Streptococcus suis est un important pathogène porcin et agent zoonotique responsable de méningites et de septicémies. À ce jour, les mécanismes impliqués dans la réponse immunitaire de l’hôte lors de l’infection par S. suis sont peu connus; et il en est de même pour les stratégies utilisées par S. suis afin de déjouer cette réponse. L’augmentation de l’incidence et de la sévérité des cas humains souligne le besoin d’une meilleure compréhension des interactions entre S. suis et le système immunitaire afin de générer une réponse immunitaire efficace contre ce pathogène. Les cellules dendritiques (DCs) sont de puissantes cellules présentatrices d’antigènes qui stimulent les lymphocytes T et B, assurant la liaison entre l’immunité innée et l’immunité adaptative. L’objectif principal de ce projet était d’évaluer le rôle joué par différents facteurs de virulence de S. suis sur la modulation de la fonction des DCs et de la réponse T-dépendante. Nous avons examiné l’effet des facteurs clés pour la virulence de S. suis, dont la capsule polysaccharidique (CPS), les modifications de la paroi cellulaire (D-alanylation de l’acide lipotéichoïque et N-déacétylation du peptidoglycane) et la toxine suilysine, sur l’activation et la maturation de DCs murines dérivées de la moelle osseuse (bmDCs). Suite à l’infection par S. suis, les bmDCs sont activées et subissent un processus de maturation caractérisé par l’augmentation de l’expression de molécules de co-stimulation et la production de cytokines pro-inflammatoires. La CPS est le principal facteur interférant avec la production de cytokines, même si les modifications de la paroi cellulaire et la suilysine peuvent également moduler la production de certaines cytokines. Enfin, la CPS, les modifications de la paroi cellulaire et la suilysine interfèrent avec la déposition du complément à la surface des bactéries et, en conséquence, avec le « killing » dépendant du complément. Les résultats ont été confirmés à l’aide de bmDCs porcines. Nous avons aussi voulu identifier les récepteurs cellulaires impliqués dans la reconnaissance de S. suis par les DCs. Nous avons démontré que la production de cytokines et l’expression des molécules de co-stimulation par les DCs sont fortement dépendantes de la signalisation par MyD88, suggérant que les DCs reconnaissent S. suis et deviennent activées majoritairement via la signalisation par les récepteurs de type Toll (TLRs). En effet, on remarque une diminution de la production de plusieurs cytokines ainsi que de l’expression de certaines molécules de co-stimulation chez les DCs TLR2-/- ou TLR2-/- et TLR9-/- double négatives. Finalement, le récepteur NOD2 semblait jouer un rôle partiel dans l’activation des DCs suite à une infection par S. suis.Enfin, nous avons évalué les conséquences de la modulation des fonctions des DCs sur le développement de la réponse T-dépendante. Les splénocytes totaux produisent plusieurs cytokines en réponse à S. suis. Des analyses in vivo et ex vivo ont permis d’observer l’implication des cellules T CD4+ et le développement d’une réponse de type « T helper » 1 (TH1) bien que la quantité de cytokines TH1 produites lors de l’infection in vivo par S. suis demeure assez basse. La CPS de S. suis interfère avec la production de plusieurs cytokines par les cellules T in vitro. Expérimentalement, l’infection induite par S. suis résulte en de faibles niveaux de production d’anticorps anti-S. suis, mais aussi d’anticorps dirigés contre l’ovalbumine utilisée comme antigène rapporteur. Cette interférence est corrélée avec la sévérité des signes cliniques, suggérant que S. suis interfère avec le développement d’une réponse immunitaire adaptative appropriée qui serait requise pour contrôler la progression de l’infection. Les résultats de cette étude mèneront à une meilleure compréhension de la réponse immunitaire de l’hôte lors de l’infection par S. suis. / Streptococcus suis is an important swine pathogen and an emerging zoonotic agent of septicemia and meningitis. Knowledge of host immune responses towards S. suis, and strategies used by this pathogen for subversion of these responses is scarce. Increased severity of S. suis infections in humans underscores the critical need to better understand the interactions between S. suis and the immune system to generate an effective immune response against this pathogen. Dendritic cells (DCs) are powerful antigen-presenting cells. Once activated, they stimulate T cells and B cells, linking innate and adaptive immunity. Thus, the main objective of this project was to evaluate the role of different S. suis virulence factors on the modulation of DC functions and the T cell-dependent response. Initially, we investigated the effect of S. suis key virulence factors, including the capsular polysaccharide (CPS), the cell wall modifications (D-alanylation of the lipoteichoic acid and N-deacetylation of the peptidoglycan) and the toxin suilysin, on the activation and maturation of mouse bone-marrow derived DCs (bmDCs). We observed that following S. suis infection, bmDCs are activated and go through a complex maturation process characterized by the up-regulation of the surface expression of costimulatory molecules and the production of pro-inflammatory cytokines. The CPS is the main virulence factor interfering with cytokine production, even if cell wall modifications and suilysin can also modulate the production of cytokines. Finally, CPS, cell wall modifications and suilysin were shown to interfere with complement deposition on S. suis, and consequently with complement-dependent killing. Results were confirmed using porcine bmDCs. We also aimed to identify the cellular receptors involved in S. suis recognition by DCs. Production of cytokines and expression of co-stimulatory molecules by DCs were shown to strongly rely on MyD88-dependent signaling pathways, suggesting that DCs recognize S. suis and become activated mostly through Toll-like receptor (TLR) signaling. Supporting this fact, TLR2-/- or double negative TLR2-/- and TLR9-/- DCs were severely impaired in the release of several cytokines and the surface expression of certain costimulatory molecules. In addition, NOD2 receptor also seems to play a partial role in DC activation by S. suis. Finally, we evaluated the consequences of the modulation of DC functions on T cell activation. In response to S. suis infection, total splenocytes readily produced several cytokines ex vivo. Ex vivo and in vivo analysis revealed the involvement of CD4+ T cells and development of a T helper 1 (TH1) response. Nevertheless, levels of TH1-derived cytokines during S. suis infection were very low. The bacterial CPS was shown to interfere with the release of several T cell-derived cytokines in vitro. As a consequence, a clinical infection resulted in low levels of not only anti-S. suis antibodies but also of those directed against ovalbumin, used as reported antigen. This interference was correlated with the presence of severe clinical signs of S. suis disease. These data suggest that S. suis impairs the development of an efficient adaptive immune response, which is required to control the infection progress. Overall, these results will permit a better comprehension of the host immune response during S. suis infection.

Streptococcus suis est un important pathogène porcin et humain, causant méningites et septicémies. Des études suggèrent que S. suis dispose de facteurs de virulence, notamment sa capsule polysaccharidique (CPS), qui lui permettent de moduler les fonctions des cellules dendritiques (DCs), situées à l’interface entre l’immunité innée et adaptative. Les difficultés à développer un vaccin efficace suggèrent aussi une altération de la voie T dépendante. L’objectif général du projet était d’évaluer l’effet de S. suis sur l’activation des cellules T CD4+ ainsi que sur la capacité de présentation antigénique des DCs. Nous avons étudié dans un modèle murin in vivo la réponse T CD4+ mémoire lors d’infections primaire et secondaire. Une faible réponse mémoire centrale a été obtenue, suggérant que la réponse adaptative générée contre S. suis est limitée. Étant donné l’importance du complexe majeur d’histocompatibilité (MHC) de classe II dans la présentation antigénique, nous avons évalué in vitro et in vivo l’expression de ces molécules chez les DCs. Une modulation de l’expression du MHC-II par S. suis a été observée. L’analyse de la transcription de gènes impliqués dans la régulation transcriptionnelle et post-transcriptionnelle du MHC-II nous permet de suggérer que S. suis régule à la baisse la synthèse de nouvelles molécules et favorise leur dégradation lysosomale. Cette stratégie, dans laquelle la CPS ne jouerait qu’un rôle partiel, permettrait à S. suis d’échapper à la réponse adaptative T dépendante. Les résultats de cette étude fourniront de nouvelles perspectives dans la compréhension de la réponse adaptative lors de l’infection par S. suis. / Streptococcus suis is an important swine and human pathogen causing meningitis and septicemia. Recent studies suggest that S. suis possesses several virulence factors, including the capsular polysaccharide, which enable this pathogen to modulate dendritic cell (DCs) functions. DCs are key immune cells that bridge innate and adaptive immunity. Moreover, the difficulties in developing an effective vaccine suggest that S. suis interferes with the T-cell dependent response. The main objective of the project was to evaluate the effect of S. suis on CD4+ T-cell activation, as well as on the antigen presentation ability of DCs. We investigated the CD4+ T-cell memory response in an in vivo mouse model. A poor central memory response was obtained following primary and secondary infections with S. suis, thus suggesting that the adaptive immune response against this pathogen is limited. The major histocompatibility complex (MHC) class II is central to the antigen presentation pathway. We thus investigated in vitro and in vivo the expression of these molecules on DCs. We observed a modulation in the expression of MHC-II by S. suis. Transcriptional analysis of genes involved in transcriptional and post-transcriptional regulation of MHC-II suggests that S. suis downregulates synthesis of MHC-II molecules and promotes their lysosomal degradation. This strategy, in which the CPS would play only a partial role, might allow S. suis to evade the T-cell dependent adaptive response. Overall, these results provide new insights into the comprehension of the adaptive immune response during the infection by S. suis.

<p>Najče&scaron;ća komplikacija nakon ugradnje silikonskih implantata za dojku je kontraktura fibrozne kapsule (KK), koja se normalno stvara oko implantata u sklopu reakcije oko stranog tela. Najozbiljnija komplikacija nakon ugradnje silikonskih implantata za dojku je anaplastični krupnoćelijski limfom koji se javlja isključivo kod pacijentkinja koje imaju ugraĎene implantate (eng. Breast-implant associated anaplastic large cell lymphoma &ndash; BIA ALCL). Uzrok nastanka ovih komplikacija ostaje nepoznat. Ustanovljeno je da se KK manje javlja kod implantata koji imaju makroteksturisanu povr&scaron;inu i kod onih koji su presvučeni poliuretanskom penom. S druge strane, BIA-ALCL se če&scaron;će dijagnostikuje kod pacijentkinja kojima su ugraĎeni upravo makroteksturisani implantati. Subklinička infekcija koja predstavlja odgovor organizma na postojanje biofilma na ugraĎenim implantatima, predstavlja jedan od najznačajnijih etiolo&scaron;kih faktora za nastanak KK i BIA-ALCL. Biofilm je konglomerat mirkoorganizama uronjenih u matriks koji ih &scaron;titi od dejstva antibiotika i antiseptika. Kako je nemoguće delovati medikamentozno na eradikaciju biofilma, brojni autori daju razne preporuke u cilju izbegavanja kontaminacije implantata tokom operativnog zahvata, a time i formiranja biofilma. Pored brojnih mera, savetuje se i ispiranje džepa u koji će se plasirati proteza kao i same proteze, nekim od antiseptičkih ili antibiotskih rastvora. Do sada ne postoje prihvaćene jasne preporuke o načinu ispiranja različitih implantata, objavljena su samo lična iskustva raznih autora. Ciljevi ovog istraživanja su bili da se ustanovi mogućnost formiranja biofilma četiri različite bakterije (Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa i Ralstonia pickettii) na tri različito teksturisana silikonska implantata za dojku (sa porama veličine 70-150 &mu;m, 50&ndash;900 &mu;m i 13 &mu;m) u in vitro uslovima; da se ispita da li ispiranje antisepticima (oktenidindihidrohloridom i povidon jodom), ili antibiotikom (cefuroksimom) ili istovremeno me&scaron;avinom povidon joda i antibiotika pre bakterijske kontaminacije sa četiri različite bakterije ima uticaja na formiranje biofilma na tri različito teksturisana implantata za dojke u in vitro uslovima; i da se ispita efekat antiseptika u odnosu na efekat antibiotika na formiranje bakterijskog biofilma na tri različito teksturisana silikonska implantata za dojku. Istraživanje je koncipirano kao prospektivna studija u vidu eksperimenta koji je izveden u Laboratoriji za mikrobiologiju, Instituta za javno zdravlje Vojvodine u Novom Sadu. Za izvoĎenje eksperimenta kori&scaron;ćeni su uzorci tri vrste silikonskih implantata za dojku sa različito teksturisanom povr&scaron;inom, odnosno porama različite veličine: 70-150 &mu;m, 50&ndash;900 &mu;m, i 13 &mu;m. Od svakog od navedenih implantata su pravljeni uzorci, sečenjem kapsula implantata na komadiće veličine 1x1 cm. Ukupno je bilo 1440 uzoraka. Na osnovu teksture uzorci su podeljeni u tri grupe: Grupa 1 (pore veličine 70-150 &mu;m), Grupa 2 (pore veličine 50&ndash;900 &mu;m) i Grupa 3 (pore veličine 13 &mu;m). Svaka od ovih grupa je dalje podeljena u jednu kontrolnu grupu i po četiri ispitivane grupe. Nakon sterilizacije uzoraka svaka kontrolna grupa je kontaminirana sa po 100&mu;l bakterijskog bujona Staphylococcus epidermidis (n=30), Staphylococcus aureus (n=30), Pseudomonas aeruginosa (n=30) i Ralstonia pickettii (n=30). Ispitivane grupe se bile podeljene prema načinima ispiranja na one u kojima su uzorci prvo ispirani: oktenidin &ndash; dihidrohloridom ili povidon jodom ili cefuroksimom ili kombinacijom povidon joda i dva antibiotika, pa potom kontaminirani sa po 100&mu;l bakterijskog bujona Staphylococcus epidermidis (n=30), Staphylococcus aureus (n=30), Pseudomonas aeruginosa (n=30) i Ralstonia pickettii (n=30). Po zavr&scaron;enoj kontaminaciji, uzorci su se inkubirali na temperaturi od 37&deg;C u trajanju od 96h, čime su stvoreni uslovi za formiranje biofilma. Nakon inkubacije, svaki pojedinačni uzorak je uronjen u sterilan tripton soja bujon, izlagan soničnoj energiji u trajanju od 1minuta i zatim vorteksiran 1 minut, čime je omogućeno odvajanje nastalog biofilma od implantata. Za ispitivanje sposobnosti formiranja biofilma kori&scaron;ćena je modifikovana tehnika sa mikrotitar pločom po Stepanoviću. Rezultati su pokazali da sve četiri ispitivane bakterije S. epidermidis, S. aureus, P. aeruginosa i Ralstonia pickettii statistički značajno vi&scaron;e stvaraju biofilm na implantatima sa porama veličine 50&ndash;900 &mu;m u odnosu na pore 70-150 &mu;m i u odnosu na pore veličine 13 &mu;m. Biofilm se statistički značajno vi&scaron;e stvara na porama veličine 70-150 &mu;m u odnosu na pore 13 &mu;m. Jedini izuzetak je Pseudomonas aeruginosa kod kojeg ne postoji statistični značajna razlika u produkciji biofilma na teksturisanim implantatima sa porama veličine 70-150 &mu;m u odnosu na one sa porama 13 &mu;m. TakoĎe, sve četiri ispitivane bakterije statistički značajano manje stvaraju biofilm nakon ispiranja povidon jodom, oktenidin-dihidrohloridom ili rastvorom antibiotika u sve tri grupe implantata, u odnosu na povr&scaron;ine koje nisu ispirane. Izuzetak je S. epidermidis u Grupi 3 kod kojeg nije utvrĎeno statistički značajno manje formiranje biofilma nakon ispiranja oktenidin dihidrohloridom u odnosu na neispiranje. Cefuroksim je bio efikasniji u sprečavanju formiranja biofilma sve četiri ispitivane bakterije u odnosu na neispiranje u Grupi 1, kao i za S. epidermidis i Ralstoniu Pickettii u Grupi 2. Cefuroksim se nije pokazao statistički značajno efikasnim u sprečavanju formiranja biofilma S. aureus i P. aeruginosa u Grupi 2, kao ni kod jedne bakterije u Grupi 3. Dalje je dokazano da su antiseptici (oktenidin-dihirohlorid i povidon jod) kao i me&scaron;avina povidon joda i dva antibiotika (cefuroksim i gentamicin), statistički značajno efikasnji od ispiranja samo antibiotikomcefuroksimom u smanjenju formiranja biofilma sve četiri ispitivane bakterije kod sva tri ispitivana, različito teksturisana silikonska implantata. Rezultati su pokazali da je ispiranje povidon jodom statistički značajno efikasnije u prevenciji stvaranja biofilma kod skoro svih ispitivanih bakterija od ispiranja oktenidin- dihidrohloridom u sve tri grupe implantata. Statistički značajna razlika nije utvrĎena u prevenciji stvaranja biofilma Staphylococcus aureusa kod sve tri grupe implantata prilikom ispiranja povidon jodom u odnosu na oktenidin- dihidrohlorid, kao i kod Ralsotnia pickettii u Grupi 2. Na osnovu rezultata ove studije, preporuka je da se koriste mikroteksturisani implantati kao i da se oni, pre ugradnje isperu povidon jodom ili me&scaron;avinom povidon jod i dva antibiotika (cefuroksim i gentamicin), u cilju prevencije stvaranja biofilma, a time i postoperativnih komplikacija koje mogu nastati nakon ugradnje implantata.</p> / <p>The most common complication after breast implant surgery is contracture of capsule, which is normally formed around implants as part of foreign body reaction. The most sincere complication after this kind of surgery is breast implant associated anaplastic large cell lymphoma (BIA-ALCL). The cause of these complications is still unknown. It is evident that capsular contracture (CC) is seen less frequently in patients with macro-textured implants and in those with implants covered with polyurethane foam. On the other hand, BIA-ALCL is diagnosed more frequently in patients with those, macro-textured implants. Subclinical infection, defined as an response of organism on presence of biofilm on the implant, is considered to be one of the most important etiologic factors for CC and BIA-ALCL. Biofilm is a conglomerate of microorganisms immersed into matrix, which protects them from influence of antibiotics and antiseptics. As it is impossible to eradicate biofilms with medicaments, many authors suggest different steps in order to avoid contamination of the implant during the operation and therefore, prevent the formation of biofilm. Among many tips, it is recommended to irrigate the pocket for breast implant and the implant itself, with some antiseptic or antibiotic solution. Up till now, there is no agreed consensus on the type of irrigation for different implants. Only personal experiences of a few authors have been published. Aims of this research were: to establish the possibility of biofilm formation of four different bacteria (Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa and Ralstonia pickettii) on three differently textured breast implants (with pore diameter of 70-150 &mu;m, 50&ndash;900 &mu;m and 13 &mu;m) in vitro; to examine whether the irrigation of implant with antiseptics (povidone iodine and octenidine dihydrochloride), antibiotics (cefuroxime) or mixture of povidone iodine and two antibiotics, before the contamination with bacteria, has an influence on the incidence on biofilm formation on three differently textured implants; and to examine the effect of antiseptics in contrast to the effect of antibiotics on biofilm formation on three differently textured breast implants. The study was conducted as a prospective research that took place at the Laboratory for microbiology, at the Institute of public health of Vojvodina in Novi Sad. For the experiment, three types of silicone breast implants were used with different pore sizes: 70-150 &mu;m, 50&ndash;900 &mu;m and 13 &mu;m. Samples were made by cutting each of these types of implants into pieces sized 1x1cm. There were 1440 samples in total. According to texture, samples were divided it three groups: Group 1 (pore size 70-150 &mu;m), Group 2 (pore size 50&ndash;900 &mu;m) and Group 3 (pore size 13 &mu;m). Furthermore, each of these groups was divided in one control and four test groups. After sterilisation of samples, every control group was contaminated with 100&mu;l of bacterial broth of Staphylococcus epidermidis (n=30), Staphylococcus aureus (n=30), Pseudomonas aeruginosa (n=30) and Ralstonia pickettii (n=30). Tested groups were divided according to type of irrigation into those where samples were firstly irrigated with either: octenidine dihydrochloride of povidone iodine or cefuroxime of mixture of povidone iodine with two antibiotics, and after the irrigation, contaminated with 100&mu;l bacterial broth of Staphylococcus epidermidis (n=30), Staphylococcus aureus (n=30), Pseudomonas aeruginosa (n=30) and Ralstonia pickettii (n=30). After contamination, samples were incubated on 37&deg;C for 96h, which created excellent conditions for biofilm formation. After incubation, each sample was dipped into sterile tripton soy broth, and then exposed to sonic energy for 1 minute and vortexed for 1 minute, which made biofilm separate from the implant. For testing the capability of biofilm formation, modified technique with microtitar plates described by Stepanović was used. Results show that all four examined bacteria S. epidermidis, S. aureus, P. aeruginosa and Ralstonia pickettii form more biofilm on implants with pore sizes 50&ndash;900 &mu;m compared to implants with pore size 70-150 &mu;m and those with 13 &mu;m. Statistical significance was found in biofilm formation on implants with pores 70-150 &mu;m compared to implants with pores 13 &mu;m. Furthermore, all four examined bacteria form statistically less biofilm after the irrigation with any of used solutions: povidone iodine, octenidine dihydrochloride, antibiotic solution of mixture of povidone iodine and two antibiotics, in all three groups of implants compared to surfaces that were not irrigated. The exception is S. epidermidis in Group 3, where no statistical significance was found on biofilm formation after the irrigation with octenidine dihydrochloride compared to non-irrigation. Cefuroxime was more efficient in biofilm prevention for all four tested bacteria compared to non-irrigation in Group 1 and for S. epidermidis and Ralstonia pickettii in Group 2. There was no statistical significance found in prevention of S. aureus i P. aeruginosa biofilms when irrigating with cefuroxime in Group 2, as well as for all tested bacteria in Group 3. Furthermore, it was verified that antiseptics (octenidin dihydrochloride and povidone iodine) and mixture of povidone iodine and two antibiotics (cefuroxime and gentamycin), were statistically more efficient in biofilm prevention of all four examined bacteria in all groups of implants, compared to irrigation with antibiotic-cefuroxime alone. Results show that irrigation with povidone iodine is statistically more efficient in biofilm prevention of almost all examined bacteria compared to irrigation with octenidine dihydrochloride in all groups of implants. There was not found any statistical significance in prevention of Staphylococcus aureus biofilm when irrigating with povidone iodine compared to octenidine dihydrochloride in all groups of implants, and also in biofilm prevention of Ralsotnia pickettii in Group 2. According to results of this research, it is recommended to use micro-textured implants and to irrigate them with povidone iodine or mixture of povidone iodine and two antibiotics (cefuroxime and gentamycin) prior the implementation, in order to prevent biofilm formation which is most probable cause of postoperative complications after implant surgery.</p>

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-09-28T11:44:16Z No. of bitstreams: 2 Dissertação - Lísia Gomes Martins de Moura Tomich - 2016.pdf: 2901743 bytes, checksum: 22cd41bfc4499cfd4754d856635357af (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-09-28T11:44:45Z (GMT) No. of bitstreams: 2 Dissertação - Lísia Gomes Martins de Moura Tomich - 2016.pdf: 2901743 bytes, checksum: 22cd41bfc4499cfd4754d856635357af (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-09-28T11:44:45Z (GMT). No. of bitstreams: 2 Dissertação - Lísia Gomes Martins de Moura Tomich - 2016.pdf: 2901743 bytes, checksum: 22cd41bfc4499cfd4754d856635357af (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-08-15 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / INTRODUCTION: Routine infant immunization with meningococcal C conjugate vaccine (MenC-V) started in Brazil in November 2010, administered at three, five and 12 months of age with no catch-up for older age-groups. However, by March 2010, a vaccination campaign with MenC-V was performed in Salvador in individuals under five years-old, and from 10 to 24 yearsold. In São Paulo state, the outbreaks occurred in teenagers and young adults prompting one-time vaccination campaign from 2010 to 2014 targeting these age-groups. OBJECTIVE: To assess the direct and indirect impact (herd effect) of vaccination on invasive meningococcal disease (MD) for capsular group C (MenC) four years after the introduction of MenC-V in three scenarios: i) Brazil as a whole (routine vaccination in childhood only); ii) Brazil except for Salvador (vaccination campaign with teenagers during the year of MenC-V introduction); and iii) São Paulo state (vaccination campaign for adolescents and young adults during 2010-2014 to control outbreaks). METHODS: We performed an ecological quasi-experimental design from 2008 to 2014 using data from the National Reference Laboratory for Meningitis, and data from the National Information System for Notifiable Diseases. A deterministic linkage was performed between the two databases to improve the accuracy of the detection of MD, especially in capsular groups. An interrupted time-series analysis was conducted using the Holt-Winters technique to control for pre-existing trends and seasonal variations. The MenC vaccination impact was evaluated as the percentage of reduction in the incidence rates of MenC in the post-vaccination period (2012 to 2014), using the pre-vaccination period (2008 to 2010) to estimate what would be expected on the post-vaccination period, whether the vaccination had not been introduced. For Salvador, we analyzed the effect of the vaccination on the number of MenC cases. RESULTS: A total of 18,136 invasive MD cases were analyzed. For Brazil as a whole, the vaccination reduced 67.4% (lower 95%CI 42.5%) the rates for MenC for infants under 12 months, 92.3% (lower 95%CI 77.7%) for the age-group 12-23 months, and 65.7% (lower 95%CI 28%) for children aged 2-4 years. Indirect impact (20-24.7%) was observed in the age-group 5-19 years. When excluding Salvador from the analysis of Brazil, the indirect impact was observed only for children in the age-group 5-9 years. In the scenario of São Paulo state, similarly to Brazil, significant impact was observed in the target age-groups, in addition to indirect impact in the age group 5-9 years. In Salvador, in addition to the effect on the vaccinated population a sharp and sustainable decline of MenC cases was observed in all age-groups not target for vaccination. Overall, 1,170 cases of MenC were averted in Brazil after the introduced of Men-C vaccination. CONCLUSION: The strategy of catch-up for adolescents and young adults, especially during the year of MenC-V introduction may lead to rapid and sustainable herd effect. / A vacina meningocócica conjugada contra o grupo capsular C (MenC-V) foi introduzida no calendário de imunização infantil brasileiro em novembro de 2010, sendo administrada aos três, cinco e 12 meses de idade sem catch-up para os demais grupos etários. Entretanto, em março de 2010, uma campanha de vacinação com MenC-V foi realizada em Salvador para indivíduos menores de cinco anos de idade e de 10 a 24 anos. No estado de São Paulo os surtos ocorreram em adolescentes e adultos jovens, determinando campanhas de vacinações de bloqueio nessa faixa etária nos anos de 2010 a 2014. OBJETIVO: Avaliar o impacto direto e indireto (rebanho) da vacinação nas taxas de incidência de doença meningocócica (DM) invasiva pelo grupo capsular C (MenC) após quatro anos da introdução da MenC-V em três cenários: i) Brasil como um todo (imunização de rotina somente de crianças); ii) Brasil exceto Salvador (campanha de vacinação em adolescentes no ano de introdução da MenCV); e iii) estado de São Paulo (vacina de rotina na infância e vacinações de bloqueio em adolescentes e adultos jovens para controlar surtos). MÉTODOS: Foi realizado um estudo ecológico quasi-experimental para avaliar o impacto da vacinação em série histórica de 2008 a 2014 usando os bancos de dados do Laboratório Nacional de Referência para Meningites Bacterianas, Instituto Adolfo Lutz (IAL) e o Sistema de Informação de Agravos de Notificação (Sinan). Um processo de vinculação (linkage) determinístico entre as duas bases foi realizado para melhorar a acurácia da detecção de casos de DM, especialmente de grupo capsulares. Uma análise de série temporal interrompida foi conduzida utilizando a técnica de Holt-Winters para controlar por tendência pré-existente e variações sazonais. O desfecho foi taxa de MenC. O impacto da vacinação foi avaliado pelo percentual de redução da incidência de MenC no período pós-vacinal (2012 a 2014), utilizando o período pré-vacinal (2008 a 2010) para estimar o que seria esperado no período pós-vacinal, caso a vacinação não tivesse sido introduzida. Para Salvador foi analisado o efeito da MenC-V no número de casos de MenC. RESULTADOS: Um total de 18.136 casos de DM invasiva foram analisados. Para o Brasil como um todo, a vacinação reduziu significativamente a DM por MenC na faixa etária alvo, com redução de 67,4% (limite inferior do IC95% 42,5%) em menores de 12 meses, 92,3% (limite inferior do IC95% 77,7%) para faixa etária de 12-23 meses e 65,7% (limite inferior do IC95% 28%) em crianças de 2-4 anos, e efeito rebanho foi observado na faixa etária de 5 a 19 anos com 20-24,7%. Quando se exclui Salvador na análise do Brasil, impacto indireto significativo foi observado somente em crianças de 5-9 anos. No cenário São Paulo, semelhante ao Brasil, observou-se impacto estatisticamente significante nas faixas etárias alvo do PNI, além do efeito rebanho na faixa etária de 5-9 anos de idade. Para Salvador, o impacto da vacinação apresentou um declínio acentuado e sustentável em todas as faixas etárias fora do alvo da vacinação. Ao todo, 1.170 casos de MenC foram evitados no período estudado. CONCLUSÃO: A estratégia de vacinação de catch-up em adolescentes e adultos jovens, especialmente no ano de introdução da MenC-V, promoveu um rápido e sustentável rebanho.