A community health nurse would recommend pneumococcal vaccine for which group?

Journal Article

Bruce Gellin,

Bruce Gellin

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Received:

28 December 2000

Revision received:

09 March 2001

Published:

01 September 2001

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  Bruce Gellin, John F. Modlin, Cynthia G. Whitney, William Schaffner, Jay C. Butler, Rethinking Recommendations for Use of Pneumococcal Vaccines in Adults, Clinical Infectious Diseases, Volume 33, Issue 5, 1 September 2001, Pages 662–675, //doi.org/10.1086/322676

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Abstract

Pneumococcus remains a major cause of morbidity and mortality worldwide in spite of the availability of vaccines. Although young children have the highest rates of pneumococcal disease, elderly persons and adults with certain chronic illnesses are also at high risk for invasive pneumococcal disease, and in industrialized countries, they are much more likely to die of pneumococcal disease than are children [1]. In spite of appropriate therapy, case-fatality rates for bacteremic pneumococcal pneumonia have a range of 7%–35% [2]. Pneumococci that are resistant to penicillin and to multiple agents are becoming increasingly common among patients in all age groups [3], which makes pneumococcal infections more difficult to treat. The emergence of antibiotic-resistant pneumococci has placed renewed emphasis on the importance of disease prevention.

Pneumococcal vaccines were used as early as 1911 [4]. The first pneumococcal polysaccharide vaccines to be licensed in the United States, 2 different 6-valent formulations, were available shortly after World War II, but interest was very low in these vaccines and both were withdrawn from the market [5]. A 14-valent formulation was licensed in 1977, and in 1983, this vaccine was replaced by the 2 currently available 23-valent pneumococcal polysaccharide vaccines [Pneumovax 23, Merck; and Pnu-Immune 23, Wyeth-Ayerst Laboratories].

Although pneumococcal polysaccharide vaccines are no longer new, new information has become available in the past few years regarding people who are at risk for pneumococcal infections and the performance of the polysaccharide vaccines in a variety of populations. Periodic review of new information is critical to ensure that vaccines are used in the best possible manner. We summarize the recent literature related to pneumococcal vaccines for adults and factors that should be considered for recommendations to prevent invasive pneumococcal disease and pneumococcal pneumonia in adults.

Current Recommendations For Use Of Pneumococcal Vaccines In Adults

Pneumococcal polysaccharide vaccines are recommended for use in adults in many countries. In the United States, use of pneumococcal polysaccharide vaccines is recommended by several governmental and professional groups, including the Centers for Disease Control and Prevention's [CDC's] Advisory Committee on Immunization Practices [ACIP], the US Preventive Services Task Force, the American College of Physicians, the Infectious Diseases Society of America, the American College of Preventive Medicine, and the American Academy of Family Physicians [1, 6–11]. Although there are some minor differences in the recommendations, all these groups recommend vaccination for all adults aged ⩾65 years and for selected people aged 200 cells/mm3 were less likely to have received pneumococcal vaccine than were control subjects without pneumococcal disease [79]. In a case-control study conducted in Atlanta and San Francisco, 23-valent pneumococcal vaccine was 49% effective [95% CI, 12%–70%] for prevention of invasive pneumococcal disease in HIV-infected people aged 18–55 years; however, in multivariable analysis, effectiveness was greater for white persons [76%; 95% CI, 35%–91%] than it was for African-American persons [24%; 95% CI, −50% to 61%] [80]. Failure to demonstrate effectiveness among African-American persons may be due to limited power because of low vaccination rates for African-Americans, immunization at a more advanced stage of AIDS progression for African-American persons, or unmeasured factors. A randomized trial of 23-valent polysaccharide vaccine among HIV-infected people in Uganda showed no evidence of efficacy [59]. It should be noted that none of these studies was conducted among people who were receiving highly active antiretroviral agents, and no published study to date has evaluated the clinical impact of pneumococcal polysaccharide vaccine for persons receiving optimal antiretroviral therapy.

Cost-effectiveness. On the basis of surveillance data collected in the late 1980s and early 1990s, and of vaccine effectiveness estimates from epidemiological studies, an analysis of cost-effectiveness of pneumococcal vaccination of all people aged ⩾65 years for prevention of bacteremia and meningitis indicated that, from a social perspective, vaccination saved $8.27 per person vaccinated [81]. The cost savings associated with pneumococcal vaccination may be greater for elderly people who are at increased risk of serious pneumococcal disease due to certain chronic medical conditions. A review of pneumonia hospitalizations and deaths among elderly people with chronic lung disease in a managed care organization indicated that cost savings were between $115 and $512 over 2 years for each person vaccinated [77].

Revaccination

Anecdotal reports suggest that the recommendations for revaccination with pneumococcal polysaccharide vaccine are a source of confusion for clinicians. [The term “revaccination” is used for second or third doses of pneumococcal polysaccharide vaccine and other vaccines that do not induce immune memory. The term “booster dose” should be reserved for subsequent doses of vaccines that induce immune memory]. The ACIP recommends a one-time revaccination for people aged ⩾65 years if the patient was first immunized before age 65 years and at least 5 years earlier [1]; this recommendation has been misinterpreted as suggesting revaccination every 5 years. Revaccination recommendations from the ACIP and US Preventive Services Task Force [6] differ, which may add to the confusion. Both groups agree that the evidence to support recommendations for revaccination is limited, and neither group strongly recommends revaccination for any population. Because the risk of developing invasive pneumococcal disease and of dying from it increase with age, the timing and frequency of revaccination to provide optimal protection are critical issues.

There are limited data regarding how long protection provided by pneumococcal polysaccharide vaccines lasts, however. Concentrations of antibodies to pneumococcal polysaccharides remain greater than prevaccination levels for >5 years in healthy adults [35, 36] but decrease more rapidly in elderly persons and in those with certain underlying illnesses [37–46]. One epidemiologic study of polysaccharide vaccine effectiveness suggested lower effectiveness 5 years after vaccination in elderly persons [74]; another found no clear difference in effectiveness in people vaccinated at least 9 years earlier compared with people vaccinated more recently [72].

Revaccination with pneumococcal polysaccharide vaccine is associated with few systemic adverse events, although a recent large study found that local side effects are more common with revaccination than with initial vaccination [54]. This study compared the frequency of side effects in 901 patients who were aged 50–74 years and who had never been immunized with those in 513 patients who were the same age and who had been immunized at least 5 years earlier. Local reactions of ⩾4 inches [10.2 cm] were more common in revaccinated people [11%] than in people receiving their first dose [3%]; healthy subjects had a 5-fold risk of a large local reaction after revaccination compared with initial vaccination. The likelihood of a large local reaction correlated with prevaccination antibody concentrations. Investigators found no difference in the frequency of systemic symptoms and no serious side effects in either group.

Several studies have compared the immune response of revaccinees to first-time vaccine recipients [42, 54, 82–85]. In all studies but one [42], a study that mostly included Alaska Natives with chronic illnesses, peak antibody concentrations were lower after revaccination than they were after initial vaccination. Aging of the study subjects has been suggested as an explanation for the suboptimal immune response after revaccination, but the interval between immunizations was only 1–6 years [82–85]. A similar finding of hyporesponsiveness on revaccination has been well documented in children and young adults who had received a second dose of meningococcal serogroup C polysaccharide vaccine [86–89]; the reason for this finding is unknown. There are no studies that have measured the effectiveness of second or third doses of pneumococcal polysaccharide vaccine. Because the quantity of antibodies that correlate with protection against pneumococcal disease has not been clearly defined, it is unknown if the lower antibody levels seen on revaccination correlate with inferior protection.

Delivering Pneumococcal Vaccine

Most patients who could benefit from pneumococcal polysaccharide vaccine have not yet received it. According to the 1997 Behavior Risk Factor Surveillance System, a phone survey of noninstitutionalized adults, only 46% of adults aged ⩾65 years reported ever having received pneumococcal vaccine [90]. Coverage levels were significantly higher in 1997 than they were in 1995, when only 37% of respondents aged ⩾65 years reported receiving vaccine [91]. Vaccine coverage levels differ by race and ethnic group, age, and health status; coverage is significantly lower among African-American persons [30% among African-Americans aged ⩾65 years] and Hispanic persons [34%] than it is among non-Hispanic white persons [47%] [91]. Only 17% of people 18–64 years old with high-risk conditions reported previous receipt of pneumococcal vaccine in another national survey conducted in 1997 [92]. Use of vaccines in institutionalized adults also is suboptimal. Estimates from the 1997 National Nursing Home Survey indicate that only 28% of people in long-term care facilities had received pneumococcal vaccines [92]. The Healthy People 2010 objectives for pneumococcal immunization call for 90% of all people aged ⩾65 years and 65% of high-risk adults 18–64 years old to receive pneumococcal vaccine [93].

The reasons why pneumococcal vaccine has not been delivered more effectively to its targeted populations are numerous and varied. They relate to adult immunization issues generally and to pneumococcal vaccine specifically. Adults often do not visit physicians regularly, and when they do, many insurance plans do not cover provision of preventive services, including vaccines. Even in instances in which insurance plans include vaccine administration, payment to the physician usually is modest, providing little incentive to aggressively pursue immunization.

Although many physicians wish to provide appropriate vaccine services to their patients, information about vaccine developments and recommendations may reach them only sporadically. Although pediatricians regularly receive updates regarding the childhood immunization schedule from public health agencies, professional societies, and vaccine manufacturers, these sources of continuing education are less likely to deliver vaccine information to physicians who care for adults. This type of information may be even less likely to reach medical subspecialists, such as rheumatologists, cardiologists, or nephrologists, who provide care for a substantial proportion of adults and who frequently are the sole source of medical care for their patients, many of whom have indications for immunization.

Some features of the successful childhood immunization program in the United States are not applicable to adult immunization activities. The National Immunization Program provides funding and technical assistance to state and local health departments in providing immunization services to infants and children. Furthermore, in many states, school entry laws require nearly all children to be vaccinated with certain vaccines. Neither of these mechanisms is available to assist in the vaccination of adults; however, some states recently have instituted requirements that pneumococcal vaccine be offered to all patients admitted to long-term care facilities. Electronic immunization registries for tracking childhood immunizations are underway in some states; whether registries would be useful or feasible for improving adult immunization is unknown.

Several factors specific to pneumococcal vaccine have impeded its more widespread use. Whereas an examination of national morbidity data clearly defines invasive pneumococcal disease as a substantial public health problem, clinicians may perceive the issue with less concern. Rates of invasive disease in the general population are sufficiently low such that even busy practitioners may go many years without encountering a case of pneumococcal bacteremia in their practice. Therefore, practitioners may not feel compelled to protect their patients against a risk that is perceived as remote. Although protection against pneumonia is considered important, the efficacy of the vaccine in preventing pneumonia continues to be treated with skepticism in the literature [65, 94]. Concern regarding side effects with revaccination may inhibit some clinicians from vaccinating patients, especially those patients with several doctors or whose vaccination records are missing or incomplete.

Nevertheless, even many patients who feel negatively about vaccines would agree to receive pneumococcal vaccine if their health care provider offered it [95]. In addition, many options are available to improve vaccine delivery. Several studies have found that the use of standing orders—orders that authorize nurses or pharmacists to administer vaccines according to a preapproved protocol and without direct physician involvement at the time of the interaction—may be the best means of improving vaccine delivery to adults in hospitals, clinics, and long-term care facilities [96–98]. A recent review of interventions to improve rates of vaccination concluded that there was strong evidence that standing orders are effective in improving vaccination coverage in adults [99]. Standing orders for vaccine delivery are recommended by the Task Force on Community Preventive Services [100], the ACIP [92], and by the Canadian Community Health Practice Guidelines Working Group [101]. Other recommended methods of improving vaccine coverage among adults include the use of client and provider reminders, patient education, interventions that reduce client out-of-pocket costs, and assessment and feedback of provider vaccination rates; for populations that are difficult to reach, home visits or expanded access to health care settings may be needed [100]. Financial incentives, such as increasing reimbursement for vaccination, providing reimbursement for preventive health visits, or ensuring that insurers cover adult immunizations, could improve vaccine coverage.

Changing pneumococcal vaccine recommendations to include all adults aged ⩾50 years has been suggested as a means of simplifying the vaccine indications, harmonizing the indications with the expanded recommendations for influenza vaccine, and improving coverage among high-risk people aged 50 years, the number of adults with a vaccine indication would increase by 17–37 million, depending on the strategy. Currently, only 2 manufacturers produce pneumococcal polysaccharide vaccine in the United States. In addition to concerns regarding the timing and effectiveness of revaccination, vaccine supply will need to be considered if health care providers were to begin immunizing new groups without causing relative shortages in vaccine availability for others at high risk. Adequacy of the vaccine supply has recently been a concern with influenza vaccine [103]. In 1994, orders for pneumococcal vaccine were delayed during a shortage that lasted a few months [R. Strikas, personal communication]; the shortage was resolved after manufacturers increased capacity to keep up with increases in demand that had occurred from 1993 through 1994.

Table 3

Number of adults in the United States with vaccine indications, according to various strategies.

New Pneumococcal Vaccines

Pneumococcal conjugate vaccines. A recent advancement in prevention of pneumococcal disease is the development of pneumococcal conjugate vaccines. A 7-valent pneumococcal conjugate vaccine was licensed in the United States for prevention of invasive pneumococcal disease in infants and young children in early 2000 [23] and is now licensed in several other countries. By conjugating polysaccharide antigens to a carrier protein, the immunologic responses elicited become T cell dependent. Memory B cells are produced and primed for booster responses—rapid and dramatic increases in antibody concentrations to subsequent immunizations with pneumococcal polysaccharide [104]. Pneumococcal conjugate vaccines appear to be safe and to induce primary and booster antibody responses in infants and young children [104, 105]. A randomized trial of 7-valent pneumococcal conjugate vaccine among 37,000 infants enrolled in a large northern California health maintenance plan documented efficacy >90% for prevention of invasive pneumococcal disease caused by the 7 serotypes included in the vaccine [106]. Several other large randomized trials assessing the efficacy of conjugate vaccines to prevent invasive infection and acute otitis media in infants are ongoing.

The role of conjugate vaccines among adults with underlying medical conditions and elderly persons remains to be determined. Preliminary data from studies of healthy people aged ⩾50 years and of patients vaccinated after treatment for Hodgkin's disease indicate that antibody responses to pneumococcal conjugate vaccines have not been substantially better than responses to the polysaccharide vaccine [107, 108]. In one study, localized reactions [pain, stiffness, and induration at the injection site] were more common among people who received the conjugate vaccine, although these symptoms were generally mild [107]. In one family, administration of pneumococcal conjugate vaccine produced IgG responses in several people who lacked the capacity to respond to polysaccharide vaccine [109]. One approach to the use of conjugate vaccines in adults is to sequentially administer conjugate vaccine and 23-valent polysaccharide vaccine; giving conjugate vaccine first could prime the immune system, and the polysaccharide vaccine could then induce a booster response to the serotypes present in both vaccines as well as induce primary T cell—independent responses to the serotypes in the 23-valent vaccine only [104, 110, 111].

A potential shortcoming of conjugate vaccines is that the number of serotypes that can be included may be limited [112], and people who are vaccinated would remain susceptible to most of the serotypes not included in the vaccine. Most conjugate pneumococcal vaccines under evaluation contain capsular polysaccharides of 7 to 11 serotypes. Among preschool-aged children in the United States, the 7 most common serotypes [4, 14, 6B, 19F, 18C, 23F, and 9V] account for 80% of blood and CSF isolates in the United States, but only 50% of isolates among older children and adults [17, 23, 113]. Therefore, vaccine formulations that are based on the most prevalent serotypes among children may not provide optimal serotype coverage for prevention of pneumococcal infections in adults. However, immunogenicity and effectiveness are limited for polysaccharide vaccine for several pneumococcal serotypes that commonly cause serious infection in adults. If conjugate vaccines are more immunogenic against these serotypes in adults, overall effectiveness could theoretically be greater with conjugate vaccines, despite more limited serotype coverage [114].

Possible future pneumococcal vaccines. A promising approach for prevention of pneumococcal infections is to develop vaccines directed against noncapsular antigens common to all pneumococcal serotypes. Candidate antigens include a number of pneumococcal proteins: neuraminidase, autolysin, pneumolysin, pneumococcal surface proteins A and C [PspA and PspC], pneumococcal surface adhesin A [PsaA or 37-kDa protein], and putative proteinase maturation protein A [PpmA] [115–119]. These proteins could not only provide protection against all pneumococcal serotypes, but they could also induce a T cell—dependent response with immunologic memory. To date, only pneumolysin, PspA, and PsaA have been extensively examined for suitability as vaccine candidates, and only PspA has been tested in humans [120]. In this trial, vaccination with PspA led to an increase in circulating antibodies, and analysis of postvaccination serum samples showed increased binding to a variety of PspA and capsule types. Intranasal immunization of mice with PspA induced mucosal and systemic antibody responses, prevented pneumococcal colonization, and provided protection against systemic infection after intravenous, intratracheal, and intraperitoneal challenge [121]. A vaccine consisting of a live recombinant Salmonella typhimurium vaccine strain expressing pneumococcal PspA colonized gut-associated lymphoid tissues, spleens, and livers of orally immunized mice, induced serum and mucosal anti-PspA antibodies, and provided protection against challenge by a mouse-virulent Streptococcus pneumoniae [122].

An innovative approach to immunization involves introduction of a DNA plasmid carrying a protein-coding gene into the vaccine recipient's own cells, which leads to expression of an antigen that elicits an immune response [so-called “DNA vaccines”]. Such immunizing agents could be manufactured more easily and may be more stable during storage and distribution than vaccines composed of inactivated or attenuated microorganism, subcellular fractions, or recombinant proteins. Results of preliminary work on a pneumococcal DNA vaccine in laboratory animals are promising. Immunization of mice with a plasmid expressing PspA has been shown to induce a significant immune response and provided some protection against a challenge with intravenously administered serotype 3 S. pneumoniae [123]. However, a great deal of research remains to be done to clearly demonstrate safety, immunogenicity, and efficacy of DNA vaccines in humans.

Conclusions

Given the substantial morbidity and mortality caused by pneumococcal disease, periodic evaluations of the appropriateness of guidelines for use of pneumococcal vaccines are important. Several recent studies have provided information that is useful for the evaluation of current vaccine recommendations. The current recommendations for use of pneumococcal polysaccharide vaccines address most adults at high risk for invasive pneumococcal disease. African-American persons and smokers have recently been noted to have higher disease rates than do white persons and nonsmokers, and the increased risk in these groups is not specifically addressed by current recommendations. Discussions of changing vaccine recommendations should include whether the expected benefit from adding new groups to the recommendations outweighs the potential problems of cost and limited vaccine supply. Vaccine coverage is suboptimal, especially in minority groups and in high-risk people aged