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Characteristics of pneumococci causing disease in adults in Portugal in a time of private use of pneumococcal conjugate vaccines in children
Publication . Horácio, Andreia das Neves; Cristino, José Augusto Gamito Melo
Invasive pneumococcal disease (IPD) and non-invasive pneumococcal pneumonia (NIPP) are important causes of morbidity and mortality worldwide, particularly among young children, the elderly and the immunocompromised. Two types of vaccines are available to prevent pneumococcal disease, but these target a limited number of the 97 pneumococcal serotypes described so far. One type is a strictly polysaccharide-based vaccine, which includes 23 serotypes and is primarily indicated for adults (23-valent pneumococcal polysaccharide vaccine, PPV23, targeting serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F). The other type are pneumococcal conjugate vaccines (PCVs). Three PCVs have been licensed to date: a 7-valent formulation (PCV7), which covers serotypes 4, 6B, 9V, 14, 18C, 19F and 23F; a 10-formulation (PCV10), which includes all serotypes of PCV7, plus serotypes 1, 5 and 7F; and a 13-valent formulation (PCV13), which targets all serotypes of PCV10 and also serotypes 3, 6A and 19A. PCV7 became available in the USA in 2000 and in Europe in 2001. Several studies reported that the use of PCV7 in children was followed by decreases in the incidence of PCV7-type IPD in children. Since PCV7 reduced colonization due to the vaccine serotypes and because children are the main reservoirs of pneumococci in the community, PCV7 serotypes became less transmitted from children to the remaining population, with this resulting in decreases in the incidence of PCV7-type IPD also in non-vaccinated people, including adults (herd protection). However, at the same time, increases in the incidence of IPD due to particular non-PCV7 serotypes occurred in children and adults. In Portugal, PCV7 was used in children between 2001 and 2009, but was not included in the national immunization program. The uptake of PCV7 was initially low (43% in 2004), but increased steadily (75% in 2008). In mid-2009 and early-2010, PCV10 and PCV13, respectively, became available for children, with PCV13 replacing PCV7. PCV10 and PCV13 were given through the private market until June 2015, when PCV13 was included in the national immunization program for children. During the availability of PCV10 and PCV13 outside the national immunization program, PCV13 was the most frequently used PCV. Even though PPV23 and PCV13 are also available for adults, in Portugal, adult pneumococcal vaccination is estimated to be low. The studies presented in this thesis aimed to evaluate the characteristics of pneumococci causing adult IPD and adult NIPP in Portugal in a time of private PCVs use in children in the country. The isolates were collected by an epidemiological surveillance network, in work since 1999, which includes several laboratories throughout the country. All isolates analyzed were collected from adult patients (≥ 18 yrs). For the characterization of adult IPD isolates we determined the serotype and antimicrobial susceptibility of isolates responsible for adult IPD between 2009 and 2014 (n = 2428). The results were compared with previously published data from the same network (1999-2008, n = 2182). Adult IPD isolates were also characterized by Multi Locus Sequence Typing (MLST) and regarding the presence and type of two pilus islands (PI-1 and PI-2). For this characterization, 50% of adult IPD isolates recovered from 2008 to 2011 (n = 871), from each serotype, were randomly chosen. For the characterization of adult NIPP isolates, we determine the serotype and antimicrobial susceptibility of a collection of isolates responsible for adult NIPP between 1999 and 2015 (n = 2735). Previous studies from this epidemiological surveillance network, which analyzed the serotypes of adult IPD isolates recovered between 1999 and 2008, found that in Portugal there was a significant decrease in the proportion of PCV7 serotypes in adult IPD in the post-PCV7 period (from 30.3% in 1999-2003 to 16.4% in 2008, p < 0.001), accompanied by increases in the proportion of specific non-PCV7 serotypes (serotypes 1, 7F and 19A). When analyzing adult IPD data from 2009 to 2014, we found further changes in the serotype distribution of pneumococci causing adult IPD. Comparing adult IPD isolates recovered in 2009-2011 with those recovered in 2012- 2014, a new but small decrease in the representation of PCV7 serotypes in adult IPD was noted (from 19% to 14%, p = 0.003). In what concerns the overall proportion of PCV13 serotypes, it peaked in 2008 (70%) and then started a significant and gradual decline until 2014 (38%, p < 0.001), the last year analyzed. Since PCV10 and PCV13 became available in Portugal only in mid-2009 and early-2010, respectively, the initial decline in the overall proportion of PCV13 serotypes was independent of childhood vaccination. The PCV13 serotypes that decreased the most from 2008 to 2011 were serotypes 1 (from 10.7% in 2009 to 4.1% in 2011, p < 0.001) and 5 (from 2.0% in 2008 to 0% in 2011, p = 0.003). The early decreases of these two serotypes may be associated with long term fluctuations and outbreaks, described elsewhere. Other serotypes, instead, decreased when a herd effect with the use of PCV13 in children was expected. This was the case of serotype 7F (from 8.2% in 2012 to 2.7% in 2014, p < 0.001) and 19A (from 9.7% in 2012 to 5.6% in 2014, p = 0.027). In the post-PCV13 period, there were also significant increases in some of the serotypes not covered by PCV13 (i.e. serotypes 8, 15A, 20 and 22F). In what concerns antimicrobial resistance, and considering current Clinical Laboratory Standards Institute (CLSI) breakpoints, in 2012-2014, o.5% of the isolates were considered penicillin non-susceptible pneumococci (PNSP) and 17% erythromycin resistant pneumococci (ERP). Regarding the characterization of adult IPD isolates by MLST we found high genetic diversity, with 206 different sequence types (STs) detected. The STs represented 80 different clonal complexes (CCs), but the six more frequent CCs accounted for half of the isolates (CC156, CC191, CC180, CC306, CC62 and CC230). Most of the STs detected related to STs described in other countries. We found the changes in serotypes occurring in adult IPD following PCV7 use in children were mostly driven by the expansion of previously circulating clones or to decreases in most of the lineages expressing a given serotype. Concerning the presence and type of PI-1 and PI-2, only a small proportion of isolates was positive for any of the PIs (31.9%). Most of the isolates expressing PCV7 serotypes presented PI-1 (87.9%), while PI-2 positive isolates were mainly found among isolates expressing serotypes 1 and 7F, which are serotypes included in PCV10 and PCV13. In what concerns the characterization of adult NIPP isolates, we found significant declines in the proportion of vaccines serotypes following the use of PCVs in children, although these declines were less marked than those occurring in adult IPD. In adult NIPP, the proportion of PCV7 serotypes declined from 31% in 1999-2003 to 11% in 2011 (p < 0.001), while the overall proportion of PCV13 serotypes declined from 44% in 2010 to 30% in 2015 (p < 0.001). When considering the 2012-2015 period, and according to current CLSI breakpoints, 1% of adult NIPP isolates were PNSP and 21.7% were ERP. Comparison of NIPP serotypes with IPD serotypes identified associations of several serotypes with either disease presentation. The studies presented in this thesis showed that in Portugal in the time of PCVs use in children outside the national immunization program there were several changes in the characteristics of pneumococci causing disease in adults. While some of the changes suggested herd protection with the use of PCVs in children, others were independent. The inclusion of PCV13 in the national immunization program for children in June 2015 may be further reducing the importance of PCV13 serotypes in adult IPD and adult NIPP. However, increases of particular non-PCV13 serotypes in adult IPD are concerning and should be monitored. Continued IPD and NIPP epidemiological surveillance is important due to different serotype distribution and dynamics of pneumococci causing each disease presentation.
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Fundação para a Ciência e a Tecnologia
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SFRH
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SFRH/BD/81205/2011