Estimating excess mortality and economic burden of Clostridioides difficile infections and recurrences during 2015-2019: the RECUR Germany study.

BACKGROUND: Clostridioides difficile infections (CDIs) and recurrences (rCDIs) remain a major public health challenge due to substantial mortality and associated costs. This study aims to generate real-world evidence on the mortality and economic burden of CDI in Germany using claims data between 2015 and 2019. METHODS: A longitudinal and matched cohort study using retrospective data from Statutory Health Insurance (SHI) was conducted in Germany with the BKK database. Adults diagnosed with CDI in hospital and community settings between 2015 and 2018 were included in the study. Patients had a minimum follow-up of 12-months. All-cause mortality was described at 6-, 12-, and 24-months. Healthcare resource usage (HCRU) and associated costs were assessed at 12-months of follow-up. A cohort of non-CDI patients matched by demographic and clinical characteristics was used to assess excess mortality and incremental costs of HCRU. Up to three non-CDI patients were matched to each CDI patient. RESULTS: A total of 9,977 CDI patients were included in the longitudinal cohort. All-cause mortality was 32%, 39% and 48% at 6-, 12-, and 24-months, respectively, with minor variations by number of rCDIs. When comparing matched CDI (n = 5,618) and non-CDI patients (n = 16,845), CDI patients had an excess mortality of 2.17, 1.35, and 0.94 deaths per 100 patient-months, respectively. HCRU and associated costs were consistently higher in CDI patients compared to non-CDI patients and increased with recurrences. Total mean and median HCRU cost per patient during follow-up was €12,893.56 and €6,050 in CDI patients, respectively, with hospitalisations representing the highest proportion of costs. A total mean incremental cost per patient of €4,101 was estimated in CDI patients compared to non-CDI patients, increasing to €13,291 in patients with ≥ 3 rCDIs. CONCLUSIONS: In this real-world study conducted in Germany, CDI was associated with increased risk of death and substantial costs to health systems due to higher HCRU, especially hospitalisations. HCRU and associated costs were exacerbated by rCDIs.

Epidemiological and clinical burden of Clostridioides difficile infections and recurrences between 2015 - 2019: the RECUR Germany study.

BACKGROUND: This real-world study assessed the epidemiology and clinical complications of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in hospital and community settings in Germany from 2015 - 2019. METHODS: An observational retrospective cohort study was conducted among adult patients diagnosed with CDI in hospital and community settings using statutory health insurance claims data from the BKK database. A cross-sectional approach was used to estimate the annual incidence rate of CDI and rCDI episodes per 100,000 insurants. Patients' demographic and clinical characteristics were described at the time of first CDI episode. Kaplan-Meier method was used to estimate the time to rCDIs and time to complications (colonic perforation, colectomy, loop ileostomy, toxic megacolon, ulcerative colitis, peritonitis, and sepsis). A Cox model was used to assess the risk of developing complications, with the number of rCDIs as a time-dependent covariate. RESULTS: A total of 15,402 CDI episodes were recorded among 11,884 patients. The overall incidence of CDI episodes declined by 38% from 2015 to 2019. Most patients (77%) were aged ≥ 65 years. Around 19% of CDI patients experienced at least one rCDI. The median time between index CDI episode to a rCDI was 20 days. The most frequent complication within 12-months of follow-up after the index CDI episode was sepsis (7.57%), followed by colectomy (3.20%). The rate of complications increased with the number of rCDIs. The risk of any complication increased by 31% with each subsequent rCDI (adjusted hazard ratio [HR]: 1.31, 95% confidence interval: 1.17;1.46). CONCLUSIONS: CDI remains a public health concern in Germany despite a decline in the incidence over recent years. A substantial proportion of CDI patients experience rCDIs, which increase the risk of severe clinical complications. The results highlight an increasing need of improved therapeutic management of CDI, particularly efforts to prevent rCDI.

Estimating excess mortality and economic burden of Clostridioides difficile infections and recurrences during 2015-2019: The RECUR England study.

OBJECTIVES: To generate real-world evidence on all-cause mortality and economic burden of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in England. METHODS: We conducted a cohort study using retrospective data from Clinical Practice Research Datalink linked to Hospital Episode Statistics. Patients diagnosed with CDI in hospital and community settings during 2015-2018 were included and followed for ≥1 year. All-cause mortality was described at 6, 12, and 24 months. Healthcare resource usage (HCRU) and associated costs were assessed at 12 months of follow-up. A cohort of non-CDI patients, matched by demographic and clinical characteristics including Charlson Comorbidity Index score, was used to assess excess mortality and incremental costs of HCRU. RESULTS: All-cause mortality among CDI patients at 6, 12, and 24 months was 15.87%, 20.37%, and 27.03%, respectively. A higher proportion of rCDI patients died at any point during follow-up. Compared with matched non-CDI patients, excess mortality was highest at 6 months with 1.81 and 2.53 deaths per 100 patient-months among CDI and ≥1 rCDI patients. Hospitalizations were the main drivers of costs, with an incremental cost of £1209.21 per CDI patient. HCRU and costs increased with rCDIs. CONCLUSION: CDI poses a substantial mortality and economic burden, further amplified by rCDIs.

Clostridioides difficile infections, recurrences, and clinical outcomes in real-world settings from 2015 to 2019: The RECUR England study.

OBJECTIVE: To estimate the epidemiological and clinical burden of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in England. METHODS: This retrospective study included adult patients diagnosed with CDI (community or hospital settings) over 2015-2019 from Clinical Practice Research Datalink and Hospital Episode Statistics databases. Incidences of CDI and rCDI were determined annually. Time to subsequent rCDI was estimated by Kaplan-Meier method. Rates of complications were assessed within 12 months from index episode. Association of risk factors with complications was evaluated using a Cox regression model. RESULTS: A total of 52,443 CDI episodes were recorded among 36,913 patients. Of these, 75% were aged ≥65 years, 59% were women; 73% were treated in community settings. CDI incidence remained stable (111 episodes per 100,000 patients in 2019). Around 21% of patients had ≥1 rCDI. Sepsis (12%) was the most common complication, followed by colectomy and ulcerative colitis. Age, gender, comorbidities, rCDI, preindex medical procedures, hospitalizations and consultations, and CDI treatment in hospital, were found to increase the risk of complication. CONCLUSIONS: CDI remains a concern in England. The study highlights the importance of managing primary and rCDI episodes via effective and improved therapies to prevent fatal complications.

Fertility signalling games: should males obey the signal?

Game theory is frequently used to study conflicting interests between the two sexes. Males often benefit from a higher mating rate than females do. A temporal component of this conflict has rarely been modelled: females' interest in mating may depend on when females become fertile. This sets conditions for male-female coevolution, where females may develop fertility signals, and males may obey the signal, such that they only target signalling females. Modelling this temporal aspect to sexual conflict yields two equilibria: (i) a trivial equilibrium without signals and with males targeting all females, and (ii) a signalling equilibrium where all females signal before ovulation, and where either some, or all, males obey the signal. The 'all males obey the signal' equilibrium is more likely if we assume that discriminating males have an advantage in postcopulatory sperm competition, while in the absence of this benefit, we find the 'some males obey the signal' equilibrium. The history of game-theoretic models of sex differences often portrays one sex as the 'winner' and the opposite sex as the 'loser'. From early models emphasizing 'battle of the sexes'-style terminology, we recommend moving on to describe the situation as non-signalling equilibria having stronger unresolved sexual conflict than signalling equilibria. This article is part of the theme issue 'Half a century of evolutionary games: a synthesis of theory, application and future directions'.

Sexual conflict over phenological traits: selection for protandry can lock populations into temporally mismatched reproduction.

In seasonal environments, competition among males can drive males to emerge before females. Females, simultaneously, should avoid emerging at times after sufficient male availability. We show that the consequent sexual conflict over timing traits can produce arms races toward ever earlier emergence, if low mate-search efficiency or sperm limitation elevate the latter risk for females. In reality, however, arms races over timing cannot proceed indefinitely as this ignores the relevant ecological context for phenology: the temporal niche of resource availability for offspring development. We model the interaction of natural and sexual selection to predict the sexual conflict load, i.e., the loss of population fitness caused by sexual conflict. We show that selection to avoid matelessness can exacerbate another problem of maladaptation: a temporal mismatch between the organism (e.g., insect) and its resource (e.g., host plant). Load frequently associates with protandry if males can mate multiply, yet lack of multiple mating does not imply zero load. A temporal mismatch can still evolve, where both sexes emerge and mate suboptimally early with respect to the seasonal resource peak, because monogamy does not guarantee that every individual finds one mate, and selection favors early individuals in mate-finding contexts.

Is more always better when it comes to mating?

Fitness usually increases when a male mates with more females, but is the same true for females? A new meta-analysis in PLOS Biology shows that females, like males, tend to have a positive relationship between the number of mates and their reproductive output. But why?

Habitat detection, habitat choice copying or mating benefits: What drives conspecific attraction in a nomadic songbird?

Conspecific attraction during habitat selection is common among animals, but the ultimate (i.e. fitness-related) reasons for this behaviour often remain enigmatic. We aimed to evaluate the following three hypotheses for conspecific attraction during the breeding season in male Wood Warblers (Phylloscopus sibilatrix): the habitat detection hypothesis, the habitat choice copying hypothesis and the female preference hypothesis. These hypotheses make different predictions with respect to the relative importance of social and nonsocial information during habitat assessment, and whether benefits accrue as a consequence of aggregation. We tested the above hypotheses using a combination of a 2-year playback experiment, spatial statistics and mate choice models. The habitat detection hypothesis was the most likely explanation for conspecific attraction and aggregation in male Wood Warblers, based on the following results: (1) males were attracted to conspecific song playbacks, but fine-scale habitat heterogeneity was the better predictor of spatial patterns in the density of settling males; (2) male pairing success did not increase, but instead slightly decreased, as connectivity with other males (i.e. the number and proximity of neighbouring males) increased. Our study highlights how consideration of the process by which animals detect and assess habitat, together with the potential fitness consequences of resulting aggregations, are important for understanding conspecific attraction and spatially clustered distributions.

Long-term population impact of infant 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in adults in Finland.

BACKGROUND: Limited data are available on long-term indirect effects of ten-valent pneumococcal conjugate vaccine (PCV10) programmes. We evaluated changes in invasive pneumococcal disease (IPD) incidence, mortality, and serotype distribution in adults up to 9 years after infant PCV10 introduction. METHODS: Culture-confirmed IPD cases ≥18 years (n = 5610; 85% were pneumonia) were identified through national, population-based laboratory surveillance; data were linked with population registry to conduct nationwide follow-up study. In a time-series model, we compared serotype-specific IPD incidence and associated 30-day mortality rates before and after PCV10 by using negative binomial regression models. RESULTS: During pre-PCV10 period (7/2004-6/2010), overall IPD incidence in adults ≥18 years increased yearly by 4.8%. After adjusting for trend and seasonality, the observed PCV10 serotype IPD incidence in 7/2018-6/2019 was 90% (12/100,000 person-years) lower than the expected rate without PCV10 program. Non-PCV10 serotype incidence was 40% (4.4/100,000 person-years) higher than expected; serotypes 3, 19A, 22F, and 6C accounted for most of the rate increase. However, incidence of non-PCV10 IPD levelled off by end of follow-up. The observed-expected incidence rate-ratio (IRR) was 0·7 (95 %CI 0·5-0.8) for all IPD and 0·7 (95 %CI 0·3-1·3) for IPD-associated 30-day mortality. Case-fatality proportion decreased from 11·9% to 10.0% (p < 0.01). In persons ≥65 years, the IRR was 0·7 (95 %CI 0·5-0.95). CONCLUSIONS: Significant indirect effects were seen for vaccine-serotype IPD and for overall IPD in all adult age groups. For non-vaccine IPD, the incidence stabilized 5 years after infant PVC10 program introduction, resulting in a steady state in which non-vaccine IPD accounted for nearly 90% of overall IPD. Substantial pneumococcal disease burden remains in older adults.

Effectiveness of 10 and 13-valent pneumococcal conjugate vaccines against invasive pneumococcal disease in European children: SpIDnet observational multicentre study.

BACKGROUND: Pneumococcal conjugate vaccines covering 10 (PCV10) and 13 (PCV13) serotypes have been introduced in the infant immunization schedule of most European countries in 2010-11. To provide additional real-life data, we measured the effectiveness of PCV10 and PCV13 against invasive pneumococcal disease (IPD) in children of 12 European sites (SpIDnet). METHODS: We compared the vaccination status of PCV10 and PCV13 serotype IPD (cases) to that of nonPCV13 serotype IPD (controls) reported in 2012-2018. We calculated pooled effectiveness as (1-vaccination odds ratio)*100, and measured effectiveness over time since booster dose. RESULTS: The PCV13 and PCV10 studies included 2522 IPD cases from ten sites and 486 cases from four sites, respectively. The effectiveness of ≥ 1 PCV13 dose was 84.2% (95 %CI: 79.0-88.1) against PCV13 serotypes (n = 2353) and decreased from 93.1% (87.8-96.1) < 12 months to 85.1% (72.0-92.1) ≥ 24 months after booster dose. PCV13 effectiveness of ≥ 1 dose was 84.7% (55.7-94.7) against fatal PCV13 IPD, 64.5% (43.7-77.6), 83.2% (73.7-89.3) and 85.1% (67.6-93.1) against top serotypes 3, 19A and 1, respectively, and 85.4% (62.3-94.4) against 6C. Serotype 3 and 19A effectiveness declined more rapidly. PCV10 effectiveness of ≥ 1 dose was 84.8% (69.4-92.5) against PCV10 serotypes (n = 370), 27.2% (-187.6 to 81.6) and 85.3% (35.2-96.7) against top serotypes 1 and 7F, 32.5% (-28.3 to 64.5) and -14.4% (-526.5 to 79.1) against vaccine-related serotypes 19A and 6C, respectively. CONCLUSIONS: PCV10 and PCV13 provide similar protection against IPD due to the respective vaccine serotype groups but serotype-specific effectiveness varies by serotype and vaccine. PCV13 provided individual protection against serotype 3 and vaccine-related serotype 6C IPD. PCV10 effectiveness was not significant against vaccine-related serotypes 19A and 6C. PCV13 effectiveness declined with time after booster vaccination. This multinational study enabled measuring serotype-specific vaccine effectiveness with a precision rarely possible at the national level. Such large networks are crucial for the post-licensure evaluation of vaccines.

Volatile social environments can favour investments in quality over quantity of social relationships.

Cooperation does not occur in a vacuum: interactions develop over time in social groups that undergo demographic changes. Intuition suggests that stable social environments favour developing few but strong reciprocal relationships (a 'focused' strategy), while volatile social environments favour the opposite: more but weaker social relationships (a 'diversifying' strategy). We model reciprocal investments under a quality-quantity trade-off for social relationships. We find that volatility, counterintuitively, can favour a focused strategy. This result becomes explicable through applying the theory of antagonistic pleiotropy, originally developed for senescence, to social life. Diversifying strategies show superior performance later in life, but with costs paid at young ages, while the social network is slowly being built. Under volatile environments, many individuals die before reaching sufficiently old ages to reap the benefits. Social strategies that do well early in life are then favoured: a focused strategy leads individuals to form their first few social bonds quickly and to make strong use of existing bonds. Our model highlights the importance of pleiotropy and population age structure for the evolution of cooperative strategies and other social traits, and shows that it is not sufficient to reflect on the fate of survivors only, when evaluating the benefits of social strategies.

Kidnapping intergroup young: an alternative strategy to maintain group size in the group-living pied babbler (Turdoides bicolor).

Both inter- and intragroup interactions can be important influences on behaviour, yet to date most research focuses on intragroup interactions. Here, we describe a hitherto relatively unknown behaviour that results from intergroup interaction in the cooperative breeding pied babbler: kidnapping. Kidnapping can result in the permanent removal of young from their natal group. Since raising young requires energetic investment and abductees are usually unrelated to their kidnappers, there appears no apparent evolutionary advantage to kidnapping. However, kidnapping may be beneficial in species where group size is a critically limiting factor (e.g. for reproductive success or territory defence). We found kidnapping was a highly predictable event in pied babblers: primarily groups that fail to raise their own young kidnap the young of others, and we show this to be the theoretical expectation in a model that predicts kidnapping to be facultative, only occurring in those cases where an additional group member has sufficient positive impact on group survival to compensate for the increase in reproductive competition. In babblers, groups that failed to raise young were also more likely to accept extragroup adults (hereafter rovers). Groups that fail to breed may either (i) kidnap intergroup young or (ii) accept rovers as an alternative strategy to maintain or increase group size. This article is part of the theme issue 'Intergroup conflict across taxa'.

Selfish migrants: How a meiotic driver is selected to increase dispersal.

Meiotic drivers are selfish genetic elements that manipulate meiosis to increase their transmission to the next generation to the detriment of the rest of the genome. One example is the t haplotype in house mice, which is a naturally occurring meiotic driver with deleterious traits-poor fitness in polyandrous matings and homozygote inviability or infertility-that prevent its fixation. Recently, we discovered and validated a novel effect of t in a long-term field study on free-living wild house mice and with experiments: t-carriers are more likely to disperse. Here, we ask what known traits of the t haplotype can select for a difference in dispersal between t-carriers and wildtype mice. To that end, we built individual-based models with dispersal loci on the t and the homologous wildtype chromosomes. We also allow for density-dependent expression of these loci. The t haplotype consistently evolves to increase the dispersal propensity of its carriers, particularly at high densities. By examining variants of the model that modify different costs caused by t, we show that the increase in dispersal is driven by the deleterious traits of t, disadvantage in polyandrous matings and lethal homozygosity or male sterility. Finally, we show that an increase in driver-carrier dispersal can evolve across a range of values in driver strength and disadvantages.

Evaluation of the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine in a cluster-randomised trial.

BACKGROUND: In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. METHODS: Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. RESULTS: From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. CONCLUSIONS: This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

Serotype Replacement after Introduction of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccines in 10 Countries, Europe.

We evaluated invasive pneumococcal disease (IPD) during 8 years of infant pneumococcal conjugate vaccine (PCV) programs using 10-valent (PCV10) and 13-valent (PCV13) vaccines in 10 countries in Europe. IPD incidence declined during 2011-2014 but increased during 2015-2018 in all age groups. From the 7-valent PCV period to 2018, IPD incidence declined by 42% in children <5 years of age, 32% in persons 5-64 years of age, and 7% in persons >65 years of age; non-PCV13 serotype incidence increased by 111%, 63%, and 84%, respectively, for these groups. Trends were similar in countries using PCV13 or PCV10, despite different serotype distribution. In 2018, serotypes in the 15-valent and 20-valent PCVs represented one third of cases in children <5 years of age and two thirds of cases in persons >65 years of age. Non-PCV13 serotype increases reduced the overall effect of childhood PCV10/PCV13 programs on IPD. New vaccines providing broader serotype protection are needed.

Disentangling Verbal Arguments: Intralocus Sexual Conflict in Haplodiploids.

AbstractIn haplodiploids, (1) alleles spend twice as many generations in females as in males, (2) males are never heterozygous and therefore express recessive alleles, and (3) males sire daughters but not sons. Intralocus sexual conflict therefore operates differently in haplodiploids than in diploids and shares strong similarities with loci on X (or Z) chromosomes. The common co-occurrence of all three features makes it difficult to pinpoint their respective roles. However, they do not always co-occur in nature, and missing cases can be additionally studied with hypothetical life cycles. We model sexually antagonistic alleles in eight different sex determination systems and find that arguments 1 and 2 promote invasion and fixation of female-beneficial and male-beneficial alleles, respectively; argument 2 also improves prospects for polymorphism. Argument 3 harms the invasion prospects of sexually antagonistic alleles (irrespective of which sex benefits) but promotes fixation should invasion nevertheless occur. Disentangling the features helps to evaluate the validity of previous verbal arguments and yields better-informed predictions about intralocus sexual conflict under different sex determination systems, including hitherto undiscovered ones.

The stagnation paradox: the ever-improving but (more or less) stationary population fitness.

Fisher's fundamental theorem states that natural selection improves mean fitness. Fitness, in turn, is often equated with population growth. This leads to an absurd prediction that life evolves to ever-faster growth rates, yet no one seriously claims generally slower population growth rates in the Triassic compared with the present day. I review here, using non-technical language, how fitness can improve yet stay constant (stagnation paradox), and why an unambiguous measure of population fitness does not exist. Subfields use different terminology for aspects of the paradox, referring to stasis, cryptic evolution or the difficulty of choosing an appropriate fitness measure; known resolutions likewise use diverse terms from environmental feedback to density dependence and 'evolutionary environmental deterioration'. The paradox vanishes when these concepts are understood, and adaptation can lead to declining reproductive output of a population when individuals can improve their fitness by exploiting conspecifics. This is particularly readily observable when males participate in a zero-sum game over paternity and population output depends more strongly on female than male fitness. Even so, the jury is still out regarding the effect of sexual conflict on population fitness. Finally, life-history theory and genetic studies of microevolutionary change could pay more attention to each other.

Parthenogenesis and the Evolution of Anisogamy.

Recently, it was pointed out that classic models for the evolution of anisogamy do not take into account the possibility of parthenogenetic reproduction, even though sex is facultative in many relevant taxa (e.g., algae) that harbour both anisogamous and isogamous species. Here, we complement this recent analysis with an approach where we assume that the relationship between progeny size and its survival may differ between parthenogenetically and sexually produced progeny, favouring either the former or the latter. We show that previous findings that parthenogenesis can stabilise isogamy relative to the obligate sex case, extend to our scenarios. We additionally investigate two different ways for one mating type to take over the entire population. First, parthenogenesis can lead to biased sex ratios that are sufficiently extreme that one type can displace the other, leading to de facto asexuality for the remaining type that now lacks partners to fuse with. This process involves positive feedback: microgametes, being numerous, lack opportunities for syngamy, and should they proliferate parthenogenetically, the next generation makes this asexual route even more prominent for microgametes. Second, we consider mutations to strict asexuality in producers of micro- or macrogametes, and show that the prospects of asexual invasion depend strongly on the mating type in which the mutation arises. Perhaps most interestingly, we also find scenarios in which parthenogens have an intrinsic survival advantage yet facultatively sexual isogamous populations are robust to the invasion of asexuals, despite us assuming no genetic benefits of recombination. Here, equal contribution from both mating types to zygotes that are sufficiently well provisioned can outweigh the additional costs associated with syngamy.

Long-term population effects of infant 10-valent pneumococcal conjugate vaccination on pneumococcal meningitis in Finland.

BACKGROUND: No previous studies have reported long-term follow-up of ten-valent pneumococcal conjugate vaccine (PCV10) program impact on pneumococcal meningitis (PM). We assessed the effects of infant PCV10 program on PM incidence, mortality and serotype distribution in children and adults during 7 years after introduction. METHODS: We conducted a population-based observational study. A case of PM was defined as isolation of Streptococcus pneumoniae from cerebrospinal fluid or, a patient with S. pneumoniae isolated from blood and an ICD-10 hospital discharge diagnosis of bacterial meningitis within 30 days before or after positive culture date.We compared age- and serotype-specific incidence and associated 30-day mortality rates in 2011-2017 (PCV10 period) with those in 2004-2010 (pre-PCV10 baseline) by using Poisson regression models. Absolute rate differences and 95% confidence intervals (CIs) were calculated from the parameter estimates by using delta method. RESULTS: During the PCV10 period, the overall incidence of PCV10 serotype meningitis decreased by 68% (95%CI 57%-77%), and the overall PM incidence by 27% (95%CI: 12%-39%). In age groups 0-4, 50-64, and ≥ 18 years, the overall PM incidence was reduced by 64%, 34% and 19%, respectively. In adults ≥ 65 years of age, a 69% reduction in PCV10 serotypes was offset by 157% (56%-342%) increase in non-PCV10 serotypes. The overall PM-related mortality rate decreased by 42% (95%CI 4%-65%). Overall case fatality proportion (CFP) was 16% in pre-PCV10 period and 12% in PCV10 period (p = 0.41); among persons 50-64 years the CFP decreased from 25% to 10% (p = 0.04). CONCLUSIONS: We observed substantial impact and herd protection for vaccine-serotype PM and associated mortality after infant PCV10 introduction. However, in older adults ≥ 65 years of age, PM burden remains unchanged due to serotype replacement.