6th World Congress of the World Society for Pediatric Infectious Diseases (WSPID)

Abstract

The 6th World Congress of the World Society for Pediatric Infectious Diseases (WSPID) was held in Buenos Aires, Argentina between 18 and 22 November, 2009. This is one of the biggest pediatric infectious disease assemblies in the world and it brought together pediatricians and pediatric infectious disease and vaccine experts. Numerous topics about pediatric infectious diseases were discussed during the congress. The scientific program focused on vaccines and vaccine-preventable diseases, including epidemiological and vaccine efficacy trials and updates on topics of childhood infectious disease. We summarize the current knowledge about some childhood vaccines and vaccine-preventable diseases, including rotavirus vaccines, conjugated pneumococcal vaccines (PCV-7, PHiD-CV and PCV-13), varicella, pertussis meningococcal and pandemic H1N1 vaccines. The next WSPID congress will be held in Melbourne, Australia between 16 and 20 November 2011.

Keywords::

• H1N1
• meningococcal vaccines
• PCV-7
• PCV-13
• pertussis
• PHiD-CV
• pneumococcal vaccine
• rotavirus vaccine
• •
• varicella vaccine
• WSPID

The 6th World Congress of the World Society for Pediatric Infectious Diseases (WSPID) was held in Buenos Aires, Argentina, and involved nearly 2700 participants from over 90 countries. WSPID was founded in 1995, with the purpose of bringing together members of national and regional pediatric infectious disease organizations. Previous meetings were held in Acapulco, Mexico (1996); Manila, The Philippines (1999); Santiago, Chile (2002); Warsaw, Poland (2005); and Bangkok, Thailand (2007). The main focus of the scientific program was vaccines and vaccine-preventable diseases, including epidemiological and vaccine efficacy trials, and updates on topics of childhood infectious diseases, such as TB, dengue and antibiotic resistance. Some of the 800 abstracts were selected for oral presentations, while some were selected to be orally presented in the poster walk session. Owing to the numerous pediatric infectious topics and issues that were discussed during this meeting, in this report we summarize the current knowledge about some childhood vaccines and vaccine-preventable diseases, including rotavirus vaccines, conjugated pneumococcal vaccines, varicella vaccines, pertussis vaccines, meningococcal vaccines and pandemic H1N1 vaccines. Prevention of infectious diseases with vaccines, increased awareness about vaccines and implementation of new vaccines for developing countries are the major aims of pediatric infectious disease experts. Vaccination is one of the great success stories in preventive medicine. However, the benefits of vaccination have been disproportionate because most of the vaccine development has been targeted toward diseases that are prevalent in industrialized countries. There have been substantial delays in the introduction of new vaccines into the markets of developing countries, while substantial financial barriers have existed against purchasing and distributing vaccines to poor countries [1]. The opening lecture (which was co-chaired by the President of WSPID, Ron Dagan [Ben Gurion University, Israel], and Angela Gentile, President of the local organizing committee) included a slide-set presentation about vaccines, which was prepared by Najwa Khuri Bulos (Amman, Jordan). This presentation included important data about the inequity of vaccine distribution around the world. She emphasized that equity in immunization is having equal access to the vaccines and its safe and timely delivery to the child. She underlined the inequity of immunization between developing countries and developed countries, and the world meeting started with a slide including the quotation, “Vaccines do not prevent disease, vaccination prevents disease”.

Rotavirus vaccines

Rotavirus is the cause of more than 2 million hospitalizations and over half a million deaths from acute gastroenteritis in infants and young children worldwide, especially in developing parts of the world such as Africa and Asia, where 85% of rotavirus deaths occur [2,3]. Therefore, rotavirus infections and preventative vaccines are major challenges and topics in world pediatric infectious disease congresses. Rotavirus vaccines (RV1, Rotarix™, GlaxoSmithKline [GSK], Belgium and RV5, RotaTeq^®, Merck, USA]) play an important role in controlling rotavirus-related diarrhea. Clinical trials suggest that the two currently available rotavirus vaccines, based on different immune concepts (VP7/VP4 homotypic specificity for RV5 vs homotypic and heterotypic specificity for RV1) are safe, immunogenic and efficacious in the Americas and Europe [4,5]. During Phase III clinical trials with RV1, high vaccine efficacy (85%) was obtained against severe rotavirus gastroenteritis (RVGE) in 11 Latin American countries and Finland [4]. In a further cohort study from ten Latin American countries, RV1 afforded sustained high protection (80.5%; 95% CI: 71.3–87.1) against severe RVGE during the first 2 years of life [6]. In a Phase III efficacy trial with RV1 in six industrialized European countries, protective efficacy rates were in general greater than those in the Latin American trial [7]. Vaccine efficacy against any RVGE until the end of the first rotavirus season was 87.1% (95% CI: 80–92) and protection against severe RVGE was 95.8% (95% CI: 89.6–98.7). RV1 also reduced hospitalizations of all-cause gastroenteritis by 75%. In this trial, RV1 demonstrated a significant cross-protection (86%) against G2P[4] rotavirus strains, while efficacy against the G2P[4] serotype was 38.6% in Latin America. RV5 was also shown to provide significant protective efficacy in both clinical trials and post-licensure monitoring. In a large Phase III trial in Europe and the USA, the Rotavirus Efficacy and Safety Trial (REST), vaccine efficacy against all RVGE and severe RVGE was 74% (95% CI: 67–80) and 98% (95% CI: 88–100), respectively [5]. At the end of its 18-month shelf life, RV5 showed efficacy rates similar to those of the REST study – that is, 73% (95% CI: 52–89) and 100% (95% CI: 13–100) against any RVGE and severe RVGE, respectively [8]. Similarly, in a large, recently completed clinical trial, Vesikari et al. suggested that RV5 was efficacious in 98.3% (95% CI: 90.2–100) of cases against severe RVGE and in 68.0% (95% CI 60.3–74.4) against any RVGE for two rotavirus seasons postvaccination [9]. Furthermore, vaccine efficacy in reducing hospitalizations and emergency department visits was also 94.5% for up to 2 years after vaccination.

Panozzo et al. presented post-licensure surveillance data from the USA [10,11]. Marked changes in patterns of rotavirus activity and reductions in rotavirus detections have occurred following the implementation of rotavirus vaccination in the USA [11]. Compared with prevaccine seasons from 2000–2006, the onset and peak of the 2007–2008 rotavirus seasons were delayed by 15 and 8 weeks, respectively. The 2007–2008 US rotavirus season was shortened substantially, lasting 14 weeks compared with a median of 26 weeks during 2000–2006. The number of rotavirus positive tests was also 69% lower than in the prevaccine period [11]. Although the number of positive test results was somewhat greater and the rotavirus season was longer during 2008–2009 compared with 2007–2008, rotavirus activity during both seasons was substantially lower than that reported during 2000–2006 [12]. The number of rotavirus positive tests in children less than 5 years of age decreased by 59–71% in 2008 compared with in the 2003–2007 period. A greater reduction was observed among children aged less than 1 year of age. Rotavirus vaccination caused a marked decrease (90%) in healthcare utilization (hospitalizations, emergency room admissions and outpatient visits) due to RVGE in 2007–2008 compared with previous years. The vaccine efficacy against RVGE requiring hospitalization or emergency room visits was 100% (95% CI: 87–100). In addition to efficacy and effectiveness data, extensive prelicensure and active 2–3.5-year postlicensure safety data from the USA (>21 million children) suggest that RV5 is not associated with an increased risk of intussusception [13]. The largest post-licensure study of RV vaccine safety to date did not identify any safety concerns regarding intussusception or other prespecified serious adverse events [14].

Overall, both rotavirus vaccines provide adequate protection against RVGE in high- and middle-income countries in the Americas and Europe. In June 2009, the WHO’s Strategic Advisory Groups of Experts (SAGE) strongly recommended the inclusion of rotavirus vaccination in the national immunization programs of all regions of the world [15] and several countries in these regions have already adopted rotavirus vaccines for their routine childhood immunization programs [16]. However, the key question for global vaccination is whether the rotavirus vaccines will provide equal protection everywhere. Recent studies from the Caribbean and Central America, as well as from the Apache Nations in the USA, provide some evidence that RV5 may also be efficacious in these less-developed settings [17]. However, a case–control study that evaluated the effectiveness of RV5 against rotavirus diarrhea in Nicaragua demonstrated a lower effectiveness after three vaccine doses [18]. The effectiveness of three doses of RV5 against all rotavirus disease was 46% (95% CI: 18–64); that against severe RVGE was 58% (95% CI: 30–74). However, the magnitude of risk reduction increased with severity of illness, with a 77% (95% CI: 39–92) reduction in very severe RVGE (Vesikari score >15). Thus, while RV5 may only halve rotavirus-associated hospital admissions or emergency department treatment of young children in Nicaragua, its impact on the most severe disease, including rotavirus mortality, could be more substantial. Patel et al. suggested that RV5 is highly effective in preventing severe RVGE-associated morbidity and mortality in Nicaragua [19]. Sanchez et al. also showed that vaccination with RV5 provided a 72.7% mortality rate reduction for nonspecific acute diarrhea in infants 3–11 months of age in Nicaragua [20]. Another study from Nicaragua noted a 12% decrease in the number of all-cause hospitalizations for acute gastroenteritis among children 0–11 months of age, whereas an approximately 5% increase was observed among unvaccinated children 12–59 months of age [21]. A similar effect was also noted in a recent study from Brazil, using a mathematical model to estimate vaccine efficacy against RVGE-related hospitalizations [22]. This model showed that RV5 is expected to have a high efficacy (79–97%) against RVGE-related hospitalizations. The expected annual reduction in RVGE-related hospitalizations attributable to vaccination in children younger than 5 years of age was estimated to be 75,719 in Brazil. Quintanar-Solares et al. presented their results concerning childhood diarrhea deaths after rotavirus vaccine introduction in Mexico where a monovalent rotavirus vaccine was introduced in May 2007 [23]. Following the introduction of the rotavirus vaccine, a significant decline in diarrhea deaths among Mexican children, particularly winter rotavirus season deaths among infants, was observed. Diarrhea mortality rate reduction was nearly 35% in children less than 5 years of age. In infants up to 11 months of age, the decline in mortality rate was 42%. Bokser et al. evaluated the incidence of diarrhea in children vaccinated with monovalent oral rotavirus vaccine in Argentina and this study showed that epidemiologic surveillance provides information about these 267 vaccinated infants, who did not have severe RVGE during their first year [24]. El Khoury et al. performed a mathematical model to estimate vaccine efficacy against RVGE-related hospitalization in Brazil and this model showed that RV5 is expected to have a high efficacy (79–97%) against RVGE-related hospitalizations [22].

In a recent vaccine trial with RV1, Phua et al. found that this rotavirus vaccine is highly efficacious in 6–17-week-old infants from Singapore, Hong Kong and Taiwan [25]. After a 20-month follow-up period, vaccine efficacy rates were 96% (95% CI: 85–100) against severe RVGE and 94% (95% CI: 81–99) against RVGE-related hospitalizations. Interestingly, efficacy rates were 100% (95% CI: 81–100) and 94% (95% CI: 75–99) against severe RVGE caused by G1 and pooled non-G1 serotypes, respectively. Furthermore, when evaluated from approximately 2 years until 3 years of age in Asian infants, RV1 showed a high efficacy (100%; 95% CI: 67.5–100) against severe RVGE [26].

A recent, double-blind, placebo-controlled, multicenter Phase III trial from South Africa and Malawi has shown that RV1 significantly reduced severe RVGE in African infants during the first year of life [27]. An overall 61.2% (95% CI: 44.0–73.2) vaccine efficacy was achieved in these African infants. In South Africa, vaccine efficacy against severe RVGE was 76.9% (95% CI: 56.9–88.4). Vaccine efficacy against severe RVGE caused by wild-type G1 was 69.8% (95% CI: 32.5–87.1) and that against non-G1 types was 85.9% (95% CI: 55.1–96.6) [28]. Furthermore, against the heterotypic G2P[4] and all P[4] types, vaccine efficacy was 91.8% (95% CI: 32.2–99.8) and 94.5% (95% CI: 60.4–99.9), respectively. Vaccine efficacy of RV1 was lower in Malawi (49.4%; 95% CI: 19.2–68.3) than in South Africa [27]. Neuzil et al. explained that the lower efficacy rates in Malawi might be due to the significantly higher rate of seropositivity in the placebo group in Malawi [29] and reflect a greater exposure to natural rotavirus infection in this study and subclinical rotavirus infections, which may have increased the immune response in the vaccine group. These data could help to explain the lower vaccine efficacy in Malawi.

However, the episodes of severe RVGE prevented in Malawian children were greater than those of the South African children: 3.9 versus 2.5 episodes per 100 vaccinated infants, respectively. An overall 30% reduction of severe gastroenteritis was observed in Malawi. In addition, no significant difference was noted in vaccine efficacy rates for children who received two and three doses: 58.7% (95% CI: 35.7–74.0) and 63.7% (95% CI: 42.4–77.8), respectively. Interestingly, Patel et al. suggested that immunization with one or two doses of RV5 conferred similar protection to a full three-dose series. The effectiveness of one or two doses was 52 and 51%, respectively, against all cases, and 67 and 63%, respectively, against severe RVGE [18].

In summary, these results confirm the significant public-health impact of rotavirus vaccines in underdeveloped countries. Although protective efficacy rates are lower than those from developed and middle-income countries, they look promising given the lack of other effective interventions. It is currently assumed that universal rotavirus vaccination can lead to a significant reduction (>30%) in severe diarrheal disease in developing countries [30]. However, further studies are needed to characterize the contribution of routine rotavirus childhood vaccination, herd immunity, or other factors.

Pandemic H1N1 vaccines

The H1N1 influenza pandemic was the most important public health problem in 2009. During WSPID, the scientific program included a plenary symposium about H1N1 vaccines and the session involved three lectures from the three companies that currently have pandemic H1N1 vaccines available: Novartis, GlaxoSmithKline and Sanofi Pasteur (Lyon cedex, France). Representatives from these companies summarized their prelicensure study results and approval progress. Sanofi Pasteur presented data about AF03-adjuvanted splint virus inactivated A (H1N1) vaccine (Humenza^®; 3.8 µg hemagglutinin [HA] with AFO3) and nonadjuvanted vaccine (Panenza^®; 15 µg HA). After performing studies including 6000 subjects (children and adults), they showed that a very strong immune response was induced by both vaccines. A very high antibody response rate following a single vaccination in adults has been observed with different amounts of HA. Between 18 and 60 years of age, geometric mean titers (GMTs) of HA after vaccinations are similar for adjuvanted and nonadjuvanted vaccines. However, a second dose is needed to increase the immune response. After two injections with and without adjuvanted vaccine, the seroprotective rate was 100%. During prelicensure studies, both adjuvanted and nonadjuvanted vaccines seemed to be safe.

Theodore Tsai from Novartis Vaccines summarized the pandemic H1N1 vaccine studies with adjuvant MF59. Novartis’ adjuvanted vaccines are Focetria^®, Fluad^® (7.5 µg HA with MF59) and Optaflu^® (3.75 µg HA with MF59). In participants 9–17 years of age, the vaccine was immunogenic in 96–100% of the study population, and in those 3–8 years of age, it was 93% immunogenic. Unadjuvanted vaccine immunogenicity was also investigated in children 3–8 years of age and it was found that for the unadujvanted vaccine two doses were needed. For the adjuvanted Novartis vaccine, on the first day after vaccination, 27% of children between 3 and 8 years of age and 43% of children between 9 and 17 years of age were immunogenic. At the 43rd day after immunization, 100% of vaccinated children were immunogenic. Novartis’ pandemic H1N1 vaccines use MF59 as an adjuvant. MF59 is a well-known adjuvant containing squalene, which has been used with different vaccines for 40 million doses worldwide. The safety of MF59-adjuvanted vaccines has been evaluated in more than 33,000 subjects, including 3000 children, and seems to be safe for both adults and children. Any difference in pregnancy outcomes in those exposed to MF59 has been reported. Ongoing studies on pandemic H1N1 vaccines are still being conducted by Novartis Vaccines in children between 6 and 35 months of age, pregnant women, and high-risk adults and children. Adjuvanted Novartis pandemic H1N1 vaccines met Committee for Medicinal Products for Human Use criteria with one dose; however, these criteria were not met with one dose of unadujvanted vaccine.

Dirk Poelaert from GlaxoSmithKline Biologicals summarized their studies about GSK’s pandemic H1N1 vaccines (Pandemrix). GSK use AS03 as an adjuvant for their pandemic vaccine, as well as for their seasonal influenza vaccines. According to studies, one dose of adjuvanted vaccine was immunogenic in adults 18–40, 41–60 and 18–60 years of age. The seroprotection rate is good for all age groups after one dose of adjuvanted vaccine. The cell-mediated immune response was higher for the adjuvanted vaccine. GSK also performed studies with a reduced HA dose with the same adjuvant and evaluated vaccine immunogenicity in children between 6 and 35 months of age and also in elderly people. The seroprotection rate was 95% in adults 18–60 years of age, 79.2% in adults over 60 years of age and 77.8% in adults older than 70 years of age. According to safety studies, acceptable safety and reactogenicity profiles were demonstrated with GSK’s H1N1 vaccines containing AS03.

These three lectures include the results of current studies for pandemic H1N1 vaccines. In reality, many countries use these vaccines for prevention of H1N1 at a country-based level, with different schedules for different risk groups in spite of antivaccine lobbies. Vaccination is the best option for preventing H1N1 infection worldwide, and following widespread vaccine use, we will be able to see its potential effectiveness and safety profile around the world.

Pertussis vaccines

Prevention strategies for pertussis was another important topic that was discussed extensively during WSPID. Pertussis was a major cause of morbidity and mortality in children in the 20th Century. After widespread immunization, morbidity and mortality decreased; however, childhood vaccination programs have failed to eliminate pertussis. Pertussis is still a problem in adolescents, adults and especially newborn babies [31]. Johannes Liese (University Children’s Hospital, Würzburg, Germany) mentioned that there are still disparities with regard to the type (acellular pertussis [acP] versus whole-cell pertussis [wP]) of vaccine used and vaccination coverage rates worldwide [32]. Both wP and acP vaccines, as well as natural pertussis infection, do not confer lifelong immunity. With a reinforcement of current immunization strategies in the general population, different interventions for new prevention strategies for pertussis have been performed worldwide. In Argentina, immunization with pertussis vaccine has been performed in all adolescents, and in Germany, immunizations for all adults have been implemented [32,33]. Immunization of healthcare workers is another strategy. Another prevention strategy – the Cocoon strategy – is to immunize all new mothers against pertussis, as well as family members and close contacts of newborns [34,35]. Mertsola et al. evaluated the safety of repeated administration of reduced antigen content diphtheria–tetanus–pertussis (dTpa) boosters [36]. Seroprotection/seropositivity rates against all antigens 1 month post-booster were at least 95.2% in all subjects. Mertsola also evaluated the immunogenicity of repeated administration of reduced antigenicity dTpa booster vaccine in adults and found that repeated dTpa boosters induce a strong immune response in adults [37].

Pneumococcal vaccines

At the beginning of a new century, we have gained significant achievements against pneumococcal infections by using pneumococcal conjugated vaccines (PCVs). In February 2000, the US FDA licensed a 7-valent conjugate vaccine (PCV-7; Prevnar^®, Prevenar^® [Wyeth Pharmaceuticals, PA, USA]) containing seven pneumococcal polysaccharides (4, 6B, 9V, 14, 18C, 19F and 23F) conjugated to a nontoxic diphtheria toxin variant carrier protein, cross-reacting material (CRM)197 [38]. PCV-7 was introduced into national immunizations programs with different schedules in nearly 40 countries worldwide, and during WSPID, data on pneumococcal seroepidemiology in the post-PCV-7 era and recent study results about new PCVs (PHiD-CV and PCV-13) were presented.

The impact of PCV-7 after the introduction of PCV-7 in national immunization programs has been clearly demonstrated in several European countries, including Germany, France, Italy, Norway and the UK, with a three-plus-one dose schedule as well as a reduced-dose schedule [39]. Ron Dagan summarized the importance of pneumonia in children and highlighted the vaccine effect [40]. In total, 95% of all cases of invasive pneumococcal disease were attributable to pneumonia. Dagan showed that serotypes associated with pneumonia are serotypes 1, 3, 5, 7F, 14 and 19A, and pointed out that bacteremic pneumonia usually represents less than 10% of all pneumonia. Noninvasive alveolar pneumonia is mainly due to serotypes 1 (19%), 5 (5.7%) and 7F (3.4%). According to the effectiveness trial, PCV-7 is effective for 8% of all-cause pneumonia and 36% of chest x-ray pneumonia. No correlates of protection exist for pneumonia, but these levels are likely to be much higher than that required for protection against invasive pneumococcal disease (IPD). For prevention of pneumonia, we need an efficacious vaccine, increased vaccine coverage and also protection of nasopharyngeal carriage.

Brandileone et al. presented data about Streptococcus pneumoniae invasive disease in the Latin America and Caribbean region with a laboratory surveillance network (SIREVA II). This has been used since 1994, with the support of PAHO/WHO and the Canadian International Development Agency, in 19 Latin American countries and one Caribbean center to monitor IPD to assess data on serotype prevalence and antimicrobial susceptibility [41]. Between 2000 and 2007, in ten countries (Argentina, Brazil, Chile, Colombia, Cuba, Dominican Republic, Mexico, Paraguay, Uruguay and Venezuela), data from children 5 years of age or younger showed that the most prevalent serotypes were 14 (30%), 6B (9%), 1 (8%), 5 (7%), 18C (6%), 19F (6%), 23F (5%), 6A (4%), 19A (4%), 7F (3%), 9V (3%), 3( 3%), 4 (3%) and others (14%). The overall potential impact of the 7-valent (plus serotype 6A), 10-valent (plus serotype 6A) and 13-valent conjugate vaccines in the 5-year old and younger age group is estimated at 63.3, 80.6 and 86.3%, respectively. Estimates of coverage for isolates from meningitis and pneumonia cases only for 7-valent, 10-valent and 13-valent vaccines are 76.5, 85.2 and 95.4% (meningitis), and 59.2, 83.3 and 90.3% (pneumonia), respectively.

Brito et al. evaluated IPD in children between 2006 and 2008 in Portugal where PCV-7 was licensed in 2001 and the potential coverage rate is actually 79% [42]. During the study period, meningitis decreased (49.9 vs 16.3%) while pneumonia (25.6 vs 46.1%) and occult bacteremia (9.2 vs 16.3%) increased. The emergence of non-PCV-7 serotypes (79.5%), especially serotypes 19A and 1, was detected. Serotype 1 was more frequent in pneumonia (87.5%) and in children over 5 years of age (66.7%) and serotype 19A in children with meningitis/sepsis/occult bacteremia (72.2%) and in those younger than 2 years of age (61.9%).

Fenoll et al. presented data about the serotype distribution of S. pneumoniae isolates from pleural fluid in Spain [43]. Throughout the studied period, there was a decrease in PCV-7 serotypes, with significant increases in serotypes 1 and 19A among pleural fluid isolates. Fenoll showed the trends of the most prevalent serotypes among 4187 invasive isolates from children in the last 12 years in Spain between 1997 and 2008 [44]. PCV-7 serotypes continued to significantly decrease from 2001 onwards, probably in relation to increasing PCV-7 distribution, and serotypes 1, 19A and 7F increased significantly in the 2000s, highlighting the need for their inclusion in future vaccines. Fenoll also presented the trends of IPD isolates in adults during the postlicensure period in Spain [45]. The four serotypes included in PCV-7 decreased after PCV-7 introduction, while there was an increase in serotypes 1, 19A and 7F. Fenoll suggested that including these serotypes in future pediatric vaccines might also favorably impact adults.

Garcia Gabarrot et al. performed an analysis on temporal trends of the most frequent IPD serotypes between 1994 and 2008 in children 0–14 years of age [46]. The most common serotypes were 14, 1, 5, 7F, 3, 6B and 19A, representing 81.7% of the isolates. During the years that both serotype 1 and serotype 5 became as frequent as serotype 14, a correlation between increased serotype 1 isolates and pleural fluids as a source among pneumonia cases was also observed.

Levy et al. evaluated the effect of PCV-7 on pneumococcal meningitis (PM) in French children from 2001 to 2008 [47]. During these 8 years, the number of cases of PM remained stable, while cases among children younger than 24 months of age significantly decreased from 70.1 to 51.2%. The prevalence of vaccine-type (VT) strains decreased from 63.9% in 2001 to 12.7% in 2008. Remaining cases (n = 166) were due to nonvaccine type (NVT) serotypes 19A (25.9%), 15B/C (11.4%) and 7F (10.8%). Among unvaccinated children, VTs decreased from 64.1% (59 out of 92) in 2001 to 33.3% (6 out of 18) in 2008.

Cohen et al. evaluated the potential effect of PCV-7 on nasopharyngeal carriage of S. pneumoniae over a 7-year survey in children [48]. Among all infants, the rate of VTs dramatically decreased from 44.6 to 7.0%, while NVT rates increased from 26.5 to 59.4%. Serotype 19A represented 12.1% of serotypes in year 1 and 20.5% in year 7.

Syriopoulou et al. evaluated pneumococcal serotype epidemiology after the introduction of PCV-7 in Greece [49]. The most common serotypes were 7F (25.6%), 19A (17.9%) and 3 (10.3%) for IPD, and 19A (44.8%), 19F (20.7%) and 6A (13.8%) for acute otitis media (AOM). In patients less than 5 years of age, 13.3% (IPD) and 23.8% (AOM) of cases were caused by VT serotypes. For both IPD and AOM, the majority of cases were caused by NVT serotypes.

Gutierrez et al. evaluated the effectiveness of PCV-7 for bacterial pneumonia in Uruguay, and in the year the vaccine was introduced there was a significant decline in community-acquired bacterial pneumonia-related hospitalization rates in children receiving medical care [50]. Cedres et al. evaluated effectiveness data from PCV-7 mass vaccination for bacterial pneumonia admission in Uruguay [51]. Average rates for bacterial pneumonia decreased from 927 cases to 729 cases, and rates for empyema decreased from 115 to 66 cases. Delfino et al. evaluated the effect of PCV-7 mass vaccination for empyema in children in Uruguay [52]. From 2005 to 2008, empyema rates decreased from 124.2 to 65.4 per 10,000 admissions. Serotypes 1, 14, 5 and 19A were the main pathogens.

A new approved 10-valent PCV (PHiD-CV, Synflorix™, GSK Biologicals) has been developed to address additional pneumococcal serotypes of global significance, and to potentially provide expanded protection against nontypeable Haemophilus influenzae (NTHi). Stephen Pelton (Boston University School of Medicine, MA, USA) emphasized that the additional serotypes in PHiD-CV may expand coverage beyond PCV-7, particularly in regions such as Latin America where serotypes 1, 5 and 7F are frequent in young children. The induction of protein D provides the potential to expand protection against AOM by targeting NTHi. The approved 10-valent pneumococcal vaccine (PHiD-CV) contains all serotypes in PCV-7 plus serotypes 1, 5 and 7F. Protein D from NTHi is the carrier protein for eight serotypes, while tetanus and diphtheria toxins are in the carrier proteins for the remaining two serotypes [53]. Timo Vesikari (University of Tampere Medical School, Finland) presented the immunogenicity and safety evaluation of the PHiD-CV vaccine. For the common serotypes, PHiD-CV elicited similar antibody levels to PCV-7 among different populations with different vaccination schedules. Following booster vaccination, almost all subjects reached predetermined ELISA and opsonophagocytic assay thresholds. PHiD-CV also elicited high antibody responses against protein D. When PHiD-CV was coadministered with other pediatric vaccines, no difference in antibody responses to any of the vaccines, as compared with coadministration of PCV-7, was observed. The safety and tolerability of PHiD-CV was comparable to that of PCV-7 [53–56]. Xavier Saez Liorens (Hospital del Nino, Panama City, Panama) summarized the PCVs and mucosal disease. S. pneumoniae and NTHi together account for more than 80% of bacterial causes of AOM worldwide. Prymula et al. showed that an investigational 11-valent protein D conjugated pneumococcal vaccine (Pn-PD) has a potential efficacy against pneumococcal otitis media and also against AOM caused by NTHi [57]. Bridging an 11-valent Pn-PD with PHiD-CV has been clearly demonstrated with experimental chinchilla models and a similar level of protection has been observed with both vaccines [58]. Prymula also presented the effect of PHiD-CV for nasopharyngeal carriage of S. pneumoniae[59]. Carriage of S. pneumoniae vaccine serotypes was reduced by 22–35% in PHiD-CV recipients. Primary and booster vaccination with PHiD-CV reduced nasopharyngeal carriage of S. pneumoniae vaccine serotypes in the second year of life and tended to increase that of nonvaccine serotypes/serogroups in line with previous experience with PCV-7.

PHiD-CV was shown to be immunogenic and well tolerated when used for primary immunization of both preterm and full-term infants [60]. Omenaca et al. evaluated the immunogenicity and safety of a booster dose of PHiD-CV in preterm newborns, and found that PHiD-CV was immunogenic for the ten vaccine pneumococcal serotypes and well tolerated when given as a booster dose [61].

Bakir et al. (Turkey) [62] and Villasenor-Sierra et al. (Mexico) [63], presented a comparison between PCV-7 and PHiD-CV. Both interventions were cost effective. PHiD-CV leads to more cost savings and better outcomes compared with PCV-7. Ongoing studies (FINIP study in Finland and Community Otitis Media and Pneumonia Study [COMPAS] involving 24,000 infants across Argentina, Panama and Colombia) aim to evaluate the efficacy of PHiD-CV against pneumonia and otitis media, nasopharyngeal carriage of S. pneumoniae and NTHi. Adriano Arguedas (Universidad Autónoma de Ciéncias Médicas, San José, Costa Rica) highlighted the point that PHiD-CV will probably have a significant public-health impact in Latin America by reducing morbidity and mortality due to diseases caused by S. pneumoniae and NTHi, by reducing the burden of otitis media, and direct and indirect costs associated with otitis media. Arguedas also mentioned that in noninvasive diseases, such as otitis media, vaccination is driven by the volume of cases, cost, and antibiotic usage and resistance.

A 13-valent pneumococcal conjugate vaccine (PCV-13, Pfizer Vaccines, NY, USA) is approved in Chile, Mexico and Mauritius, and has just been approved by the EMA. PCV-13 uses CRM197 as a carrier, similar to the current PCV-7, and covers serotypes 1, 3, 5, 6A, 7F and 19A, in addition to the serotypes of PCV-7 (serotypes 4, 6B, 9V, 14, 18C, 19F and 23F). Gail Rodgers (Pfizer Vaccines) summarized current data about PCV-13 and expressed that it is safe and well tolerated with other pediatric vaccines in infants, according to clinical trials. IgG anticapsular polysaccharide-binding concentrations and opsonophagocytic assay responses are similar and noninferior between PCV-13 and PCV-7 and, according to immunogenicity studies, PCV-13 has a greater potential to protect against pneumococcal diseases with the additional six serotypes [64]. Recently, the EMA approved PCV-13 in the European region. Serotype 19F in PCV-7 appears to produce poor protection against serotype 19A; although small compared with the overall reduction in IPD, there has been an increase in serotype 19A IPD since the introduction of PCV-7. It is estimated that the six additional serotypes in the PCV13 vaccine will increase coverage for prevention of IPD to 89% in Europe, 92% in the USA and Canada, 86% in Oceania, 87% in Africa and Latin America, and 73% in Asia, according to epidemiological data prior to the introduction of PCV-7 [64]. Expanded-coverage conjugated vaccines will give us opportunities for greater protection worldwide.

Simoes et al. evaluated the safety of an investigational 11-valent pneumococcal conjugate vaccine (PCV-11) in 12,194 children aged 18–24 months in the Phillipines [65]. The majority of serious adverse events (SAEs)/clinical episodes (CEs) occurred within 28 days following receipt of vaccines and acute lower respiratory infections (ALRIs) were most often diagnosed during follow-up hospital investigations. In-depth analysis of SAE/CEs revealed no difference in either clinical bacterial or radiographic pneumonia; however, this difference was statistically higher for viral pneumonia. There was an excess of respiratory SAEs in the PCV-11 group after receipt of one or two doses of vaccine, but not after the third dose. Simoes et al. also evaluated the efficacy of a PCV-11 vaccine against severe and nonsevere viral lower respiratory infections (LRIs) [66]. They did not demonstrate any effect of PCV-11 on virus-associated LRI. There was likewise no effect seen on pneumonia hospitalizations associated with any of these agents. However, there was an increase in cytomegalovirus-associated LRIs; 46 in the PCV-11 group compared with 27 in the placebo group.

Varicella vaccination

Jorge Quian and colleagues (Montevideo, Uruguay) presented their experiences of varicella vaccination in Uruguay. Although it is usually a self-limiting disease, varicella can result in serious complications and occasionally death, even in previously healthy children. In countries where routine childhood vaccination against varicella has been implemented, it has had a positive effect on disease prevention and control. The introduction of routine childhood immunization with a single dose of varicella vaccine in Uruguay in 1999 has substantially reduced varicella-related morbidity and mortality [67]. Quian et al. suggest that there were 91% fewer varicella-related hospitalizations 8 years after the introduction of universal routine vaccination [68]. Although one dose of varicella vaccination provides high and sustained protection against severe disease, this is not yet enough to prevent all breakthrough disease. Quian and colleagues showed that breakthrough disease was observed in 39% of varicella cases during 2004–2008 in Uruguay [69]. Similarly, in the USA, one dose of varicella vaccination resulted in a decrease in hospitalizations and deaths due to varicella, but breakthrough disease and outbreaks were noted in highly vaccinated school communities [70]. Breakthrough disease may be due to waning immunity and, to some extent, primary vaccine failure. In either case, two doses of varicella vaccine offer a solution. As a result, two doses of varicella vaccine are officially recommended in the USA [71] and are also used in certain countries in Europe [72]. Prymula et al. presented data on the immunogenicity of two doses of varicella vaccine in the second year of life [73]. Seroconversion rates were: 99.1% (immunofluorescent assay) and 98.3% (ELISA) 6 weeks post-dose 1 and reached 100% post-dose 2 with both assays. A ninefold increase in the GMT/geometric mean concentration of varicella zoster virus IgG antibody after the second dose was observed compared with the first dose, regardless of the assay used. Two doses of varicella vaccine are highly immunogenic in the second year of life. The availability of the quadrivalent measles–mumps–rubella–varicella vaccine will facilitate implementation of these recommendations.

Meningococcal vaccines

Infections caused by Neisseria meningitidis are responsible for considerable morbidity and mortality throughout the world. On the first day of the WSPID meeting, during the plenary session that was organized by the European Society for Paediatric Infectious Diseases (ESPID), Michael Levin (Imperial College London, UK) summarized the recent developments about the pathophysiology and immunopathogenesis of the disease and genetic factors associated with susceptibility to or outcomes of meningococcal disease [74]. Early candidate gene studies focusing on the complement and coagulation pathways have demonstrated associations between meningococcal disease susceptibility or severity, and variants in genes in the complement, inflammation and coagulation pathways. Levin described genetic factors associated with meningococcal infections, such as complement mannan-binding lectin deficiency, Factor H gene polymorphism (C96T) and other factors such as Toll-like receptor mutations. Plasminogen activator inhibitor 1 gene 4G/5G promoter gene polymorphisms are associated with the severity of meningococcal disease. Levin described the organization scheme of a new consortium, which was funded by ESPID, linking research teams in the UK, Holland, Austria and Singapore, and has established a cohort of 1500 highly characterized patients with meningococcal disease, together with appropriate controls [74].

One of the striking features of meningococcal disease epidemiology is that it varies dramatically by serogroup, both geographically and over time. Although 13 N. meningitidis serogroups have been identified, the majority of invasive meningococcal disease cases are caused by five serogroups: A, B, C, W-135 and Y. Safadi summarized the global seroepidemiology of meningococcal infections [75]. Serogroup A is associated with epidemic disease in developing countries, with the highest burden in sub-Saharan Africa, which is known as the ‘Meningitis Belt’. In developed countries, like the USA and European countries, the disease is mostly endemic. In Europe, after the introduction of routine meningococcal C conjugate (MCC) vaccines, incidence rates of serogroup C disease decreased dramatically and serogroup B is now the major serogroup causing invasive disease, particularly in those under 20 years of age. Australia also controlled serogroup C disease after introducing MCC vaccines. In Asia, based on limited information, most disease is caused by serogroups A and C. In the Americas, serogroups B and C are responsible for the majority of cases reported, but emergence of serogroups W135 and Y has been observed in some countries. After the introduction of MCC vaccines in several European countries, Canada and Australia, a dramatic decline of serogroup C disease was observed, with evidence of herd immunity and, importantly, no serogroup replacement.

De Lemos et al. evaluated invasive meningococcal disease in Latin America and the Caribberan region (SIREVA II; PAHO/WHO) [76]. Serogroup B was predominant (63%) followed by C (31%), Y and W135 (2.8% each), but the global data presented a bias because more than 60% of the cases came from Brazil. Looking at data from individual countries, it is remarkable that serogroup C increased dramatically in Brazil, representing nearly 60% of cases in 2007 and even more in 2008, with similar trends in Mexico, El Salvador, Honduras and Peru. Serogroup Y increases were observed in Colombia but also in Costa Rica, the Dominican Republic and Venezuela. More recently, an important rise of serogroup W135 was noticed in Argentina (13% in 2007 and 40% in 2008) with similar trends observed in the south of Brazil and Paraguay.

Corso et al. presented national surveillance data results of N. meningitidis causing invasive disease in Argentina between 1998 and 2008 [77]. Serogroup B increased from 26.4% (1998/1999) to 69.6% (2006/2007) and then decreased to 51% (2008). Serogroup C decreased from 67.7% (1998/1999) to 4.5% (2008). Serogroup Y increased from 3.6% (1998/1999) to 11.2% (2002/2003) and then decreased to 4.5% (2008). Serogroup W135 increased from 2.3% (1998/1999) to 11.6% (2006/2007), then increased to 38.9% in 2008. The changes in the prevalence of serogroups B and C, the worrisome increase of serogroup W135, the high frequency of penicillin-nonsusceptible strains and the emergence of resistance to fluorquinolones, highlight the epidemiological relevance of the resistant strains.

Meningococcal vaccines are the best method of preventing meningococcal disease. Safadi showed data proving that meningococcal polysaccharide vaccines have played a pivotal role in disease prevention for several decades [78]. They were proved to be safe and effective in controlling outbreaks and epidemics. However, as they are unconjugated polysaccharide vaccines, they do not generate adequate immune response in infants under 2 years of age. Meningococcal polysaccharide–protein conjugate vaccines can induce immunologic memory, providing an excellent anamnestic response (booster effect) on re-exposure. They can also reduce nasopharyngeal carriage of N. meningitidis and so unvaccinated individuals may be protected indirectly through herd immunity.

Andrew Pollard (University of Oxford, UK) summarized the current status of meningococcal vaccines and upcoming new vaccines [79]. Serogroup C meningococcal protein–polysaccharide conjugate vaccines have been available for a decade and have effectively controlled disease caused by this organism in many countries. After widespread use of the MCC vaccine (with direct and indirect effects), quadrivalent vaccines that should prevent disease caused by serogroup A, C, Y and W135 meningococci have more recently become available and are now in routine use in North America. A MenACWY vaccine with a diphtheria toxoid carrier protein (MenACWY–D) was licensed in North America in 2005 and it is currently recommended for adolescents in the USA. An investigational MenACWY vaccine conjugated with CRM197 carrier protein (MenACWY–CRM) is in late-stage development and is immunogenic from early infancy and has been compared with plain polysaccharide ACWY vaccines and MenACWY–D. These vaccines appear to elicit functional antibodies, which persist after adolescent immunization.

An investigational ACWY–tetanus toxoid (TT) tetravalent conjugate vaccine using TT as carrier, developed by GSK (MenACWY–TT), is also in clinical development. Current studies showed that MenACWY–TT is well-tolerated and immunogenic in children between 1 and 10 years of age [80]. Vesikari et al. evaluated the immunogenicity of one dose of an investigational MenACWY–TT vaccine in toddlers and children after 1 year [81]. After 1 year following ACWY–TT vaccination, protective antibody levels against all four serogroups persisted, with bactericidal antibody levels in serum measured with baby rabbit complement (rSBA) of at least 1:8 in 98.1–100% of MenACWY–TT recipients. For toddlers, retention of rSBA–MenC antibodies was significantly higher compared with MenC–CRM197. For children, ACWY–TT responses were significantly higher compared with ACWY–polysaccharide, as evidenced by the percentage of subjects seropositive for rSBA–MenA (99.5 vs. 90.1%), MenC (99.5 vs 80.0%) and MenY (100 vs 90.1%); the percentage of subjects with rSBA of 1:128 or higher (MenA: 99.5 vs 80.3%; MenC: 89.3 vs 58.5%; MenW-135: 99.1 vs 93.3%; MenY 99.5 vs 78.9%); and GMTs (MenA: 2448 vs 359; MenC: 490 vs 114; MenW-135: 2983 vs 463; MenY: 2172 vs 332) for all serogroups. For MenW-135, 100% of children had rSBA of 1:8 or higher for both vaccines. After 1 year postvaccination, over 98% of ACWY–TT recipients retained rSBA titers of 1:8 or higher, for all serogroups – higher than with MenC–CRM197 or ACWY–PS. The ACWY–TT conjugate vaccine could provide increased, sustained protection against invasive meningococcal disease. Borja-Tabora et al. evaluated the immunogenicity of one dose of an MenACWY–TT vaccine in 300 children 11–17 years of age [82]. After 1 month following vaccination, a vaccine response (fourfold rise, or rSBA titer of 1:32 or higher) in ACWY–TT recipients was observed in 81.7, 96.7, 96.7 and 94.0% of subjects against serogroups A, C, W-135 and Y, respectively, and GMTs were significantly higher for all four serogroups. After 1 year postvaccination, rSBA titers of 1:8 or higher persisted in 98.6–100% of subjects for all four serogroups. In 11–17-year-old adolescents, the MenACWY–TT vaccine induced an immune response against all four serogroups, which persisted 1 year postvaccination, with at least 98.6% of ACWY–TT recipients maintaining rSBA titers of 1:8 or higher, and significantly higher GMTs for MenA, MenW-135 and MenY.

MenB is found globally, occurs in both endemic and epidemic patterns, has its highest incidence among young infants, and causes significant morbidity and mortality, yet it is not yet prevented by immunization. Outer membrane vesicle (OMV) vaccines, developed from single strains and used for clonal epidemics of meningococcal disease (e.g., in Cuba, Norway and New Zealand) have demonstrated the possibility that disease can be controlled by vaccines constructed from surface structures. An OMV vaccine is being used today for an ongoing clonal outbreak of meningococcal disease in France, and the Finlay Institute in Cuba continues production of its OMV vaccine. Unfortunately, endemic disease in most countries is not caused by a single clone but by a number of hyperinvasive serogroup B lineages, driving the search for approaches that provide broader protection. Such a vaccine was developed using a ‘reverse vaccinology’ approach in the research laboratories of Novartis. Using genomic and other analyses, over 350 MenB proteins were evaluated for surface expression, conservation across strains and the ability to induce serum bactericidal antibodies. Using a multicomponent vaccine should provide better universal strain coverage and possibly both synergistic and complementary immunity. In Phase I and II trials in adults and infants, the Novartis vaccine has been demonstrated to have reasonable safety, tolerability and immunogenicity. Epidemiologic evidence suggests that it was also protective during its use in New Zealand during an epidemic between 2004 and 2007. These results will be reviewed along with newer data from Phase III trials. This may be the most promising MenB vaccine candidate for global use [79,83].

Conclusion

Prevention of infectious diseases with vaccines, increased awareness about vaccines and implementation of new vaccines for developing countries are the major aims of pediatric infectious disease experts. One of the greatest success stories in preventive medicine was achieved by vaccination. We will hear current success results of these important vaccines from around the world, including in developing countries, in the next few years. In aiming to achieve one of the Millennium Development Goal targets of 2015, the main target of vaccine experts is to attempt to discover new vaccines for malaria, TB and HIV, and also increase the distribution of current vaccines such as pneumococcal and rotavirus vaccines in countries where the mortality associated with these diseases is high. The next WSPID congress will be held in Melbourne, Australia between 16 and 20 November 2011, and we hope to hear and see good news for childhood vaccine-preventable diseases.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.