V(H)3 antibody response to immunization with pneumococcal polysaccharide vaccine in middle-aged and elderly persons

Pneumococcal disease continues to cause substantial morbidity and mortality among the elderly. Older adults may have high levels of anticapsular antibody after vaccination, but their antibodies show decreased functional activity. In addition, the protective effect of the pneumococcal polysaccharide vaccine (PPV) seems to cease as early as 3 to 5 years postvaccination. Recently, it was suggested that PPV elicits human antibodies that use predominantly V_H3 gene segments and induce a repertoire shift with increased V_H3 expression in peripheral B cells. Here we compared V_H3-idiotypic antibody responses in middle-aged and elderly subjects receiving PPV as initial immunization or revaccination. We studied pre- and postvaccination sera from 36 (18 vaccine-naïve and 18 previously immunized subjects) middle-aged and 40 (22 vaccine-naïve and 18 previously immunized subjects) elderly adults who received 23-valent PPV. Concentrations of IgGs to four individual serotypes (6B, 14, 19F, and 23F) and of V_H3-idiotypic antibodies (detected by the monoclonal antibody D12) to the whole pneumococcal vaccine were determined by enzyme-linked immunosorbent assay (ELISA). PPV elicited significant IgG and V_H3-idiotypic antibody responses in middle-aged and elderly subjects, regardless of whether they were vaccine naïve or undergoing revaccination. Age did not influence the magnitude of the antibody responses, as evidenced by similar postvaccination IgG and V_H3 antibody levels in both groups, even after stratifying by prior vaccine status. Furthermore, we found similar proportions (around 50%) of elderly and middle-aged subjects experiencing 2-fold increases in V_H3 antibody titers after vaccination. Age or repeated immunization does not appear to affect the V_H3-idiotypic immunogenicity of PPV among middle-aged and elderly adults.Streptococcus pneumoniae is the leading cause of bacterial pneumonia and bacterial meningitis in the United States, resulting in 175,000 hospitalizations and 7,000 to 12,000 deaths annually. Groups with the highest incidences of pneumococcal infection include the very young, the elderly, persons who are immunocompromised, smokers, and certain other demographic groups (2, 8). In persons 65 years or older, the incidence of invasive pneumococcal disease (IPD) is around 50 per 100,000 individuals per year and is associated with a case fatality rate of 20%, whereas among those aged 85 years or older, the fatality rate increases to 40% (2, 34).The Advisory Committee on Immunization Practices recommends vaccinating all adults aged 65 years or older with the 23-valent pneumococcal polysaccharide vaccine (PPV). One-time revaccination for this age group is also recommended if subjects received their first dose ≥5 years previously and before the age of 65 years (6). A recent meta-analysis provided evidence supporting the recommendation for PPV to prevent IPD in adults. However, it did not provide compelling evidence to support the routine use of PPV to prevent all-cause pneumonia or mortality (15). In addition, significant protection against IPD seems to be lost as early as 3 to 5 years after vaccination in persons older than 65 years (28, 29).A common surrogate for antibody-mediated protection is the measurement of postvaccination IgG antibody to capsular polysaccharides contained in PPV. Validation of this measure may be disputed given the fact that even adequate IgG concentrations in the elderly may have significant reductions in antibody functional activity toward pneumococcal polysaccharide antigens (25). Molecular characterization of the immune response to pneumococcal polysaccharides is seldom performed in clinical vaccine studies (24); however, there is a large body of literature on this subject (3, 5, 7, 22, 38). Recent studies have demonstrated that PPV stimulates increased expression of variable region heavy chain family 3 (V_H3) genes in peripheral B cells from immunocompetent subjects, yielding serum polysaccharide-specific antibodies and/or B cells that express V_H3 (1, 7, 32, 33). V_H3 responses may also correlate with functional activity of antipneumococcal antibodies (3).Previous studies on gene expression of the total circulating B-cell population demonstrated a shift toward V_H4 and V_H1 expression in aging humans, compared with predominant V_H3 expression in young subjects (35). This repertoire shift has been postulated as a possible mechanism of decreased pneumococcal anticapsular antibody function in older populations. In this regard, a preliminary report (30) found lower levels of V_H3-idiotypic antibody responses to capsular polysaccharides from serotype 4, but not serotype 14, in the elderly than in young individuals. A subsequent study (11) of the V_H gene repertoire of human peripheral B cells specific for these two capsular polysaccharides (4 and 14) revealed that the responses in both age groups were dominated by the V_H3 gene family (>90%). The V_H1, V_H4, and V_H5 gene families were also isolated from both groups, but they constituted <10% of the total heavy chain repertoire. Given the attractiveness of the study of V_H3-idiotypic antibody responses to assess the immunogenicity of pneumococcal polysaccharide antigens and the need for further studies on its role in aging, we evaluated IgG and V_H3-idiotypic antibody responses after administration of PPV in sera from a subset of vaccine-naïve and revaccinated middle-aged and elderly subjects enrolled in a pneumococcal vaccine clinical trial (19).