Pneumococcal vaccination of older adults

Abstract

Invasive pneumococcal disease continues to be important problem for older adults. Pneumococcal polysaccharide vaccine (PPV23) has a clinical effectiveness of 43–81%, and following primary vaccination and revaccination, antibody responses last 5–10 y. Hyporesponsiveness to a second dose of vaccine has not been shown to be a significant problem. The use of pneumococcal conjugate vaccines (initially PCV7; more recently PCV13) has led to a dramatic fall in the incidence of conjugate vaccine-type invasive pneumococcal disease in children. Because PCVs are immunogenic in older adults, the question has arisen as to whether to also use PCVs in this age group. However, PCV vaccination of children has also reduced the incidence of conjugate vaccine-serotype disease in older adults, and so wherever PCVs are used in children, there is no epidemiological reason to vaccinate older adults with PCV. The cost-effectiveness of PPV for older adults has changed wherever PCVs have been used for children, and this needs to be periodically re-evaluated.

Keywords: :

• pneumococcal polysaccharide vaccine
• pneumococcal conjugate vaccine
• older adults
• cost-effectiveness

Early mortality in pneumococcal bacteremia

Historical studies have shown the importance of early intervention in improving survival in patients with pneumococcal bacteremia and pneumococcal pneumonia (non-bacteremic as well as bacteremic cases) (Fig. 1).¹ This insight provided the basis for developing the first pneumococcal polysaccharide vaccine. The clinical efficacy of an experimental 13-valent pneumococcal polysaccharide vaccine was shown in a clinical trial among South African gold miners. In this trial, vaccine efficacy in preventing pneumococcal bacteremia was 82.3% (Table 1).² The vaccine was also efficacious in preventing all cases of pneumococcal pneumonia and in preventing more than half of all cases of radiographically-confirmed pneumonia, regardless of microbial cause.³

Figure 1. Diagrammatic representation of the overlap between pneumococcal pneumonia and invasive pneumococcal disease.

A number of case-control studies have been conducted to assess the effectiveness of pneumococcal polysaccharide vaccine in preventing invasive pneumococcal disease in older adults. Vaccination effectiveness has ranged from 43–81%. A recent report has reviewed the long-term antibody responses to 23-valent pneumococcal polysaccharide vaccine (PPV23) in older adults and the impact of vaccination on serotype-specific incidence of invasive pneumococcal disease.⁴ The reviewers concluded that PPV23 was effective, particularly in healthy individuals less than 75 y of age, but protection waned after 5 y. There was no discernible impact of PPV23 on population incidence of IPD. Based on vaccine efficacy estimates, PPV23 was still considered a cost-effective intervention for the low-risk elderly.

Long-term protection

Antibody persistence following PPV23 vaccination was examined in a large study of ambulatory adults ≥ 50 y of age.⁵ Study subjects were PPV23 naïve and had no previous history of invasive pneumococcal disease. Immunoglobulin G (IgG) and functional antibody levels were measured in 444 primary vaccination subjects and in 564 revaccination subjects. In the primary vaccination group, IgG antibodies were evaluated in 308 subjects at 5 y and in 72 subjects at 10 y. In the revaccination group (median time since primary vaccination = 3.9 y), IgG and functional antibody levels 3–5 y after primary vaccination and revaccination were similar. Ten years after revaccination, mean IgG concentrations still exceeded vaccine-naïve levels.⁵ Although the results indicated that increased antibody levels persisted for many years, there are still no data on long-term clinical protection afforded by primary vaccination or revaccination with PPV23.

Revaccination and hyporesponsiveness?

It has been hypothesized that revaccination of older adults with PPV23 is associated with hyporesponsiveness.⁶ Earlier studies of combined schedules of PPV23 and pneumococcal conjugate vaccine (PCV) vaccination showed lower antibody responses one month after the second dose in subjects previously vaccinated with PPV23. These findings suggested that PPV23 vaccination caused hyporesponsiveness following subsequent vaccination with PPV23 and PCV, and called into question the value of PPV23 revaccination. To test this hypothesis, PPV23 revaccination was evaluated in adults aged 55–74 y who had been vaccinated with 1 to 4 doses of PPV23.⁷ Antibody responses were measured 30 d after vaccination. Repeat PPV23 vaccination of older adults was found to be safe and immunogenic, and there was no evidence of hyporesponsiveness. Other studies in infants have shown that nasopharyngeal carriage of S. pneumoniae shortly before pneumococcal conjugate vaccine (PCV) 7 causes serotype-specific hyporesponsiveness in infants.⁸ Clearly, some degree of hyporesponsiveness may occur in some individuals following both repeated doses of PPV23 and recent natural exposure to S. pneumonia. Nonetheless, there is no evidence that these findings are clinically important.

PCV7 vs. PPV23

The immunogenicity of PCV7 vs. PPV23 was compared in adults 50–80 y of age.⁹ IgG antibody responses to both vaccines were similar, suggesting that either vaccine could be administered to these individuals, However, epidemiological studies in the US and other countries have shown dramatic reductions in the incidence of invasive pneumococcal disease (IPD) in older adults after the introduction of PCV7 vaccination of children.¹⁰ IPD rates caused by serotype 19A and other non-PCV7 types have increased, but have remained low relative to decreases in PCV7-type IPD. When changes in the incidence of IPD were examined for older adults in England and Wales during the period 1998/99 to 2009/10, it was found that while the overall incidence of all serotype- and PPV23-serotype IPD did not change, the incidence of PCV7-serotype IPD declined after PCV7 was introduced for children. The incidence of IPD due to serotypes unique to PPV23 (not in PCV7) increased, as did the incidence for non-vaccine type IPD.^4,11,12

Economic considerations

Data from the US have shown that the direct and indirect costs of pneumococcal diseases among older adults are substantial (Fig. 2), despite increased coverage with PPV23 and indirect benefits afforded by PCV7 vaccination of young children.¹³

Figure 2. Estimated economic burden of pneumococcal infections in older adults in the US. Direct costs of hospital care are dominant.

PPV23

Several years ago, before the widespread introduction of PCV7 vaccination for children, the cost-effectiveness of PPV23 vaccination to prevent invasive pneumococcal disease was evaluated in 10 Western European countries (PPV23 was given concomitantly with influenza vaccine).¹⁴ PPV23 was found to be acceptably cost-effective in all 10 countries studied (Fig. 3).

Figure 3. Data showing the cost-effectiveness of PPV23 vaccination to prevent invasive pneumococcal disease alone in 10 Western European Countries.

An earlier study reported that even a low level of clinical effectiveness against non-bacteremic pneumococcal pneumonia dramatically improved the overall cost-effectiveness of PPV.¹⁵ While encouraging, these studies may not be relevant in countries that have introduced widespread vaccination of children with pneumococcal conjugate vaccines.

PCV13

Immunogenicity studies of PCVs in older adults have found no convincing advantage of PCVs over PPV23. Because PCV7 vaccination of children has led to a decrease in PCV7 serotype IPD in older adults, PCV13 vaccination of children should result in a similar decrease in PCV13 serotype IPD in older individuals. As a result, there will be little PCV13 serotype pneumococcal disease in this age group that could be prevented by vaccination with PCV13. It follows that PCV13 vaccination of older adults will not be cost-effective in preventing either IPD or non-bacteremic pneumococcal pneumonia. However, because of the overall decline in the incidence of PCV13 serotype disease following the introduction of PCV13 vaccination of children, the cost-effectiveness of PPV23 vaccination in older adults will inevitably decrease.¹⁶

Conclusions

IPD and pneumococcal pneumonia remain important health problems for older adults. PPV23 is clinically effective and cost-effective in reducing IPD and community-acquired pneumonia hospitalizations and deaths. Antibody responses to PPV23 vaccination and revaccination last up to 10 y, although direct evidence of long-term clinical protection afforded by PPV23 vaccination has never been obtained. PCV vaccination of children leads to lower incidence of PCV serotype IPD in older adults. Many have suggested that older adults should be vaccinated with PCV13 instead of PPV23. However, immunogenicity studies show no convincing advantage of PCVs over PPV23 in older adults.¹⁷ Moreover, soon after the introduction of PCV13 vaccination for children, the incidence of PCV13 serotype disease in older adults will become so low that there will be no epidemiological reason to vaccinate them with PCV13.¹⁸

In future years, health officials should continue their surveillance of IPD in all age groups following the introduction of PCV13 vaccination of children. They should also evaluate the changing cost-effectiveness of PPV23 in older adults. Ultimately, better control of pneumococcal disease in populations will probably require a universal, protein-based vaccine for both children and adults. Better management of individual patients with severe pneumococcal infections may eventually be achieved by treating them with immunomodulatory agents (e.g., statins).¹⁹

Disclosure of Potential Conflicts of Interest

DSF discloses no conflicts of interest.