Higher-valency pneumococcal conjugate vaccines in older adults, taking into account indirect effects from childhood vaccination: a cost-effectiveness study for the Netherlands.

BACKGROUND: New 15- and 20-valent pneumococcal vaccines (PCV15, PCV20) are available for both children and adults, while PCV21 for adults is in development. However, their cost-effectiveness for older adults, taking into account indirect protection and serotype replacement from a switch to PCV15 and PCV20 in childhood vaccination, remains unexamined. METHODS: We used a static model for the Netherlands to assess the cost-effectiveness of different strategies with 23-valent pneumococcal polysaccharide vaccine (PPV23), PCV15, PCV20, and PCV21 for a 65-year-old cohort from a societal perspective, over a 15-year time horizon. Childhood vaccination was varied from PCV10 to PCV13, PCV15, and PCV20. Indirect protection was assumed to reduce the incidence of vaccine serotypes in older adults by 80% (except for serotype 3, no effect), completely offset by an increase in non-vaccine serotype incidence due to serotype replacement. RESULTS: Indirect effects from childhood vaccination reduced the cost-effectiveness of vaccination of older adults, depending on the serotype overlap between the vaccines. With PCV10, PCV13, or PCV15 in children, PCV20 was more effective and less costly for older adults than PPV23 and PCV15. PCV20 costs approximately €10,000 per quality-adjusted life year (QALY) gained compared to no pneumococcal vaccination, which falls below the conventional Dutch €20,000/QALY gained threshold. However, with PCV20 in children, PCV20 was no longer considered cost-effective for older adults, costing €22,550/QALY gained. As indirect effects progressed over time, the cost-effectiveness of PCV20 for older adults further diminished for newly vaccinated cohorts. PPV23 was more cost-effective than PCV20 for cohorts vaccinated 3 years after the switch to PCV20 in children. PCV21 offered the most QALY gains, and its cost-effectiveness was minimally affected by indirect effects due to its coverage of 11 different serotypes compared to PCV20. CONCLUSIONS: For long-term cost-effectiveness in the Netherlands, the pneumococcal vaccine for older adults should either include invasive serotypes not covered by childhood vaccination or become more affordable than its current pricing for individual use.

The burden of invasive meningococcal disease in the Netherlands, 2011-2020.

INTRODUCTION: Representative information on disease course and outcome of invasive meningococcal disease (IMD) is important because of the shift in meningococcal epidemiology that recently occurred in the Netherlands. With this study, we update earlier research on the burden of IMD in the Netherlands. MATERIAL AND METHODS: We performed a retrospective study using Dutch surveillance data on IMD from July 2011 to May 2020. Clinical information was collected from hospital records. The effect of age, serogroup, and clinical manifestation on disease course and outcome was assessed in multivariable logistic regression analyses. Grouping of infecting isolates was performed by Ouchterlony gel diffusion or by PCR. RESULTS: Clinical information was collected for 278 IMD cases of which the majority had IMD-B (55%), followed by IMD-W (27%), IMD-Y (13%), and IMD-C (5%). Most patients presented with meningitis (32%) or sepsis (30%). Hospitalisation for ≥ 10 days was most frequent among 24-64 year olds (67%). ICU admission was highest among 24-64 year olds (60%), and in case of sepsis (70%), or sepsis plus meningitis (61%). Sequelae at discharge was lower for patients with mild meningococcaemia compared to patients with sepsis plus meningitis (OR: 0.19, 95% CI: 0.07-0.51). The overall case fatality rate was 7%, and was highest for IMD-Y (14%) and IMD-W (13%) patients. CONCLUSIONS: IMD remains a disease with high morbidity and mortality. Sepsis (with or without meningitis) is associated with a more severe disease course and outcome compared to other clinical manifestations. The high disease burden can be partly prevented by meningococcal vaccination.

Evolution of Bordetella pertussis in the acellular vaccine era in Norway, 1996 to 2019.

We described the population structure of Bordetella pertussis (B. pertussis) in Norway from 1996 to 2019 and determined if there were evolutionary shifts and whether these correlated with changes in the childhood immunization program. We selected 180 B. pertussis isolates, 22 from the whole cell vaccine (WCV) era (1996-1997) and 158 from the acellular vaccine (ACV) era (1998-2019). We conducted whole genome sequencing and determined the distribution and frequency of allelic variants and temporal changes of ACV genes. Norwegian B. pertussis isolates were evenly distributed across a phylogenetic tree that included global strains. We identified seven different allelic profiles of ACV genes (A-F), in which profiles A1, A2, and B dominated (89%), all having pertussis toxin (ptxA) allele 1, pertussis toxin promoter (ptxP) allele 3, and pertactin (prn) allele 2 present. Isolates with ptxP1 and prn1 were not detected after 2007, whereas the prn2 allele likely emerged prior to 1972, and ptxP3 before the early 1980s. Allele conversions of ACV genes all occurred prior to the introduction of ACV. Sixteen percent of our isolates showed mutations within the prn gene. ACV and its booster doses (implemented for children in 2007 and adolescents in 2013) might have contributed to evolvement of a more uniform B. pertussis population, with recent circulating strains having ptxA1, ptxP3, and prn2 present, and an increasing number of prn mutations. These strains clearly deviate from ACV strains (ptxA1, ptxP1, prn1), and this could have implications for vaccine efficiency and, therefore, prevention and control of pertussis.

Pathogen- and Type-Specific Changes in Invasive Bacterial Disease Epidemiology during the First Year of the COVID-19 Pandemic in The Netherlands.

COVID-19 control measures have resulted in a decline in invasive bacterial disease caused by Neisseria meningitidis (IMD), Streptococcus pneumoniae (IPD), and Haemophilus influenzae (Hi-D). These species comprise different serogroups and serotypes that impact transmissibility and virulence. We evaluated type- and pathogen-specific changes in invasive bacterial disease epidemiology in the Netherlands during the first year of the SARS-CoV-2 pandemic. Cases were based on nationwide surveillance for five bacterial species with either respiratory (IMD, IPD, Hi-D) or non-respiratory (controls) transmission routes and were compared from the pre-COVID period (April 2015−March 2020) to the first COVID-19 year (April 2020−March 2021). IMD, IPD, and Hi-D cases decreased by 78%, 67%, and 35%, respectively, in the first COVID-19 year compared to the pre-COVID period, although effects differed per age group. Serogroup B-IMD declined by 61%, while serogroup W and Y-IMD decreased >90%. IPD caused by serotypes 7F, 15A, 12F, 33F, and 8 showed the most pronounced decline (≥76%). In contrast to an overall decrease in Hi-D cases, vaccine-preventable serotype b (Hib) increased by 51%. COVID-19 control measures had pathogen- and type-specific effects related to invasive infections. Continued surveillance is critical to monitor potential rebound effects once restriction measures are lifted and transmission is resumed.

Pertussis epidemiology including direct and indirect effects of the childhood pertussis booster vaccinations, Norway, 1998-2019.

BACKGROUND: The acellular pertussis vaccine has been used in the Norwegian national immunisation program since 1998. Following an increase in pertussis incidence in all age groups, booster doses were introduced for 7-8-year-olds in 2006, and for 15-16-year-olds in 2013. We assessed the effects of the booster doses on pertussis incidence in different age groups to inform potential changes in vaccination policy. METHODS: We included all pertussis cases notified to the Norwegian Surveillance System for Communicable Diseases in 1998-2019. We calculated annual incidence rates (IR, per 100,000 inhabitants) by age group. We estimated average annual changes in IRs (incidence rate ratios, IRR) for each age group for 2006-2012 and 2013-2019 using Poisson regression. RESULTS: In 1998-2019, 74,675 cases of pertussis were notified. Coinciding with booster introduction, between 2006 and 2012 the IR decreased among 8-15-year-olds (from 433 to 199/100,000, IRR 0.89 [95% confidence interval 0.88-0.90]). A similar decrease was seen between 2013 and 2019 among 16-19-year-olds (from 171 to 77/100,000, IRR 0.84 [0.82-0.86]). There was no significant change in IRs among children < 1 year of age between 2006 and 2012 (IRR 0.99 [0.95-1.04]) or 2013-2019 (IRR 0.96 [0.91-1.02]). The IR decreased in both periods among adults aged 20-39 and 40+ (IRR 0.94 [0.93-0.95] and 0.92 [0.91-0.92] in 2006-2012; IRR 0.97 [0.96-0.99] and 0.97 [0.96-0.99] in 2013-2019, respectively). Despite steady, high vaccination coverage, in 2013-2019, there was an increase in the IR among children aged 1-7 (63 to 86/100,000, IRR 1.05 [1.03-1.07]) and 8-15 years (88 to 122/100,000, IRR 1.08 [1.06-1.10]). CONCLUSIONS: Pertussis booster doses have offered direct protection in the targeted age groups. Our findings suggest indirect protection in adults, while the incidence in infants hasn't changed. The recent increase in IRs among 1-15-year-olds warrants close monitoring and further evaluation of the vaccination schedule.

Household Transmission of SARS-CoV-2: A Prospective Longitudinal Study Showing Higher Viral Load and Increased Transmissibility of the Alpha Variant Compared to Previous Strains.

We studied the secondary attack rate (SAR), risk factors, and precautionary practices of household transmission in a prospective, longitudinal study. We further compared transmission between the Alpha (B.1.1.7) variant and non-Variant of Concern (non-VOC) viruses. From May 2020 throughout April 2021, we recruited 70 confirmed COVID-19 cases with 146 household contacts. Participants donated biological samples eight times over 6 weeks and answered questionnaires. SARS-CoV-2 infection was detected by real-time RT-PCR. Whole genome sequencing and droplet digital PCR were used to establish virus variant and viral load. SARS-CoV-2 transmission occurred in 60% of the households, and the overall SAR for household contacts was 50%. The SAR was significantly higher for the Alpha variant (78%) compared with non-VOC viruses (43%) and was associated with a higher viral load. SAR was higher in household contacts aged ≥40 years (69%) than in younger contacts (40-47%), and for contacts of primary cases with loss of taste/smell. Children had lower viral loads and were more often asymptomatic than adults. Sleeping separately from the primary case reduced the risk of transmission. In conclusion, we found substantial household transmission, particularly for the Alpha variant. Precautionary practices seem to reduce SAR, but preventing household transmission may become difficult with more contagious variants, depending on vaccine use and effectiveness.

Increase in invasive disease caused by Haemophilus influenzae b, the Netherlands, 2020 to 2021.

The incidence of most respiratory-transmitted diseases decreased during the COVID-19 pandemic as a result of containment measures. In contrast, in the Netherlands we noted an increase in invasive disease caused by Haemophilus influenzae b (Hib) (from < 0.3/100,000 before 2019 to 0.39 and 0.33/100,000 in 2020 and 2021) in vaccinated and unvaccinated age groups. We did not find a change in vaccine effectiveness against Hib invasive disease (effectiveness > 90%). We discuss factors that may have contributed to this rise.

The Risk of Invasive Pneumococcal Disease Differs between Risk Groups in Norway Following Widespread Use of the 13-Valent Pneumococcal Vaccine in Children.

The elderly and adults with medical risk conditions remain at high risk of invasive pneumococcal disease (IPD), highlighting the importance of adequate preventive efforts. In an observational population-based study in Norway (pop ≥ 5 years, 2009-2017) covering six years post-PCV13 implementation, we explored the incidence and risk of IPD associated with age and comorbidities. We obtained the data on 5535 IPD cases from the Norwegian Surveillance System for Communicable Diseases and the population data from Statistics Norway. To define comorbidities, we obtained ICD-10 codes from the Norwegian Patient Registry for the cases and the Norwegian population. The average annual decrease in PCV13 IPD incidence was significant in all risk groups and decreased post-PCV13 introduction by 16-20% per risk group, implying a nondifferential indirect protection from the childhood vaccination. The IPD incidence remained high in the medical risk groups. The relative importance of medical risk conditions was 2.8 to 6 times higher in those aged 5-64 versus ≥65 years for all types of IPD, since age itself is a risk factor for IPD. In groups without medical risk, the risk of IPD was eight times higher in those aged ≥65 compared to those 5-64 years (RR 8.3 (95% CI 7.3-9.5)). Our results underscore the need for age- and risk-group-based prevention strategies.

European data sources for computing burden of (potential) vaccine-preventable diseases in ageing adults.

BACKGROUND: To guide decision-making on immunisation programmes for ageing adults in Europe, one of the aims of the Vaccines and InfecTious diseases in the Ageing popuLation (IMI2-VITAL) project is to assess the burden of disease (BoD) of (potentially) vaccine-preventable diseases ((P)VPD). We aimed to identify the available data sources to calculate the BoD of (P)VPD in participating VITAL countries and to pinpoint data gaps. Based on epidemiological criteria and vaccine availability, we prioritized (P) VPD caused by Extra-intestinal pathogenic Escherichia coli (ExPEC), norovirus, respiratory syncytial virus, Staphylococcus aureus, and pneumococcal pneumonia. METHODS: We conducted a survey on available data (e.g. incidence, mortality, disability-adjusted life years (DALY), quality-adjusted life years (QALY), sequelae, antimicrobial resistance (AMR), etc.) among national experts from European countries, and carried out five pathogen-specific literature reviews by searching MEDLINE for peer-reviewed publications published between 2009 and 2019. RESULTS: Morbidity and mortality data were generally available for all five diseases, while summary BoD estimates were mostly lacking. Available data were not always stratified by age and risk group, which is especially important when calculating BoD for ageing adults. AMR data were available in several countries for S. aureus and ExPEC. CONCLUSION: This study provides an exhaustive overview of the available data sources and data gaps for the estimation of BoD of five (P) VPD in ageing adults in the EU/EAA, which is useful to guide pathogen-specific BoD studies and contribute to calculation of (P)VPDs BoD.

Pre-screening and preventive quarantine likely explains the low SARS-CoV-2 prevalence among Norwegian conscripts.

Objective: We aim to discuss whether preventive quarantine can mitigate the spread of Covid-19 during the pandemic. Design: We did a cross-sectional, observational study design in a mass-screening program in the enrolment to the Norwegian military during April 19-28th 2020 (COVID-NOR-MIL). Subjects: 1170 presumptively healthy young Norwegian conscripts. Setting: A structured interview encouraged the coming conscripts to a self-imposed preventive quarantine the last two weeks before enrolment. Main outcome measures: All conscripts underwent a PCR-based test with nasopharyngeal swabs at the day of enrolment. Results: Only two tested positive. The study discusses the predictive value of the RT-PCR test and the risk of false positive and false negative results, particularly when using the test in a low-prevalent cohort, even if the test properties of sensitivity and specificity is almost 100%. Further, the study discusses the challenge of whether a positive SARS-CoV-2 PCR-test represent viable and contagious virus or only viral remnants. Conclusion: The adherence to self-imposed preventive quarantine is a challenge and is a subject to further research. Implications: We want to draw the attention to the potential value of a thorough pre-screening processes and self-imposed preventive quarantine to minimize the potential spread of SARS-Cov-2.

Severe acute respiratory syndrome coronavirus 2 prevalence in 1170 asymptomatic Norwegian conscripts.

BACKGROUND: Accurate estimates of SARS-CoV-2 infection in different population groups are important for the health authorities. In Norway, public infection control measures have successfully curbed the pandemic. However, military training and service are incompatible with these measures; therefore extended infection control measures were implemented in the Norwegian Armed Forces. We aimed to describe these measures, discuss their value, and investigate the polymerase chain reaction (PCR) prevalence and seroprevalence of SARS-CoV-2, as well as changes in antibody titer levels over the 6-week military training period in a young, asymptomatic population of conscripts. METHODS: In April 2020, 1170 healthy conscripts (median age 20 years) enrolled in military training. Extended infection control measures included a pre-enrollment telephone interview, self-imposed quarantine, questionnaires, and serial SARS-CoV-2 testing. At enrollment, questionnaires were used to collect information on symptoms, and SARS-CoV-2 rapid antibody testing was conducted. Serial SARS-CoV-2 PCR and serology testing were used to estimate the prevalence of confirmed SARS-CoV-2 and monitor titer levels at enrollment, and 3 and 6 weeks thereafter. RESULTS: At enrollment, only 0.2% of conscripts were SARS-CoV-2 PCR-positive, and seroprevalence was 0.6%. Serological titer levels increased nearly 5-fold over the 6-week observation period. Eighteen conscripts reported mild respiratory symptoms during the 2 weeks prior to enrollment (all were PCR-negative; one was serology-positive), whereas 17 conscripts reported respiratory symptoms and nine had fever at enrollment (all were PCR- and serology-negative). CONCLUSIONS: The prevalence of SARS-CoV-2 was less than 1% in our sample of healthy Norwegian conscripts. Testing of asymptomatic conscripts seems of no value in times of low COVID-19 prevalence. SARS-CoV-2 antibody titer levels increased substantially over time in conscripts with mild symptoms.

COVID-19 cases reported to the Norwegian Institute of Public Health in the first six weeks of the epidemic. / Covid-19 rapportert til Folkehelseinstituttet de første seks ukene av epidemien.

BACKGROUND: The first case of SARS-CoV-2 infection in Norway was confirmed on 26 February 2020. Following sharpened advice on general infection control measures at the beginning of the outbreak, extensive national control measures were implemented on 12 March, and testing was focused on those with severe illness. We describe the first six weeks of the outbreak in Norway, viewed in light of testing criteria and control measures. MATERIAL AND METHOD: We described all laboratory-confirmed cases of COVID-19 reported to three different surveillance systems under the Norwegian Institute of Public Health up to 5 April 2020, and compared cases reported up to 12 March with those reported from 13 March. RESULTS: By 12 March, 1 128 cases had been reported. Their median age was 47 years, 64 % were male, 66 % had travelled abroad, 6 % were hospitalised at the time of reporting, and < 1 % had died. The median age of the 4 742 cases reported from 13 March was 48 years, 47 % were male, 18 % had travelled abroad, 15 % were hospitalised, and 3 % died. INTERPETATION: The distribution of COVID-19 cases before and after 12 March reflects different phases of the outbreak. However, findings must be interpreted in the light of criteria for testing, testing activity, control measures and characteristics of surveillance systems.

Poor self-reported adherence to COVID-19-related quarantine/isolation requests, Norway, April to July 2020.

To limit SARS-CoV-2 spread, quarantine and isolation are obligatory in several situations in Norway. We found low self-reported adherence to requested measures among 1,704 individuals (42%; 95% confidence interval: 37-48). Adherence was lower in May-June-July (33-38%) compared with April (66%), and higher among those experiencing COVID-19-compatible symptoms (71%) compared with those without (28%). These findings suggest that consideration is required of strategies to improve people's adherence to quarantine and isolation.

Antimicrobial susceptibility and clonality of Streptococcus pneumoniae isolates recovered from invasive disease cases during a period with changes in pneumococcal childhood vaccination, Norway, 2004-2016.

Changes in pneumococcal antimicrobial resistance (AMR) have been reported following use of pneumococcal conjugate vaccines (PCVs) in childhood vaccination programmes. We describe AMR trends and clonality in Norway during 2004-2016; we studied 10,239 invasive pneumococcal disease (IPD) isolates in terms of serotypes, antimicrobial susceptibility, and for a systematically collected subset of 2473 isolates, multilocus sequence types (ST). The IPD cases were notified to the Norwegian Surveillance System for Communicable Diseases and pneumococcal isolates were collected through the National Reference Laboratory for Pneumococci. The cases are sourced from the entire Norwegian population. We supplemented the IPD isolates with isolates from carriage studies in children attending day-care, performed in 2006 (before mass childhood vaccination with PCV7), 2008 (2 years after PCV7 introduction), 2013 (2 years after the transition to PCV13), and 2015. IPD cases were 0-102 years old; median 64 years. Carriage study participants were typically aged 1-5 years. Overall, AMR was low; a maximum of 7% of IPD isolates were resistant, depending on the antimicrobial. Erythromycin and trimethoprim/sulfamethoxazole resistant IPD (ERY-R and SXT-R, respectively) decreased in the PCV7 period (2006-2010). In the PCV13 period (2011-2016) however, we saw an indication of increased non-susceptibility among IPD isolates. This increase was mainly due to non-vaccine serotypes 15A-ST63 (multidrug resistant), 24F-ST162 (SXT-R), 23B-ST2372 (penicillin non-susceptible and SXT-R) and 33F (ERY-R and clindamycin resistant). Resistant or non-susceptible IPD isolates were often clones introduced into Norway during the study period. The exception was ERY-R isolates; initially, these largely consisted of an established serotype 14-ST9 clone, which disappeared after introducing PCV7. The carriage study results mostly resembled the changes seen in IPD with a maximum of 9% of the participants per study carrying resistant pneumococci. As actual PCVs are not fully limiting AMR, higher-valency vaccines and prudent use of antimicrobials are still needed to temper pneumococcal AMR.

High overall confidence in childhood vaccination in Norway, slightly lower among the unemployed and those with a lower level of education.

In Norway, childhood immunisation is offered on voluntary basis, free of charge and is delivered through trained nurses at > 650 child health centres and school health services. Maintaining high confidence in the vaccination programme is key to sustaining high vaccine uptake. We aimed to investigate confidence in childhood vaccination in the general population and to identify determinants for lower confidence. In 2017 and 2018, Statistics Norway asked questions on confidence in childhood vaccination (to all respondents) and children's vaccination history (to parents) in their routine cross-sectional survey. Respondents reported their level of agreement on a five-point Likert scale. Using a weighted analysis we calculated proportions agreeing [95% confidence interval] by respondent characteristics. Overall, 2169 individuals participated (54% response). 95.8% [94.8-96.7] answered that vaccination is important, 93.4% [92.2-94.4] thought that vaccines are safe, 96.0% [95.0-96.8] thought that vaccines are effective and for 93.4% [92.2-94.4] vaccination was compatible with their basic values. Those with lower level of education expressed lower confidence in vaccination due to conflict with their basic values (88.2% [84.7-91.0] answered positively). Those unemployed expressed lower confidence due to conflict with their basic values (81.9% [71.8-88.9]) and because of concerns about vaccines' safety (83.5% [73.7-90.1]). 96.3% [94.3-97.6] of parents (n = 580) had their children fully vaccinated, despite that one fifth answered that they at least once have had doubts on whether or not to vaccinate their children. There is high confidence in childhood vaccination in Norway. Those with a lower level of education and the unemployed reported comparatively lower confidence. To maintain high confidence in childhood vaccination, we recommend maintaining the well-informed system with easily accessible vaccinations. Furthermore, we recommend maintaining surveillance of vaccine confidence, supplemented with targeted studies on subgroups who are less confident, express doubts and/or oppose vaccination. Those studies should inform communication strategies tailored to subgroups.

Indirect Effects of Pneumococcal Childhood Vaccination in Individuals Treated With Immunosuppressive Drugs in Ambulatory Care: A Case-cohort Study.

BACKGROUND: The extent to which iatrogenically-immunosuppressed individuals benefit from indirect effects of childhood vaccination with pneumococcal conjugate vaccines (PCVs) is unknown. We determined how the sequential introduction of PCV7 (2006) and PCV13 (2011) in the Norwegian childhood vaccination program has affected the epidemiology of invasive pneumococcal disease (IPD) in individuals treated with immunosuppressants in ambulatory care. METHODS: We conducted a case-cohort study comprising 7926 IPD cases reported to the Norwegian Surveillance System for Communicable Diseases in 2005-2014 and 249998 individuals randomly selected from the National Registry in 2012. We defined immunosuppressive treatment groups based on dispensed prescriptions retrieved from the Norwegian Prescription Database. Incidences and age-adjusted relative risks (RR) were estimated. RESULTS: IPD incidences decreased in all groups. The PCV13 incidence decreased by 5-12% across groups. The non-PCV13 incidence increased by 4-10%, mostly in individuals on chemotherapy (overlapping 95% confidence intervals). In the PCV13 era, the RR for IPD was highest (significant) and the percentage of cases caused by the polysaccharide vaccine PPV23 serotypes lowest (numerical) in individuals on chemotherapy (RR = 20.4, PPV23 = 52%), followed by individuals on corticosteroids (RR = 6.2, PPV23 = 64%), other immunosuppressants (RR = 5.6, PPV23 = 68%), and no immunosuppressants (RR = 1 [reference], PPV23 = 74%). CONCLUSIONS: IPD incidences declined after PCV introduction in both immunocompetent and iatrogenically-immunosuppressed individuals, underscoring the benefit of childhood vaccination for the entire population. Still, individuals treated with immunosuppressants in ambulatory care are at increased risk of IPD caused by a more diverse group of serotypes.

The relative invasive disease potential of Streptococcus pneumoniae among children after PCV introduction: A systematic review and meta-analysis.

OBJECTIVES: Burden of pneumococcal disease depends on the prevalence and invasive disease potential of serotypes. We aimed to estimate the invasive disease potential of serotypes in children under 5 years of age by combining data from different settings with routine immunisation with pneumococcal conjugate vaccines (PCV). METHODS: We conducted a systematic review, supplemented by unpublished data, to identify data on the frequency of pneumococcal serotypes in carriage and invasive pneumococcal disease (IPD). We estimated the invasive disease potential of serotypes as the ratio of IPD in relation to carriage (odds ratio and 95%CI) compared with 19A (reference serotype) by meta-analysis. We report results based on a random effects model for children aged 0-23, 24-29, and 0-59 months and by invasive clinical syndromes. RESULTS: In comparison with 19A, serotypes 1, 7F, and 12F had a significantly higher invasive disease potential in children aged 0-23 and 0-59 months for all IPD and clinical syndromes (OR > 5). Several non-vaccine types (NVTs) (6C, 15A, 15BC, 16F, 23B, in these two age groups) had a lower invasive disease potential than 19A (OR 0.1-0.3). NVTs 8, 12F, 24F, and 33F were at the upper end of the invasiveness spectrum. CONCLUSIONS: There is substantial variation among pneumococcal serotypes in their potential to cause IPD and disease presentation, which is influenced by age and time after PCV introduction. Surveillance of IPD and carriage is critical to understand the expected effectiveness of current PCVs (in the longer term) and guide the development of future vaccines.