The stubborn persistence of adult pneumococcal pneumonia as a public health problem

Sirs: We appreciate the opportunity to respond to Dr Fedson’s reply to our letter in which we stated that effectiveness of polysaccharide pneumococcal vaccines for the prevention of noninvasive pneumococcal pneumonia or all-cause community acquired pneumonia has not been established. We stand by that statement. We did not overlook any reviews or meta-analyses previously published; we cited two of the most recent because their methodology is sound. Furthermore, we contend that if the positive or negative effects of pneumococcal polysaccharide vaccines (PPSVs) were clear cut, we would not still be debating after nearly 30 y of worldwide use. The impact of 23-valent PPSV (PPSV23) has been recently estimated in the United Kingdom. In England and Wales, the PPSV23 program was expanded over the years 2003–2005 to include all those aged 65 y and older. As a result, the proportion of those aged ≥65 y who received PPSV23 increased from approximately 30% to 75%. The impact of this program was evaluated by the Health Protection Agency (now Public Health England) using national invasive pneumococcal disease (IPD) surveillance data. Between 1998 and 2006, IPD incidence due to PPSV23 serotypes in the targeted age groups was unchanged. At an individual level, the case-control study reported PPSV23 vaccine effectiveness for prevention of IPD declined from 48% (95% CI; 32% to 60%) within two years of vaccination to 15% (-3% to 30%) after five years. Furthermore, vaccine efficacy varied significantly by serotype, ranging from -23% (−85% to 19%) for serotype 3 to 63% (29% to 81%) for 12F (P = 0.005). Dr Fedson discusses his reference to the 7-valent pneumococcal conjugate vaccine (PCV7) rather than the 13-valent PCV (PCV13) data in the original review. Although the pivotal clinical immunogenicity studies that supported licensure for PCV13 for adults ≥50 y of age were not published in a peer-reviewed journal until July 2013, these data are presented in the package inserts for this product which, for example, has been publicly available in the United States since December 2011. They are also presented and discussed in the FDA briefing document that supported licensing discussions in the United States, as well as in the European Public Assessment Report, which was made publicly available in September 2011. Referring to earlier studies of PCV7 that do not assess functional antibodies is misleading. When appraising any vaccine, hyporesponsiveness must not be taken lightly. In immunocompetent individuals, absent or low responses to pneumococcal polysaccharide vaccine antigens 7F and 23F preceded cases of pneumococcal pneumonia due to these serotypes; if re-vaccination results in lower antibody responses than the first vaccination, it appears likely that hyporesponsiveness will be the precursor of clinical failure. Dr Fedson states, incorrectly, that the conclusions of the costeffectiveness studies of Weycker et al. and Smith et al. are unreliable because of their assumed levels of indirect effects. His argument relies on selective data from a single study, a retrospective evaluation of hospital administrative records (2005–2006 compared with 1997–1999); this is but one piece of evidence in an accumulating body of literature on herd effects due to conjugate vaccines. For example, for all-serotype IPD, Simonsen et al. reported a 36% reduction in cases among persons aged 40–64 y and 47% among persons aged ≥65 y from widespread PCV7 use in children. However, these estimates are higher (substantially so for younger adults), than those reported by Pilishvili et al. for laboratory-confirmed cases from the Centers for Disease Control and Prevention’s (CDC) Active Bacterial Core (ABC) surveillance (2007 compared with 1998–1999), which report an 18% reduction among persons aged 50–64 y and a 37% reduction among persons aged ≥65 y. It is unlikely that studies utilizing healthcare utilization data are more accurate than studies describing the impact on laboratory-confirmed cases. The Weycker et al. evaluation was informed by the herd effects reported by the CDC’s ABC data, with estimated reductions ranging from 26–32%, depending on age. For non-bacteremic pneumococcal pneumonia, Simonsen et al. reported a 44% reduction in hospitalized cases among persons aged 40–64 y and 54% among persons aged ≥65 y. In the only other study that evaluated pneumococcal pneumonia, Grijalva et al. reported much smaller reductions in hospitalized cases (2004 compared with 1997–1999); 10% among persons aged 40–64 y and 20% among persons aged ≥65 y. Both of these studies operationally defined pneumococcal pneumonia based on the appearance of