|Home | About | Journals | Submit | Contact Us | Français|
Persons with spinal cord injury (SCI) are predisposed to develop pneumonia. This study was undertaken to determine the effect of revaccination with the pneumococcal vaccine on the immune response and the frequency of adverse reactions in this population.
An enzyme-linked immunosorbent assay was used to measure immunoglobulin G to selected pneumococcal capsular polysaccharides on sera collected from 23 persons who were revaccinated 5 years after primary vaccination. Sera were collected just prior to, 1 month, and 1 year following revaccination. Functional activities of serotype-specific antibodies were determined by opsonophagocytosis assays.
Several subjects maintained protective antibody concentrations at baseline. Increases in antibody concentrations were observed for all serotypes at 1 month and 1 year. Opsonophagocytic activity increased over baseline when evaluated 1 month and 1 year after revaccination, and a significant positive correlation was observed between antibody concentration and opsonophagocytic activity at all 3 time points. Three persons (13%) experienced transient and self-limited local swelling and pain at the injection site following revaccination.
Protective antibody may be present in some persons for at least 5 years after vaccination. Revaccination induces a secondary surge in antibody concentration and opsonophagocytic activity that varies according to serotype but may be of lesser magnitude than the primary response. Revaccination of persons with SCI is not associated with significant adverse effects. Whether revaccination is needed beyond 5 years will require additional investigation.
Approximately 10,000 new spinal cord injuries (SCI) occur annually in the United States with an estimated 247,000 survivors in 2004, with a projected increase to 276,000 by 2014 (1). Persons with SCI are living longer than ever before, even though life expectancies are still lower than in the general population. With increasing life expectancy, there is also increased opportunity for development of secondary medical complications that can negatively impact quality of life.
Among persons with SCI, the elderly and individuals with tetraplegia and/or complete lesions are especially predisposed to develop pneumonia because of a variety of mechanical problems resulting from respiratory muscle paralysis and loss of neural control mechanisms. Persons with SCI are more likely to die of pneumonia than are comparable individuals in the general population (2). In fact, respiratory complications, including pneumonia, are the most common causes of death during acute and chronic phases of SCI according to multiple studies (2–4). Pneumonia occurs in nearly one third of all patients during their initial hospitalization after injury (5). Thus, infectious complications of the respiratory tract are of significant importance from the initial period following injury throughout the remainder of the lives of persons with SCI. Progressive compromise of the respiratory system and diminished ability to counteract infections as part of the normal aging process are also reasons for concern as more persons with SCI are growing older. Given the importance of respiratory complications as secondary conditions following SCI, preventive strategies should receive high priority.
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and is the most common pathogen leading to hospitalization for pneumonia (6). The risks of developing invasive pneumococcal bacteremic disease and dying from it increase with age (7). The 23-valent pneumococcal polysaccharide vaccine, licensed in the United States in 1983, has been shown to reduce the occurrence of pneumococcal pneumonia and bacteremia, especially in young adults (8). Our previous study (6) demonstrated that an immune response was maintained for at least 1 year following vaccination in a cohort of persons with SCI, and we recommended that administration of pneumococcal vaccine be part of standard care soon after injury. Studies of other patient populations have shown that postvaccination antibody levels and protective efficacy decline over time, suggesting that vaccine-induced protection may not be lifelong because the vaccine does not induce significant T-cell activation or immune memory (8–14). Since SCI occurs most often in young persons, the need for studies on long-term immunogenicity of the current 23-valent pneumococcal vaccine and the risks and benefits of revaccination is apparent.
In the present investigation, we sought to quantify and determine functional activities of antibodies directed against multiple representative pneumococcal serotypes, the effect of revaccination on the immune response, and the frequency of adverse reactions in a group of persons with SCI who received 0.5 mL of the 23-valent pneumococcal vaccine PNEUMOVAX 23 (Merck and Co, West Point, PA) in the deltoid or lateral mid-thigh at least 5 years after primary vaccination. This study was performed with approval of the Institutional Review Board for Human Use, and informed consent was obtained from all participants.
The study population consisted of 23 community-residing adults with SCI who received primary pneumococcal immunization from 1993 through 1998. Most participants were young to middle-aged men of either white or African American ethnicity who were either tetraplegic or paraplegic, none of whom was older than age 65 years (Table 1). None of the participants had significant chronic underlying conditions or immunosuppressive illnesses that would make them unlikely to mount an immune response following vaccination. Participants were revaccinated when 5 years (±1 month) had elapsed following the primary vaccination. Sera were obtained just prior to, 1 month, and 1 year following revaccination. All sera were stored frozen at −70°C until tested. All serum samples from each individual were tested at the same time to assure comparability of results.
Antibody concentrations against 5 pneumococcal serotypes (3, 4, 14, 19F, and 23F) included in the 23-valent vaccine and known to cause pneumococcal infections in adults were measured spectrophotometrically in microtiter plates coated with 100 μL of serotype-specific pneumococcal polysaccharide antigens (American Type Culture Collection, Manassas, VA) using an enzyme-linked immunosorbent assay (ELISA) (15). Data were imported into a desktop computer and stored as an ASCII text file. The Centers for Disease Control and Prevention (CDC) ELISA software program (15) abstracted the standard series, individual serum samples, and quality control samples from this file and calculated a standard curve using a 4-parameter logistic-log method that was then used to interpolate antibody concentrations in each specimen.
Measurement of antibody responses to capsular polysaccharides by ELISA provides the basis for assessing vaccine immunogenicity in vitro, but this may not correlate directly with the protective function of pneumococcal antibodies, especially for adults, and does not differentiate nonprotective low-avidity antibodies from protective high-avidity antibodies. Thus, tests measuring opsonophagocytic activity and the functional quality of antibodies produced may ultimately be more relevant for evaluating response to pneumococcal vaccination since host protection is mediated primarily by phagocytosis with participation of serum opsonins such as antibody and complement (16–18).
We performed the opsonophagocytic killing assay (OPKA) for 3 selected serotypes (14, 19F, and 23F) on sera collected at the various time points to determine functional antibody activity that was then compared with ELISA results. Performance of OPKA for each of the 3 pneumococcal serotypes involved measurement of complement-dependent opsonic activity of serum samples incubated with S pneumoniae of the homologous serotype and differentiated phagocytic cells HL-60 cells from the promyelocytic leukemia line (19). Phagocytosis was determined by viable counts of S pneumoniae, and OPKA titers were expressed as the reciprocal of the serum dilution that had 50% bacterial killing. Values greater than the upper limit of the assay (8748) were reported as 17,496. Values less than the lower limit of 4 were reported as 2. The cost and time-consuming aspects of performing OPKA assays required us to limit evaluation to only 3 pneumococcal serotypes.
Administration of a second pneumococcal vaccine can be associated with a higher incidence of local Arthus-type reactions caused by formation of antigen-antibody complexes at the injection site. Such local reactions may correlate with higher levels of circulating antibodies (9), so there is some concern about administering a second vaccine. All 23 persons who received a secondary pneumococcal vaccination were contacted by telephone after 24, 48, and 72 hours and after 7 days to inquire about occurrence of fever, tenderness, induration, and erythema at the site of injection, as well as myalgias, chills, and other systemic complaints.
The numbers and percentages of persons with an antibody protein concentration greater than or equal to 0.35 μg/mL for each serotype as measured by ELISA and considered protective (20) were calculated at the 3 respective time points along with the respective 95% confidence intervals. The value of 0.35 μg/mL or greater has been suggested as a threshold for protective antibody concentrations for children. It was used in our study population due to the lack of another rigorously defined criterion specific for younger adults. The percentage of persons with at least twofold increases in antibody concentration over baseline at 1 month and 1 year and the respective 95% confidence intervals were also described for each serotype at each time point, as suggested by the CDC Advisory Committee on Immunization Practices (ACIP) to define a clinically significant antibody response in young adults (21). The ELISA and OPKA data were transformed logarithmically and expressed as geometric means (GM) at each time point stratified by capsular serotypes. Statistical significance of comparisons in log-transformed data among the various time points was examined using a paired t test. A P ≤ 0.05 was considered significant. Pearson correlation analysis was performed to assess the correlation between the log-transformed ELISA and OPKA measures at each time point, stratified across capsular serotypes.
Several of the 23 study participants had protective antibody concentrations of 0.35 μg/mL or higher at baseline. The numbers of persons with such protective antibody concentrations varied according to serotype, ranging from 9 (39%) for serotype 3 to 23 (100%) for serotype 19F, consistent with the fact that all of these individuals had received pneumococcal immunization in the past (Table 2). When evaluated 1 month following revaccination, the number of participants with protective antibody concentrations increased, ranging from 16 (70%) for serotype 3 to 100% for serotypes 12 and 19F. One year following revaccination, the majority of persons maintained protective antibody concentrations ranging from 13 (57%) against serotype 3 to 100% for serotypes 19F and 23F.
An increase in antibody concentration at least twofold above baseline level was observed 1 month after revaccination in some participants for each serotype (Table 3). The percentages ranged from 35% for serotype 19F to 65% for serotype 4. The number of study participants that maintained this twofold or greater increase above baseline levels 1 year following revaccination had diminished somewhat for all of the serotypes tested. Only 3 persons (13%) maintained this twofold or greater increase in antibody concentration above baseline for serotype 19F, whereas 12 (52%) maintained this level against serotype 4.
Comparison of GM antibody concentrations for the study population at 1 month and 1 year following revaccination stratified by serotype (Table 4) showed a significant increase over baseline values for all 5 serotypes at both time points except for serotype 19F at the 1-year time point (P = 0.08). As expected, GM antibody concentrations were highest at 1 month following revaccination; they had declined somewhat after 1 year had elapsed, but were still greater than baseline values for all 5 serotypes.
Geometric mean OPKA titers ranged from 17.96 (serotype 19F) to 314.27 (serotype 14) at baseline. Significant increases in GM OPKA titers over baseline were observed when evaluated 1 month after revaccination for serotypes 14, 19F, and 23F. One year after revaccination, the increased GM OPKA titer remained significant only for serotypes 14 and 23F (Table 5).
Correlation coefficients of association (r values) determined between GM antibody concentrations and GM OPKA titers for serotypes 14, 19F, and 23F measured at baseline, 1 month and 1 year following revaccination showed a significant positive correlation at all 3 time points for all serotypes tested (Table 6).
Three of 23 persons (13%) experienced transient and self-limited local swelling and pain at the injection site within a few hours following the second vaccination. No fever, systemic complaints, or other adverse events were reported.
Antibody levels to pneumococcal vaccine antigens remain elevated for at least 5 years in healthy adults after initial vaccination, but may decline more rapidly in elderly persons and those with underlying illnesses, eventually decreasing to prevaccination levels (7,22,23). Data from one epidemiologic study suggested that vaccination may provide protection for at least 9 years (24), while another found lower effectiveness 5 years after vaccination in elderly persons (13). Comparatively little information is available regarding vaccine effectiveness in younger persons since most of them do not meet the current criteria for receiving the vaccine unless underlying diseases are present. For this reason, persons with SCI, who are typically injured at relatively young ages while otherwise in good health, are especially valuable for study of the immunogenicity of pneumococcal polysaccharide vaccines.
Concern for declining vaccine effectiveness in protection against pneumococcal infections over time led to consideration for the need to administer secondary vaccinations in persons at greatest risk for poor outcome from invasive pneumococcal infections. The CDC recommends revaccination of immunocompetent adults who are at highest risk for serious pneumococcal infection and those who are likely to have a rapid decline in pneumococcal antibody levels, provided that 5 years have elapsed since receipt of the first dose of pneumococcal vaccine (25). Persons who are aged 65 years or older should be revaccinated once if they were aged less than 65 years at the time of primary vaccination. However, no specific recommendations for revaccination of persons with SCI are provided, and no data on the benefits or safety of revaccination for this population have been reported to date.
The general conclusion of most studies on revaccination reported to date is that while a secondary immune response occurs, it is of similar or sometimes lower magnitude than the response following initial vaccination, and antibody levels will again decline over time (9,10,14,17,21,26–32). Since immunologic memory is not induced by this polysaccharide vaccine, revaccination cannot be expected to produce an anamnestic or “booster” response (8,17). It should be noted that earlier studies of revaccination have included small numbers of subjects and have been limited to antibody quantitation, rather than measuring their functional capacity. Possible explanations why secondary vaccination induces a less robust immune response have included the possibility that underlying comorbidities may affect ability to mount an immune response or the induction of immunologic tolerance due to prior antigen exposure (33).
Although no clinical studies have correlated measurement of antibody function with vaccine effectiveness, some data suggest opsonophagocytic activity may be important in protection against pneumococcal disease (17). However, the assay is complex to perform and is not standardized. Therefore, slight variations can be expected in actual titers that are measured. To our knowledge, this study is the first in any population to investigate the immune response following a second pneumococcal vaccination utilizing antibody quantitation as well as assessment of functional antibody activity.
In this study, we evaluated in a quantitative manner the immune response following revaccination in 23 persons with SCI by measuring the overall rise of GM antibody concentrations above baseline; documenting a rise in antibody concentration at least twofold over baseline; and documenting the occurrence of protective antibody concentrations with data stratified across 5 pneumococcal serotypes. Since all 23 subjects had received primary pneumococcal vaccination at least 5 years previously, it was not surprising that the majority of them had protective antibody concentrations at baseline against 4 of the 5 serotypes and that some degree of antibody increase occurred following revaccination, the magnitude of which was greater at 1 month than after 1 year. As expected, we found some differences in the immune response according to serotype, consistent with findings of our earlier study (6). In our initial study of 41 persons with SCI who received primary pneumococcal vaccination (6), 32% to 73% of those individuals had a twofold or greater increase in antibody concentrations against 5 serotypes measured 1 month after vaccination. This compares to 35% to 65% for the same serotypes in the present study following revaccination. Thus, we can conclude that some protection is still evident for at least 5 years following primary vaccination for many persons with SCI and that revaccination will elicit an immune response that varies according to serotype.
We were especially interested in assessing the degree of opsonophagocytic activity of serotype-specific anticapsular antibodies following revaccination because so few data are available. We observed that opsonophagocytic activity was detectable at baseline with GM OPKA titers ranging from 17.96 for serotype 19F to 314.27 for serotype 14. Titers increased significantly for all 3 serotypes 1 month following revaccination, and this significant increase over baseline was maintained after 1 year with the exception of serotype 19F, for which the GM titer after 1 year was still greater than baseline, but not significantly so (P = 0.06). As we observed for antibody concentrations, the OPKA titers varied according to serotype, with serotype 14 having the highest OPKA titers at all 3 time points. At present, there is no universally accepted definition of what constitutes a protective OPKA titer for young adults, but it was especially encouraging that we were able to detect significant increases over baseline values following revaccination. Our finding of a strong correlation of antibody functional activity with concentration in this population following revaccination is consistent with limited studies performed following primary vaccination of other populations (34,35).
The potential for adverse effects associated with revaccination has been addressed in some of the studies that investigated immunogenicity. Jackson et al (10) compared postvaccination events among persons aged 50 to 74 years who were revaccinated 5 or more years following initial vaccination with persons being vaccinated for the first time. They determined that local injection site reactions were more common among persons who were revaccinated than for first-time vaccine recipients (11% vs 3%), but such reactions were self limited and resolved within a median of 3 days time. Rates of systemic symptoms, including fever, were low and did not differ between the 2 groups. No serious adverse events were identified. Other studies of revaccination of elderly and/or chronically ill persons have concluded that revaccination is generally safe, and any side effects that occur are primarily mild, local, and self-limited (9,21,30,31). The 13% rate of self-limited local reactions at the injection site in our subject population comprised primarily of younger persons with SCI was comparable to that reported earlier (10), and we did not encounter any instances of more severe adverse events. No data are available to allow estimates of adverse reaction rates among persons who received more than 2 doses of pneumococcal vaccine.
Our data suggest that protective levels and functional antibodies persist against multiple serotypes in many persons with SCI who are under 65 years of age for at least 5 years after pneumococcal vaccination. Moreover, revaccination of persons with SCI induces a secondary surge in antibody concentration that varies according to serotype but may be of smaller magnitude than the primary response for some serotypes. This increase in antibody concentration is highly correlated with functional opsonophagocytic activity, which also increases following revaccination. Revaccination of persons with SCI is not associated with significant adverse effects. The results of this study do not support the need to revaccinate persons with SCI who are under 65 years of age after 5 years have elapsed since many of them have maintained antibodies against multiple pneumococcal serotypes at this time. Whether revaccination is needed at a later time point will require additional investigation involving longer follow-up times. This study did not address revaccination of older persons with SCI, but we have no reason to disagree with the current CDC recommendations for the general population that all persons who are 65 years of age or older should be revaccinated if the initial vaccination was given prior to age 65 and at least 5 years have elapsed.
The authors thank Drs Amie Jackson and C. T. Huang for allowing access to their patients and encouraging them to participate in this study. The technical assistance of Rob Burton and Catherine Wernette for performance of the opsonophagocytosis and enzyme-linked immunosorbent assays is gratefully acknowledged.
This work was supported by grant H133B980016 from the National Institute on Disability and Rehabilitation Research and was presented in part at the International Symposium on Pneumococci and Pneumococcal Diseases, Helsinki, Finland, May 10, 2004.