Invasive pneumococcal disease in persons with predisposing factors is dominated by non-vaccine serotypes in Southwest Sweden

Invasive pneumococcal disease (IPD) caused by the bacterium Streptococcus pneumoniae remains a major cause of morbidity and mortality despite the introduction of pneumococcal conjugate vaccines (PCVs) in the child vaccination programs worldwide [1].

In January 2009, the conjugate vaccine PCV7 covering serotypes 4, 6B, 9 V, 14, 18C, 19F and 23F was offered to all children in Sweden at three, five and 12 months of age with no catch-up campaign for older children. PCV7 was, a year later replaced by the 10- or 13-valent conjugate vaccines (PCV10, PCV13) with the addition of serotypes 1, 5 and 7F (PCV10) and further with 3, 6A and 19A (PCV13). PCV13 was approved in Sweden for adults in 2011 and has, since 2016 been recommended for adults with specified predisposing factors, in addition to the polysaccharide pneumococcal vaccine (PPV23) [2].

Following vaccine introduction, there has been a striking reduction of IPD among children below two years of age [3‐6]. Furthermore, through herd immunity, the incidence of IPD among unvaccinated adults has declined in many countries, although an increase in non-vaccine serotypes has been observed [7‐9]. The latter is attributable to the fact that non-vaccine serotypes have replaced vaccine serotypes as nasopharyngeal colonizers in preschool children [10]. In Sweden around one third to one half of all preschool children were asymptomatic nasopharyngeal carriers of pneumococci in the pre-PCV era. However, there was a shift to non-vaccine serotypes subsequent to PCV introduction [11, 12].

The clinical course of IPD may vary from mild with no sequelae to fulminant septic shock with lethal outcome. In addition to age, factors associated with poor outcome include comorbidities such as hematological malignancies, cardiovascular disease and pulmonary disease [13, 14]. Moreover, some pneumococcal serotypes can be more invasive. They may be associated with particular clinical manifestations or may even be lethal [15‐17].

Several studies have assessed the serotype distribution of IPD in the post-vaccine era [3‐5, 8, 10, 12, 18] but few related clinical manifestations and outcome to different serotypes [17, 19‐22]. The aim of this study was to assess serotype distribution in relation to age, risk factors, clinical manifestations and outcome in patients with IPD seven years after introduction of the PCVs in Southwest Sweden.

Seven years after the introduction of PCV in the child vaccination program the pneumococcal serotypes causing IPD in Southwest Sweden have shifted from a minority of non-PCV13 serotypes in 2009, to the vast majority in 2015, especially among persons ≥65 years of age and, as reported in previous studies, in persons with predisposing factors [21, 22]. Bacteremia with unknown focus and manifestations other than pneumonia and meningitis were more commonly caused by non-PCV13 serotypes than serotypes included in the PCV13. Conclusively, the spectrum of serotypes as well as the clinical manifestations of IPD have changed subsequent to the PCV introduction into the child vaccination program and the resulting herd immunity.

The overall case fatality rate (CFR) was 13% in our study; however, no specific serotype was significantly associated with a higher CFR. Instead, a lower CFR was found among patients having IPD caused by serotype 7F. Serotype 3 has previously been associated with lethal outcome in patients with IPD, septic shock, and also bacteremic pneumonia [19, 22, 27, 28]. In this study the CFR was 18% for serotype 3, supporting previous observations that IPD caused by serotype 3 is severe. We further found that patients with IPD caused by serotypes 3 and 4 required ICU-care to a greater extent than IPD caused by other serotypes. Other non-bacterial factors, including predisposing factors and age may result in admissions to ICU-care. However, we found no association between serotype 3 and any predisposing factor or advanced age.

The capsule of serotype 3 is thick due to an extended polysaccharide layer which favors nasopharyngeal carriage [27]. It is therefore less likely to be invasive compared to other serotypes. However, if it does invade, it is more prone to cause severe disease [27]. Most, but not all, studies show a poor protection of PCV13 against serotype 3 [8, 18, 29, 30]. Here we show that serotype 3 is still prevalent, despite an overall decrease in PCV13 serotypes. In fact, serotype 3 was the most prevalent serotype in IPD cases in mainly the same area 30–40 years ago [16], subsequently losing its top position before the introduction of PCVs in favor of serotypes 1, 7F and 9 V [15], and then regaining a top position together with serotype 22F post-PCV, as shown here. Serotype 3 was also the most prevalent serotype in Stockholm, Sweden, after the vaccine introduction, mainly due to the widespread CC180 clone among the elderly [12]. Thus, there are temporal trends in serotypes circulating in the population at the time [21, 31] in addition to vaccine effects.

The changes in serotype distribution found here are in concordance with studies from US and Western Europe. These also show a non-PCV serotype dominance among IPD cases, with serotype 3 being the most prevalent in many countries [4, 8, 21, 22, 32].

There are pneumococcal serotypes with more invasive potential, including 1, 5 and 7F, which are infrequent colonizers of the nasopharynx [33]. In parallel with previous studies [15, 34], we found that serotypes 1 or 7F were associated with invasive pneumonia, low CFR (3–4%) and more often occurred in young and otherwise healthy individuals. The most common clone of serotype 1 (MLST306) expresses a non-hemolytic pneumolysin that aids the bacteria in avoiding the innate immune system. It is believed that this increases invasiveness though it is less fatal [35]. During the study period, probably through vaccine-effect and herd immunity, both serotypes became scarcer.

As shown in the multivariable analysis, having one or more predisposing factors was associated with having IPD caused by a non-PCV10 or a non-PCV13 serotype. More specifically, malignancy and immune deficiency were both positively associated with IPD caused by non-PCV13 and non-PPV23 serotypes. We observed these positive associations only between the various predisposing factors and IPD caused by non-vaccine serotypes. This demonstrates that serotypes not included in the current vaccines are overall more prone to cause disease among persons with predisposing factors than are those serotypes included in the vaccines.

The non-PCV13 serotypes constituted 75% of all IPD cases in 2015 and the trend remained the same in 2020, on a national level [36]. Among persons with predisposing factors, the non-PCV13 serotypes clearly dominated. This was similar to the US and UK in the post-vaccine era [21, 22, 32]. This raises the question as to the rationale for recommendations of PCV13 for adults, including patients with chronic cardiovascular disease, pulmonary disease and malignancies. The Advisory Committee on Immunization Practices and the Public Health Agency in Sweden recently revised their recommendations for PCV13 for immunocompetent adults ≥65 years of age due to the diminishing incidence of PCV13 serotypes [2, 37]. There are ongoing clinical trials being performed with conjugate vaccines covering 15 (PCV13 + 22F and 33F) and 20 (PCV13 + 8, 10A, 11A, 12F, 15 BC, 22F and 33F) pneumococcal serotypes [38, 39]. Based on the data presented in this study, these vaccines would have covered 46% (77/166) and 64% (107/166), respectively, of the IPD-causing serotypes in Southwest Sweden 2015. They could thus be more appropriate for immunization in adults, in combination with PPV23, which covered 72% of the invasive serotypes in the same year. However, the expectation of a continuous serotype shift indicates the need for continuous surveillance and further vaccine development.

Strengths of this study include the detailed clinical characteristics and outcomes in patients as well as the low incidence of excluded IPD episodes.

Limitations include the use of ICU-care as a proxy for disease severity, and patients with septic shock were not identified. It is possible that information relating to substance abuse and smoking may be limited to the retrospective design of the study. Furthermore, the odds ratios in our univariable and multivariable analyses have to be considered within the context of sample size, and larger-scale studies are warranted to confirm the findings.

Since the introduction of PCVs into the child vaccination program in Sweden 2009, a serotype shift has occurred with non-PCV13 serotypes becoming most frequent in adults ≥65 years of age and in patients with predisposing factors. This raises the question of whether the use of PCV13, as a supplement to PPV23, should be recommended for adults with predisposing factors.