNIT VACCINE. INACTIVATED VACCINES.

.  .. 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&x00025; 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. 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.

VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. USE AND FUTURE OF LIVE VACCINES IN HOSTS WITH IMPAIRED IMMUNITY. SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES.

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 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.

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).

Although the terms &x0201c;vaccination&x0201d; and &x0201c;immunization&x0201d; are often used interchangeably, their meanings are not identical. The terms &x0201c;vaccine&x0201d; and &x0201c;vaccination&x0201d; are derived from vaccinia, a virus used to prevent smallpox. Immunization has its roots in the Latin word immune, which originally referred to an exception to taxation. Vaccination is the act of administering a vaccine.

Immunization is the process by which immunity to a pathogen is elicited or transferred. Vaccination does not necessarily mean that immunization has occurred, because the individual may not make an immune response to the vaccine.

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.

VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES.

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.

VACCINE EFFICACY DATA.

INACTIVATED VACCINES. POLYSACCHARIDE VACCINES.

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 ).

VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES.

INACTIVATED VACCINES. POLYSACCHARIDE VACCINES. REFERENCES. VACCINE EFFICACY DATA

Determinations of antibody binding to antigen are influenced by a complex set of variables including antibody amount, affinity, avidity, and functional efficacy. 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.

SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES.

PRINCIPLES OF VACCINATION WITH LIVE VACCINES. SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES. LIVE VACCINES

However, several epidemics of adenovirus infection, resulting in significant morbidity, have occurred among military recruits during their time of basic training ( 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.

Measles is an RNA virus that causes a syndrome of cough, fever, and rash in children. Although measles is usually a self-limited infection, a significant number of patients can develop severe complications including pneumonia and encephalitis. A live attenuated vaccine has been available in the United States since 1963. Initially, the vaccine was administered at 15 months of age to avoid interference by residual maternal antibodies to measles virus.

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&x00025;, respectively ( 143 ). The live attenuated measles vaccine appears to be significantly less immunogenic in children with HIV infection.

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 ).

. 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.

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&x00025; ( 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.

. 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. 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. 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 ). ... Varicella-Zoster Vaccine.. 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.

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&x00025; and the rate after more than one dose was 92&x00025; ( 100 ). Administration of varicella vaccine to 437 children with leukemia in remission resulted in a seroconversion rate of 89&x00025; after one dose and 98&x00025; after two doses ( 99 ). After 5 years, 30&x00025; of children were seronegative and chickenpox was documented in 8&x00025; of vaccinated children ( 99 ).

Follow-up studies of leukemic children without breakthrough varicella revealed that more than 90&x00025; had antibodies in serum 8 to 10 years after vaccination.

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 ).

. 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&x00025; 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. ... Bacillus Calmette-Gu&x000e9;rin Vaccine..

The bacillus Calmette-Gu&x000e9;rin (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.

VACCINE RISK VERSUS BENEFIT IN PATIENTS WITH IMPAIRED IMMUNITY. VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. USE AND FUTURE OF LIVE VACCINES IN HOSTS WITH IMPAIRED IMMUNITY. SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES. CONCLUSIONS. REFERENCES. . USE AND FUTURE OF LIVE VACCINES IN HOSTS WITH IMPAIRED IMMUNITY.. 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.

Response rates to live vaccine agents by individuals with impaired.immunity 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 ).

VACCINE RISK VERSUS BENEFIT IN PATIENTS WITH IMPAIRED IMMUNITY. ADJUVANTS. VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES. REFERENCES.

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.

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 ).

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 ).

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.

VACCINE RISK VERSUS BENEFIT IN PATIENTS WITH IMPAIRED IMMUNITY. ADJUVANTS. VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. USE AND FUTURE OF LIVE VACCINES IN HOSTS WITH IMPAIRED IMMUNITY. SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES. CONCLUSIONS. REFERENCES. INACTIVATED VACCINES 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 ).

At present, the diphtheria-pertussis-tetanus (DPT) vaccine is universally recommended in all patient groups ( 50 ). As of December 1996, the acellular pertussis vaccine is also recommended for primary vaccination ( 64 ).

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 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.

Response rates of individuals with impaired immunity to influenza.vaccination 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&x00025; seroconversion rate, in contrast to a 94&x00025; 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&x00025; 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&x00025; response rate ( 209 ).

A similar booster regimen increased antibody responses in the elderly ( 38 ).

Influenza vaccination has been recommended in HIV-infected patients, but there has been concern about immune system activation of HIV-infected CD4&x0002b; 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&x00025; of HIV-infected individuals with more than 500 CD4&x0002b; cells ( 255 ).

Although 30 to 90&x00025; of all subjects in this study manifested threefold or greater increases in plasma viremia following vaccination, only those with more than 500 CD4&x0002b; cells had a return to baseline viremia after 4 weeks. 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 ).

TERMINOLOGY. LICENSED VACCINES. VACCINE RISK VERSUS BENEFIT IN PATIENTS WITH IMPAIRED IMMUNITY. ADJUVANTS. VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. USE AND FUTURE OF LIVE VACCINES IN HOSTS WITH IMPAIRED IMMUNITY. SUBUNIT VACCINE. INACTIVATED VACCINES. POLYSACCHARIDE VACCINES. CONCLUSIONS. REFERENCES. POLYSACCHARIDE VACCINES . 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 ). 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 ).

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.

Mechanisms of antibody-mediated protection against encapsulated pathogens include nonspecific immune mechanisms, such as complement activation by capsular polysaccharides, and specific mechanisms, such as antibody-dependent opsonization, phagocytosis and killing of opsonized organisms by effector cells, and cell-mediated mechanisms. Immunosuppressed patients with asplenia and a variety of primary and chemotherapy-induced defects in humoral immunity have a markedly increased risk of infection with encapsulated bacteria, although for most individuals an increased susceptibility to encapsulated bacteria is associated with impaired antibody responses to capsular polysaccharides.

Indications for the administration of polysaccharide and polysaccharide-protein conjugate vaccines differ, and they are not all recommended in all individuals. A major problem that is associated with the vaccination of hosts with impaired immunity against encapsulated pathogens is that the mechanisms which prevent the development of natural immunity also prevent the development of vaccine-elicited immunity.

The duration of protection following polysaccharide vaccination is unknown.

Response rates of individuals with impaired immunity to PRP polysaccharide conjugate and purified pneumococcal polysaccharide.vaccinea Meningococcal Vaccines Classic studies by Goldschneider et al. demonstrated that serotype-specific antibodies acquired during the carrier state with Neisseria meningitidis could protect against infection ( 109 ). Natural antibodies against meningococci are acquired from nasopharyngeal carriage of meningococcal organisms and exposure to cross-reactive antigens ( 225 ).

Purified meningococcal polysaccharides of groups A, C, Y, and W135 are licensed for the prevention of epidemic meningococcal meningitis. The vaccine is used primarily in populations at high risk for meningococcal infections, such as military recruits. The incidence of serotype A and C meningococcal infections has been drastically reduced since 1971, when routine vaccination of recruits with a bivalent serotype AC meningococcal polysaccharide vaccine began.

At present, the primary serotype of sporadic meningococcal disease in the United States is serotype B, which is not among the serotypes included in the tetravalent vaccine ( 168 ). Age is a major determinant of meningococcal vaccine immunogenicity. The antibody responses of 2-year-old children are 10&x00025; of those of adult vaccinees ( 168 ).

The rate of antimeningococcal antibody decline in asplenic subjects was slightly lower than that in controls, but subjects with Hodgkin&x02019;s disease had marked declines after completion of either chemotherapy or bimodal therapy with radiation ( 251 ). After therapy, Hodgkin&x02019;s disease patients did not manifest spontaneous recovery of antibodies, nor did they mount antibody responses to booster vaccination, although normal individuals may also fail to respond to booster polysaccharide vaccination ( 13 ).

In view of their increased risk of infection, it is recommended that Hodgkin&x02019;s disease patients receive the tetravalent meningococcal vaccine before the beginning of therapy ( 50 , 251 ). The timing of vaccine administration is critical, and vaccination should take place at least 7 days before therapy is begun.

. In 1933, Fothergill and Wright established that the age-related risk of H. influenzae meningitis resulted from an absence of serum bactericidal antibodies ( 87 ). It then took many decades to establish that the protective efficacy of bactericidal serum was attributable to antibodies that bind the type b polyribosyl-ribitol-phosphate (PRP) capsular polysaccharide determinant of type b H. influenzae (Hib) ( 243 ).

The recognition that PRP was poorly immunogenic in young children and infants led to the concept of PRP-protein conjugate vaccines. The landmark work of Goebel and Avery with bacterial conjugates early in the 20th century ( 108 ) provided the scientific underpinnings for the development of PRP conjugates. These vaccines elicit T-dependent antibody responses and are immunogenic in infants as young as 2 months of age ( 62 , 224 ).

The first PRP conjugate, PRP-D (PRP conjugated to diphtheria toxoid), was licensed in December 1987. In the decade since its introduction, this and other PRP conjugates have steadily eliminated Hib infections from the pediatric population ( 27 , 224 ). Available PRP conjugates include PRP-OMPC, for which the protein determinant is the outer membrane protein of N. meningitidis (PedvaxHIB; Merck Sharp and Dohme); PRP-T, for which the protein determinant is tetanus toxoid (ActHIB; Pasteur Merieux); and HbOC, for which a short oligosaccharide of PRP is conjugated to a nontoxic derivative of diphtheria toxin (HibTITER; Praxis Biologics).

An earlier generation PRP-diphtheria toxoid conjugate was used in some of the studies reviewed below (ProHIBIT; Connaught Laboratories). HbOC and PRP-T elicit antibodies with higher avidity than does PRP-OMPC ( 241 ), but the impact of antibody avidity differences on antibody function is unknown. . Children with sickle cell disease have impaired splenic function, which has been hypothesized to contribute to their increased susceptibility to encapsulated pathogens including Hib.

PRP-TT conjugate vaccination was as immunogenic in a group of children with sickle cell anemia as it was in normal children of similar ages ( 144 ). Since conjugate vaccines are T-dependent antigens, they should elicit antibody responses that are longer lived than polysaccharide-elicited antibodies. Seven months after vaccination, children with sickle cell disease who were vaccinated with a HIB-TT conjugate manifested antibody levels that were 40-fold greater than their preimmune antibody levels ( 238 ).

Different PRP conjugates have different immunogenicities in infants ( 111 , 241 ). A single injection of a Hb-OC conjugate (HibTITER) was more immunogenic that a PRP-D conjugate (ProHIBiT) in children with sickle cell disease: children who received HibTITER had a geometric mean PRP antibody level of 51.4 &x003bc;g/ml 6 months after vaccination, and those who received ProHIBiT had 2.29 &x003bc;g/ml ( 235 ), although both levels exceeded the protective level of antibody for long-term protection ( 146 ).

Persistence of Hib antibody in children with sickle cell disease who were 2 to 6 months of age at the time of vaccination required three doses of a Hb-OC conjugate ( 105 ), whereas two doses of a PRP-D conjugate were needed in children who were 3 to 17 months of age ( 178 ). PRP-protein conjugates are immunogenic in children with sickle cell disease, but children with anatomic or functional asplenia may require higher levels of Hib antibody in serum for protection against encapsulated H. influenzae infections ( 234 ).

The necessity for revaccination of asplenic children will have to be critically evaluated as those who were vaccinated in infancy and early childhood reach young adulthood. . Vaccination with a PRP conjugate vaccine is recommended for asplenic patients ( 50 ). Antibody responses to the PRP-D conjugate vaccine (ProHIBIT) were evaluated in 13 children who underwent splenectomy (7 for Hodgkin&x02019;s disease, 2 for hereditary spherocytosis, and 4 for idiopathic thrombocytopenia) ( 7 ).

These children responded with higher mean anti-Hib antibody concentrations than did healthy control children who received a purified polysaccharide vaccine instead of the conjugate. The antibody response of asplenic controls and subjects with Hodgkin&x02019;s disease to purified PRP was equivalent to healthy controls 3 to 4 weeks after vaccination, although the patients with Hodgkin&x02019;s disease had markedly decreased responses after the completion of lymphocytic therapy ( 83 ).

The timing of vaccine administration should take into account the fact that polysaccharide vaccine antibody responses of patients with lymphoid cancers are markedly decreased after the initiation of antineoplastic therapy but nearly normal before therapy. In patients with Hodgkin&x02019;s disease or leukemia, posttreatment vaccination with either purified polysaccharide (PRP) or a conjugate vaccine (ProHIBiT) resulted in markedly decreased anti-Hib antibody levels ( 83 , 251 ).

One dose of HibTITER was immunogenic in adults who had completed therapy for Hodgkin&x02019;s disease at least 2 years prior to vaccination ( 188 ). It has been suggested that levels of anti-Hib antibodies should be used to determine the necessity for revaccination of children undergoing splenectomy who have received prior Hib vaccination ( 7 ). . The postvaccination Hib antibody titers in 80 to 100&x00025; of children with leukemia and solid tumors have exceeded the levels thought to confer protection ( 165 , 221 , 278 ).

However, the antibody levels in children with cancer are lower than those in normal children ( 83 , 165 , 278 ), and one study found protective antibody levels in only 50&x00025; of children with leukemia after 6 months ( 165 ). Children older than 2 years with acute lymphoblastic leukemia who were treated with chemotherapy for less than 12 months responded like normal controls, but only 18&x00025; who received more than 12 months of treatment responded to Hib conjugate vaccine ( 83 ).

The latter children had mean antibody concentrations that were one-half to one-third lower than those in normal children, which declined significantly after 12 months ( 83 ). The geometric mean antibody titer in children with cancer on maintenance therapy (13 of 18 had leukemia) who were vaccinated with PRP-T was 1.4 &x003bc;g/ml, but only 50&x00025; had antibody levels greater than 1 &x003bc;g/ml 1 to 2 months postimmunization ( 144 ).

These infections are the result of waning natural immunity and impaired de novo antibody responses. The most significant correlate of decreased antibody responses in BMT recipients appears to be T-cell depletion. Neither intravenous immunoglobulin therapy nor graft-versus-host disease has been consistently shown to have an effect on Hib conjugate-induced antibody responses ( 116 , 189 ). Vaccination with a Hib conjugate vaccine has been suggested at 12 and 24 months after either autologous or allogeneic transplantation ( 8 ).

Vaccination of 35 BMT recipients with Hb-OC (HibTITER) resulted in a protective level of antibody (above 1.0 &x003bc;g/ml) in 56&x00025; of the subjects immunized 24 months posttransplantation, but 80&x00025; of those who were immunized at both 12 and 24 months attained significantly higher levels of antibody ( 116 ). In comparison to controls, all vaccinees had significantly lower IgG2 concentrations in serum (the IgG subclasses of anti-Hib antibodies were not reported) and the magnitude of their anti-Hib antibody responses was markedly lower ( 116 ).

Although their antibody responses were decreased compared to normal subjects, 85&x00025; of allogeneic BMT recipients responded to two doses of a PRP-T (HIB-T; Pasteur Merieux) conjugate with antibody levels greater than 1 &x003bc;g/ml ( 28 ).

Although the protective effect of antiserum was first demonstrated before the turn of the century ( 21 , 49 ), the inaugural hexavalent pneumococcal vaccine was soon withdrawn after its introduction in 1946, despite the success of clinical trials with the vaccine ( 21 ). The introduction of penicillin diminished interest in pneumococcal vaccination, and nearly two decades passed before the need for pneumococcal vaccines was accepted and led to a new initiative to develop pneumococcal polysaccharide vaccines in the late 1960s ( 22 , 80 ).

Therefore, the goal of pneumococcal polysaccharide vaccination is to elicit anti-capsular antibodies. Adult IgG to pneumococcal capsular polysaccharides is restricted largely to IgG2, including opsonic antibodies ( 90 , 152 , 175 , 215 , 237 , 294 ). As a risk factor for infection with encapsulated organisms, the role of IgG2 deficiency remains controversial.

First, the vaccine is indicated in individuals at high risk for infection. Second, it is difficult to compare the results of many studies, because the methods used to determine immunogenicity often measure different parameters. The radioimmunoassay that was used to evaluate the 8-valent and 14-valent and some of the 23-valent vaccines was contaminated by CWPS and did not identify individual immunoglobulin isotypes.

The determination that 300 ng of antibody nitrogen/ml was associated with protection against S. pneumoniae was based upon radioimmunoassay measurements of antibody ( 80 , 163 ). More recent studies have used ELISA techniques for the measurement of antibody levels ( 80 , 197 ).

Splenectomized children and adults without underlying cancer manifest antibody responses similar to those of normal controls ( 80 ). The immunogenicity of pneumococcal vaccination in children with sickle cell disease was evaluated extensively in the 1980s ( 29 , 30 , 60 , 61 , 139 , 211 , 219 , 287 , 288 ). The success of pneumococcal vaccination in this population has been assessed by measurements of serotype-specific antibody concentrations and serum opsonic activity and by attempts to discern vaccine efficacy based on predicted rates of pneumococcal infection ( 287 ).

An early study indicated that 2 years after immunization, an octavalent pneumococcal polysaccharide vaccine protected a cohort of 77 individuals with sickle cell disease ranging in age from 2 to 25 years ( 10 ). No infections occurred in the immunized individuals, whereas eight infections with S. pneumoniae occurred in 106 unimmunized controls with sickle cell disease ( 10 ). Postvaccination serum opsonization of S. pneumoniae was increased in children with sickle cell disease who were older than 2 years ( 61 ).

Postvaccination antibody levels are influenced by preimmunization antibody levels ( 211 ). Preimmune serotype-specific antibody concentrations are significantly lower in children with sickle cell disease who are younger than 2 years, and these children manifest lower pre- and postvaccination antibody levels and serum opsonic activity ( 61 , 210 ), although polyvalent pneumococcal polysaccharide vaccines are poorly immunogenic in all children younger than 2 years ( 61 , 287 ).

Serospecific vaccine failures have been reported with poorly immunogenic serotypes, such as serotype 6, and with vaccine serotypes 6b, 14, 18, 19F, and 23F in children with sickle cell disease ( 39 , 139 , 287 ). . Antibody levels frequently decline in children with sickle cell disease; revaccination increases antibody levels ( 219 , 277 ), but rarely above primary postvaccination levels ( 277 ).

The major risk of pneumococcal infection in children with sickle cell disease begins at the age of 4 months and continues until the age of 4 to 5 years ( 80 ). Therefore, the current recommendations for prophylaxis against S. pneumoniae in these children are to institute oral penicillin prophylaxis at the age of 4 months and to vaccinate with a polyvalent pneumococcal polysaccharide vaccine beginning at the age of 2 years ( 64 ).

One investigational pneumococcal polysaccharide conjugate vaccine was reported to elicit protective levels of antibody in 2- to 5-year-old children with sickle cell disease ( 238 ), suggesting that conjugate vaccination might be able to elicit protective antibody levels in infants with sickle cell disease. Studies of pneumococcal conjugates are under way. No efficacy studies are available, but several different conjugates appear to be immunogenic in young children ( 145 ).

. Patients with multiple myeloma, chronic lymphocytic leukemia, or Hodgkin&x02019;s disease are at increased risk for infections with S. pneumoniae, and the lack of specific antibody is a critical factor in susceptibility to these infections ( 8 , 58 ). Comparisons between cohorts of patients with multiple myeloma and normal subjects revealed that 21 of 37 ( 242 ) and 4 of 13 ( 166 ) myeloma patients had twofold increases in serotype-specific antibody levels against 6 of the vaccine serotypes in the 23-valent pneumococcal polysaccharide vaccine.

In some cohorts of patients with multiple myeloma, reduced antibody responses have been associated with low levels of prevaccination antipneumococcal antibodies and the administration of multiagent chemotherapy ( 166 , 242 ). . Patients with Hodgkin&x02019;s disease generally respond to pneumococcal polysaccharide vaccines prior to the initiation of antineoplastic therapy, but afterwards they have markedly decreased and short-lived responses ( 12 , 89 , 251 , 253 ).

Poor responses to polyvalent pneumococcal polysaccharide vaccination have been documented for as long as 7 years after treatment for Hodgkin&x02019;s disease ( 89 ). Children with Hodgkin&x02019;s disease who were vaccinated before undergoing splenectomy responded to 67&x00025; of the pneumococcal antigens tested, but those immunized after undergoing splenectomy responded only to 40&x00025; of the antigens ( 76 ).

Decreased levels of IgG2 in serum have been proposed to correlate with poor antibody responses to pneumococcal and other polysaccharide antigens ( 252 ). For those who have received intensive therapy for Hodgkin&x02019;s disease, the preimmune IgG2 concentration in serum correlated with the ability to respond to pneumococcal polysaccharides and with the postvaccination antibody levels 6 months after vaccination ( 252 ).

. An investigational heptavalent pneumococcal conjugate vaccine that links serotypes 4, 9V, 14, 18, 19F, 23F, and 6b to the outer membrane protein of N. meningitidis (Merck) was administered to treated patients with Hodgkin&x02019;s disease who had not relapsed or developed a second cancer ( 188 ). In this cohort, a single dose of the pneumococcal conjugate was less immunogenic than a 23-valent polysaccharide vaccine.

Postvaccination antibody determinations of each individual serotype and for total antipneumococcal IgG levels were lower for conjugate vaccinees than for both 23-valent polysaccharide vaccinees with Hodgkin&x02019;s disease and normal conjugate-vaccinated subjects ( 188 ).

This phenomenon results from waning pretransplantation antipneumococcal antibody levels and delayed maturation of polysaccharide antibody responses by donor lymphocytes ( 8 ). Only 19&x00025; of allogeneic and autologous BMT recipients vaccinated with Pneumovax had at least to 300 ng of antibody nitrogen/ml against pneumococcal serotypes 1, 3, 6A, 7F, 8, and 9, and none of 14 autologous BMT recipients had protective levels for all six vaccine serotypes tested ( 116 ).

Allogeneic BMT recipients who were vaccinated with a 14-valent polyvalent pneumococcal polysaccharide vaccine had prevaccination antibody levels that were 2- to 12-fold lower and postvaccination antibody levels that were significantly lower than those in normal controls ( 286 ). Pneumococcal infection developed in 12.8&x00025; (5 of 39 patients) of the patients who were vaccinated within 6 months of transplantation.

In a study that compared postvaccination antibody levels in different patient populations with renal disease, 90&x00025; of normal controls manifested a twofold increase and the patients undergoing hemodialysis responded like these normal subjects, but only 43&x00025; of those with chronic renal failure and 80&x00025; with renal allografts responded ( 102 ). Pneumococcal vaccination is recommended while patients are on dialysis prior to renal transplantation, because dialysis patients have higher pre- and postvaccination antibody levels ( 169 ).

TERMINOLOGY. LICENSED VACCINES. VACCINE RISK VERSUS BENEFIT IN PATIENTS WITH IMPAIRED IMMUNITY. ADJUVANTS. VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. USE AND FUTURE OF LIVE VACCINES IN HOSTS WITH IMPAIRED IMMUNITY. SUBUNIT VACCINE. INACTIVATED VACCINES.

Summary of recommendations for active vaccination of immunocompromised hosts with HIV infection or severe and mild.immunosuppressiona .. . Efficacy is defined as the ability of a vaccine to prevent infection or its complications. In this article, we have attempted to evaluate the efficacy and safety of licensed vaccines in patients with impaired immunity by reviewing the literature.

In retrospect, this approach was problematic, because for most vaccines we asked a question that available studies on vaccine efficacy cannot answer. With the exception of the varicella and hepatitis B vaccines, efficacy studies prior to vaccine licensing were performed in normal hosts, not in patients with impaired immunity. Studies of administration of vaccines to individuals with impaired immunity that have been performed after licensure have relied exclusively on surrogate markers of the immune response which were determined in normal hosts, and the relevance of these parameters to the immunocompromised host are undefined.

Unfortunately, one cannot conclude that immune system responses associated with protection in normal hosts will be protective in individuals with impaired immunity, even if the assays do not reveal quantitative or qualitative differences between the immune system responses of normal and impaired hosts. Antibody responses are usually a measure of the immunogenicity of the vaccine preparation, and the presence of serum antibody does not necessarily imply immunity.

For instance, impaired effector cell function and nonspecific immune system mechanisms such as complement activation may lead to ineffective antibody-mediated immunity. Hence, efficacy data that are relevant for vaccine utilization in patients with impaired immunity are not available for most licensed vaccines. . The evaluation of true vaccine efficacy in patients with impaired immunity remains a major challenge, because these individuals represent a heterogeneous population and the prevalence of most vaccine-preventable infections is too low to rapidly assess efficacy in relatively small populations.

The mechanisms of protective immunity are not completely defined for many infectious diseases, and protective immune responses in patients with impaired immunity may be qualitatively different than those in normal hosts. Immunocompromised hosts are now a major challenge in the control of infectious diseases. When possible, such individuals should be included in future studies of vaccine efficacy.

. What should physicians do when confronting the issue of vaccinating patients with impaired immunity' First, they should consult the most recent recommendations on vaccine use that are issued by the Centers for Disease Control and Prevention (Atlanta, Ga.) from the Advisory Committee on Immunization Practices (see, e.g., reference 50 ). Second, they should avoid live-agent vaccines when possible, unless these vaccines have been shown to be safe in the group being vaccinated.

Third, they should consider that efficacy data are lacking for most vaccines in patients with impaired immunity and that the decision to vaccinate must be based on individual risk-benefit calculations for each patient.

TERMINOLOGY. LICENSED VACCINES. VACCINE RISK VERSUS BENEFIT IN PATIENTS WITH IMPAIRED IMMUNITY. ADJUVANTS. VACCINE EFFICACY DATA. PRINCIPLES OF VACCINATION WITH LIVE VACCINES. LIVE VACCINES. USE AND FUTURE OF LIVE VACCINES IN HOSTS WITH IMPAIRED IMMUNITY. SUBUNIT VACCINE. INACTIVATED VACCINES.

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. J Exp Med. 1995 Dec 1; 182(6):1727-37. [J Exp Med. 1995]. See more articles cited in this paragraph .. Review T cell-independent antigens type 2. . Annu Rev Immunol. 1995; 13():655-92. [Annu Rev Immunol. 1995] Restricted Ig H chain V gene usage in the human antibody response to Haemophilus influenzae type b capsular polysaccharide.

1993] Analysis of human monoclonal antibodies elicited by vaccination with a Cryptococcus neoformans glucuronoxylomannan capsular polysaccharide vaccine.

IgG anti-PC antibodies express restricted numbers of V and C regions.

Correlation between serum IgG-2 concentrations and the antibody response to bacterial polysaccharide antigens.

Review Conjugate vaccines: practice and theory.

Impact on public health and implications for other polysaccharide-based vaccines.

. J Infect Dis. 1982 Mar; 145(3):292-5. [J Infect Dis. 1982]. See more articles cited in this paragraph .. Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children three months to five years of age.

Review Critical appraisal of immunization strategies for prevention of infection in the compromised host.

Human immunity to the meningococcus. I. The role of humoral antibodies.

Antibody responses to meningococcal polysaccharide vaccine in adults without a spleen.

Immunization of humans with polyribophosphate, the capsular antigen of Hemophilus influenzae, type b.

Review Critical appraisal of immunization strategies for prevention of infection in the compromised host.

Immunity to disease caused by Hemophilus influenzae type b. Specificity and some biologic characteristics of "natural," infection-acquired, and immunization-induced antibodies to the capsular polysaccharide of Hemophilus influenzae type b.

1996] The impact of conjugate vaccine on carriage of Haemophilus influenzae type b.

1992] The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. [J Infect Dis. 1983]. See more articles cited in this paragraph .. Hepatitis E among U.S. travelers, 1989-1992. . MMWR Morb Mortal Wkly Rep. 1993 Jan 15; 42(1):1-4. [MMWR Morb Mortal Wkly Rep. 1993]. Response to Haemophilus influenzae type B conjugate vaccine in children undergoing splenectomy.

. J Pediatr Surg. 1992 Aug; 27(8):1045-7; discussion 1048. [J Pediatr Surg. 1992]. Risk of Haemophilus influenzae type b disease in children with cancer and response of immunocompromised leukemic children to a conjugate vaccine.

Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin disease. Ann Intern Med. 1995 Dec 1; 123(11):828-34. [Ann Intern Med. 1995]. See more articles cited in this paragraph .. Immunization of leukemic children with Haemophilus conjugate vaccine.

Immunization response varies with intensity of acute lymphoblastic leukemia therapy. . Am J Dis Child. 1991 Aug; 145(8):887-91. [Am J Dis Child. 1991]. Antibody response to immunization with Haemophilus influenzae type b polysaccharide vaccine in children with cancer. . J Pediatr. 1987 Nov; 111(5):727-9. [J Pediatr. 1987] Risk of Haemophilus influenzae type b disease in children with cancer and response of immunocompromised leukemic children to a conjugate vaccine.

Review Critical appraisal of immunization strategies for prevention of infection in the compromised host.

1994] Immunogenicity of Haemophilus influenzae type b conjugate vaccine in allogeneic bone marrow recipients.

1984] Review Pneumococcal disease during HIV infection.

Review Serum therapy revisited: animal models of infection and development of passive antibody therapy.

Pneumococcal polysaccharide vaccine efficacy.

The 1979 J. Burns Amberson lecture.

Plasma anti-pneumococcal antibody activity of the IgG class and subclasses in otitis prone children.

IgG and IgM pneumococcal polysaccharide antibody responses in infants.

Correlation of serum opsonins with in vitro phagocytosis of Streptococcus pneumoniae.

1983] Pneumococcal polysaccharide immunization of children with sickle cell disease.

Bacterial meningitis and septicemia in sickle cell disease.

Pneumococcal polysaccharide immunization of children with sickle cell disease. Serologic response and pneumococcal disease following immunization.

Antibody response to pneumococcal vaccine in patients with multiple myeloma.

Antibody response to pneumococcal vaccine in patients with early stage Hodgkin's disease.

Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin disease.

Pneumococcal conjugate vaccine primes for antibody responses to polysaccharide pneumococcal vaccine after treatment of Hodgkin's disease.

Review Critical appraisal of immunization strategies for prevention of infection in the compromised host. . Hematol Oncol Clin North Am. 1993 Oct; 7(5):1027-50. [Hematol Oncol Clin North Am. 1993]. Polysaccharide conjugate vaccine responses in bone marrow transplant patients. . Transplantation. 1994 Mar 15; 57(5):677-84. [Transplantation. 1994] Pneumococcal vaccination of recipients of bone marrow transplants.

1994]. Pneumococcal immunity and response to immunization with pneumococcal vaccine in bone marrow transplant patients: the influence of graft versus host reaction. . Support Care Cancer. 1993 Jul; 1(4):195-9. [Support Care Cancer. 1993] Class- and subclass-specific pneumococcal antibody levels and response to immunization after bone marrow transplantation. . Clin Exp Immunol. 1992 Jun; 88(3):512-9.

[Clin Exp Immunol. 1992] Pneumococcal vaccination of recipients of bone marrow transplants. . Arch Intern Med. 1983 Sep; 143(9):1735-7. [Arch Intern Med. 1983]. See more articles cited in this paragraph .. Impaired response to pneumococcal vaccine in systemic lupus erythematosus. . Arthritis Rheum. 1980 Nov; 23(11):1287-93 [Arthritis Rheum. 1980] Persistence of pneumococcal antibodies after immunization in patients with systemic lupus erythematosus.

. J Rheumatol. 1984 Jun; 11(3):306-8. [J Rheumatol. 1984] Pneumococcal immunization in patients with systemic lupus erythematosus treated with immunosuppressives.

Review Pneumococcal disease during HIV infection.

Deficient antipneumococcal polysaccharide responses in HIV-seropositive patients.

1995] Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1.

Activation of virus replication after vaccination of HIV-1-infected individuals.

Human Genome. Influenza Virus.