Vacina Pneumocócica Conjugada 13-valente para imunização de crianças de até cinco anos de idade contra doença pneumocócica invasiva e pneumonia / 13-valent Pneumococcal Conjugate Vaccine for immunization of children up to five years of age against disease invasive pneumococcal and pneumonia

INTRODUÇÃO: A doença pneumocócica invasiva (DPI) e pneumonia, causadas pela bactéria Streptococcus pneumoniae, são caracterizadas pela gravidade do quadro clínico do paciente e podem conduzi-lo à hospitalização, ou até mesmo a óbito. Verifica-se que a melhor forma de prevenção a patologias pneumocócicas ocorre através da vacinação (direta e indireta) e sua eficácia na proteção contra o pneumococo. No Brasil, atualmente, são registradas três vacinas pneumocócicas disponíveis: a vacina pneumocócica polissacarídica PPV23 e as vacinas pneumocócica conjugadas PCV10 e PCV13, sendo esta última disponibilizada até o momento apenas para pacientes, acima de 5 anos de idade de risco gravíssimo, nos Centros de Referência para Imunobiológicos Especiais ­ CRIE. Nesse sentido está sendo solicitada a ampliação de uso para crianças até 5 anos de idade atendidas no SUS. Pergunta: A vacina pneumocócica conjugada 13-valente (PCV13) é mais eficaz e segura em comparação à vacina pneumocócica conjugada 10-valente (PCV10) na prevenção da doença pneumocócica invasiva (DPI) e pneumonia por qualquer sorotipo, em crianças até 5 a

Incidence of invasive pneumococcal disease in children with commercial insurance or Medicaid coverage in the United States before and after the introduction of 7- and 13-valent pneumococcal conjugate vaccines during 1998-2018.

BACKGROUND: Invasive pneumococcal disease (IPD) is a major cause of pediatric morbidity and mortality. Pneumococcal conjugate vaccines (PCVs) were introduced in the US in 2000 (PCV7) and 2010 (PCV13). This study estimated the annual incidence rates (IRs) and time trends of IPD to quantify the burden of disease in children before and after the introduction of PCV7 and PCV13 in the US. METHODS: IPD episodes were identified in the IBM MarketScan Commercial and Medicaid Databases using claims with International Classification of Diseases 9/10th Revision, Clinical Modification codes. Annual IRs were calculated as the number of IPD episodes/100,000 person-years (PYs) for children < 18 years and by age group (< 2, 2-4, and 5-17 years). National estimates of annual IPD IRs were extrapolated using Census Bureau data. Interrupted time series (ITS) analyses were conducted to assess immediate and gradual changes in IPD IRs before and after introduction of PCV7 and PCV13. RESULTS: In commercially insured children, IPD IRs decreased from 9.4 to 2.8 episodes/100,000 PY between the pre-PCV7 (1998-1999) and late PCV13 period (2014-2018) overall, and from 65.6 to 11.6 episodes/100,000 PY in children < 2 years. In the Medicaid population, IPD IRs decreased from 11.3 to 4.2 episodes/100,000 PY between the early PCV7 (2001-2005) and late PCV13 period overall, and from 42.6 to 12.8 episodes/100,000 PY in children < 2 years. The trends of IRs for meningitis, bacteremia, and bacteremic pneumonia followed the patterns of overall IPD episodes. The ITS analyses indicated significant decreases in the early PCV7 period, increases in the late PCV7 and decreases in the early PCV13 period in commercially insured children overall. However, increases were also observed in the late PCV13 period in children < 2 years. The percentage of cases with underlying risk factors increased in both populations. CONCLUSIONS: IRs of IPD decreased from 1998 to 2018, following introduction of PCV7 and PCV13, with larger declines during the early PCV7 and early PCV13 periods, and among younger children. However, the residual burden of IPD remains substantial. The impact of future PCVs on IPD IRs will depend on the proportion of vaccine-type serotypes and vaccine effectiveness in children with underlying conditions.

Health and economic burden associated with 15-valent pneumococcal conjugate vaccine serotypes in Korea and Hong Kong.

Use of pneumococcal conjugate vaccines (PCVs) has greatly reduced the incidence of invasive pneumococcal disease (IPD). V114 (VAXNEUVANCE™, Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA) is a 15-valent PCV currently approved in adults in the United States, containing the 13 serotypes in licensed PCV13 and 2 additional serotypes (22F and 33F) which are important contributors to residual pneumococcal disease. This study quantified the health and economic burden of IPD attributable to V114 serotypes in hypothetical birth cohorts from Korea and Hong Kong. A Markov model was used to estimate the case numbers and costs of IPD in unvaccinated birth cohorts over 20 years. The model was applied to 3 scenarios in Korea (pre-PCV7, pre-PCV13, and post-PCV13) and to 2 scenarios in Hong Kong (pre-PCV7 and post-PCV13). For Korea, the model predicted 62, 26, and 8 IPD cases attributable to V114 serotypes in the pre-PCV7, pre-PCV13, and post-PCV13 scenarios, respectively. Costs of V114-type IPD fell from $1.691 million pre-PCV7 to $.212 million post-PCV13. For Hong Kong, the model estimated 62 V114-associated IPD cases in the pre-PCV7 scenario and 46 in the post-PCV13 scenario. Costs attributed to all V114 serotypes were $2.322 million and $1.726 million in the pre-PCV7 and post-PCV13 periods, respectively. Vaccine-type serotypes are predicted to cause continuing morbidity and cost in Korea (19A) and Hong Kong (3 and 19A). New pediatric pneumococcal vaccines must continue to protect against serotypes in licensed vaccines to maintain disease reduction, while extending coverage to non-vaccine serotypes.

Impact of pneumococcal conjugate vaccines on healthcare utilization and direct costs for otitis media in children ≤2 years of age in two Swedish regions.

In Sweden, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 and replaced by the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) or the 13- valent PCV (PCV13) from late 2009. We assessed the impact of PCVs on rates of antibiotic prescribing, tympanostomy tube placement (TTP), and healthcare resource utilization and direct costs of physician- diagnosed otitis media/acute otitis media (OM) in children ≤2 years of age living in Skåne (PCV7 then PHiD- CV) or Västra Götalandsregionen (VGR; PCV7 then PCV13). Retrospective cohort study using linked patient- level data from national and regional (Skåne and VGR) healthcare databases in Sweden from July 1, 2005, to December 31, 2013 (NCT02742753). Descriptive time-series analyses showed antibiotic prescriptions and TTP incidence declined after PHiD-CV/PCV13 introduction versus the pre-PCV period. The annualized mean frequencies of antibiotic use, primary care visits, outpatient visits, TTP and myringotomy procedures all decreased after PHiD-CV/PCV13 compared with pre-PCV cohorts. Annualized mean total OM-associated healthcare costs decreased in the PCV7 versus pre-PCV cohorts by 20.0% in Skåne and 10.2% in VGR, and further declined in the PHiD-CV and PCV13 cohorts (20.7% and 15.3%, respectively, relative to the PCV7 cohort), although the duration of PCV7 use differed between regions. Decreases in adjusted annualized cost ratios between cohorts per child susceptible to OM were statistically significant after PCV7 introduction and again with either PHiD-CV or PCV13 introduction in both regions. Following sequential PCV introduction, OM-related healthcare utilization and associated costs decreased in the study regions in Sweden. PLAIN LANGUAGE SUMMARY: What is the context?Otitis media is one of the most frequent reasons for healthcare visits and antibiotic use among young children. Although it is considered as a mild illness, the overall economic burden is substantial due to its high frequency.Otitis media can be caused by different bacteria including Streptococcus pneumoniae, which is also responsible for pneumonia and meningitis. Pneumococcal conjugate vaccines Prevenar (Pfizer Inc.), Synflorix (GSK), and Prevenar 13 (Pfizer Inc.) protect against pneumococcal diseases and reduce its occurrence.However, it is not known how the routine use of these vaccines may affect otitis media-related healthcare resources and costs.What is new?In this study, we assessed trends in rates of healthcare utilization and associated costs due to otitis media in young children before (2005-2008) and after (2009-2013) use of pneumococcal conjugate vaccines. The study was conducted in two Swedish regions; one used Prevenar then Synflorix, while the other used Prevenar then Prevenar 13.We found that compared to the period before pneumococcal conjugate vaccine implementation, the postpneumococcal conjugate vaccine period was associated with:What is the impact on current thinking?The use of pneumococcal conjugate vaccines effectively reduces healthcare utilization and resources associated with otitis mediaThis indirect effect on the reduction of otitis media burden provides further benefit to the implementation of pneumococcal vaccination.

Pneumococcal Conjugated Vaccines Decreased Acute Otitis Media Burden: A Population-Based Study in Israel.

OBJECTIVE: To study time trends in all-cause acute otitis media (AOM) burden by calculating incidence rates of AOM episodes and recurrent acute otitis media (rAOM) cases in highly immunized pediatric population during the pre- and post-pneumococcal conjugated vaccine (PCV) years. STUDY DESIGN: In this population-based study, AOM episodes and rAOM cases were identified in Clalit Health Services-insured Israeli children aged 0-10 years between 2005 and 2018 by using a data-sharing platform. Because a near-sequential implementation of PCV-7/PCV-13 occurred within a 1-year period (2009/2010), we compared AOM visits before (2005-July 2009) and after (August 2009-2018) the introduction of PCVs. We focused on children younger than 2 years of age, who are the target population of PCVs and are at AOM peak age. RESULTS: We identified 805 389 AOM episodes contributed by 270 137 children. The median number of AOM episodes was 2 (IQR 1-4). A downward trend of incidence rates of AOM episodes was observed during the post-PCV years in children younger than age 9 years (P < .001). The largest decrease (21%) was observed in children younger than 1 year, from 807/1000 children during the pre-PCV years to 640/1000 during the post-PCV years (P < .001). An average annual decrease of ∼14/1000 AOM episodes was calculated in children younger than 1 year old (ß = -13.39, 95% CI -16.25 to -10.53, P < .001). Of rAOM cases, documented in 84 237 (31.2%) children, 74% were in children younger than 2 years, and 55% were in boys. The risk to develop rAOM significantly decreased during the post-PCV years in children younger than 2 years (hazard ratio 0.893, 95% CI 0.878-0.908; P < .001). CONCLUSIONS: AOM burden significantly decreased following PCVs introduction in highly immunized children.

Health and economic burden associated with 15-valent pneumococcal conjugate vaccine serotypes in children in the United States.

AIMS: V114 is an investigational 15-valent pneumococcal conjugate vaccine (PCV) containing the 13 Streptococcus pneumoniae serotypes in 13-valent PCV (PCV13) plus two additional serotypes. This study quantified the health and economic burden of invasive pneumococcal disease (IPD) and acute otitis media (AOM) caused by V114 types among children in the United States. MATERIALS AND METHODS: A Markov model estimated the number of V114-type IPD and AOM cases and costs in a hypothetical, unvaccinated US birth cohort over 20 years. Three time periods were analyzed using time-specific epidemiological data to determine the number of IPD and AOM cases associated with all 15 serotypes in V114. The time periods were: (1) pre-PCV7 (1999); (2) pre-PCV13 (2009); (3) post-PCV13 (2017). Costs were estimated from a societal perspective (2018 US dollars) and discounted at 3%. RESULTS: The model estimated 18,983 IPD cases and 5.4 million AOM cases associated with V114 serotypes pre-PCV7, 4,697 IPD cases and 3.0 million AOM cases pre-PCV13, and 948 IPD cases and 0.2 million AOM cases post-PCV13. Total discounted costs associated with V114 serotypes were $1.7 billion pre-PCV7, $730 million pre-PCV13, and $75 million US dollars post-PCV13. LIMITATIONS: Post-meningitis sequelae, cases of non-bacteremic pneumonia, and direct non-medical costs were not included. CONCLUSIONS: IPD and AOM cases and costs were estimated in a hypothetical US birth cohort followed for 20 years at three time periods. In all three periods, the serotypes targeted by V114 contributed to significant morbidity and costs. New pediatric pneumococcal vaccines must continue to retain serotypes in licensed vaccines to maintain disease reduction while extending coverage to non-vaccine serotypes.

Vacina pneumocócica conjugada 13-valente contra doenças pneumocócicas em pacientes de risco / 13-valent pneumococcal conjugate vaccine against pneumococcal disease in at-risk patients

INTRODUÇÃO: A doença pneumocócica (DP) é causada pela bactéria Streptococcus pneumoniae, conhecida como pneumococo, sendo esta a causadora de doenças que atingem o trato respiratório e o cérebro. A DP pode ser classificada em dois tipos: a doença pneumocócica invasiva (DPI) ­ nos casos em que a bactéria invade a corrente sanguínea, e a doença pneumocócica não invasiva, sendo esta de menor gravidade, mas com maior recorrência e consequentemente maior peso econômico para o sistema de saúde. A infecção causada pelo pneumococo é uma das principais causas de morbimortalidade no mundo. Em 2005 a Organização Mundial de Saúde estimou a ocorrência de 1,6 milhão de mortes por ano por doença pneumocócica. Outros agravantes da situação são o aumento da resistência aos antibióticos pela bactéria e facilidade com que os sorotipos resistentes se disseminaram progressivamente pelo mundo. Atualmente, existem dois tipos de vacinas pneumocócicas, disponíveis no Sistema Único de Saúde (SUS), para prevenção das DPs: a vacina polissacarídica 23-valente (VPP-23) para pacientes de alto risco e a vacina conjugada 10-valente (VPC-10) para crianças de risco até os 5 anos de idade. TECNOLOGIA: Vacina pneumocócica conjugada 13-valente (Prevenar 13®). PERGUNTA: O uso da vacina pneumocócica conjugada 13-valente em combinação com a vacina pneumocócica polissacarídica 23-valente (VPC-13 + VPP-23) é eficaz e segura na prevenção de doença pneumocócica em pacientes de risco, acima de cinco anos de idade, de acordo com os critérios do Programa Nacional de Imunizações do Ministério da Saúde? EVIDÊNCIAS CIENTÍFICAS: Análise baseada em ensaios clínicos randomizados que avaliaram a sua aplicação em adultos/idosos com condição crônica preexistente (doenças cardiovasculares, pulmonares, hepáticas, distúrbios renais ou diabetes mellitus) e adultos HIV positivos. Para adultos/idosos com condição crônica preexistente, os resultados encontrados, de modo geral, evidenciaram que as médias geométricas dos títulos (MGTs) de AOP (atividade opsonofagocítica) da vacinação sequencial (VPC-13+VPP-23) foram não inferiores e/ou maiores, com significância estatística, para alguns dos 13 sorotipos, quando comparadas com as respostas da VPP-23 sozinha, ou combinada com ela mesma, a depender do intervalo de tempo entre as doses. Observa-se a vantagem potencial da administração inicial da VPC-13, que permite o estabelecimento de um estado imunológico que resulta em respostas de memória apropriadas para sorotipos em comum após a imunização subsequente com VPP-23. Tal resposta geral é consistentemente ausente quando a VPP-23 é administrada antes da VPC-13. Em adultos HIV positivos, com contagem de CD4>200 células/mm3, a combinação da VPC-13 com a VPP-23 obteve uma maior magnitude da resposta imunológica de IgG e de títulos da AOP em comparação com a VPP-23 isolada. A informação de eficácia é limitada a dados imunológicos (média geométrica dos títulos de atividade opsonofagocítica-MGT de AOP), faltando informações sobre a redução nas taxas de pneumonia (DPI) e outros resultados clínicos. AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-efetividade utilizando parâmetros extraídos da literatura e dados dos sistemas de informação do SUS e do IBGE, de forma combinada. Os resultados demonstraram que a vacinação sequencial (VPC-13 + VPP-23) proporcionou redução de custos com ganho em efetividade (cenário dominante) quando comparada à imunização com a VPP-23 isoladamente. Além disso, tanto os resultados da análise de sensibilidade univariada quanto da probabilística ratificaram o cenário de dominância da vacinação sequencial frente à VPP-23 isolada. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário foi calculado para 5 anos, 2019 a 2013, na perspectiva do SUS, considerando dois cenários: Cenário 1 ­pessoas, que são tratadas no SUS, com pelo menos uma das 17 condições clínicas de risco para as doenças pneumocócicas; Cenário 2 ­pessoas, que são tratadas no SUS, com pelo menos uma das 17 condições clínicas de risco para as doenças pneumocócicas estratificada segundo gravidade da condição clínica de risco: a)risco gravíssimo e b) risco grave. CONSIDERAÇÕES: Os achados da literatura apoiam as recomendações atuais de vacinação contra pneumococos nos Estados Unidos e na Europa para indivíduos infectados pelo HIV. A introdução da VPC-13 no esquema sequencial com a VPP-23, para populações de risco (pacientes que vivem com HIV/Aids, pacientes oncológicos e para indivíduos submetidos a transplante de medula óssea), foi recomendada pelo Comitê Técnico Assessor de Imunizações (CTAI) do Programa Nacional de Imunizações (PNI). Considera-se que a expansão do uso da vacina conjugada, em maiores de cinco anos de idade, para outros grupos, será tema abordado em revisões futuras. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário, na 72ª reunião ordinária, realizada no dia 07 de novembro de 2018, indicaram que o tema seja submetido à Consulta Pública com recomendação preliminar a favor da incorporação no SUS da vacina pneumocócica conjugada 13-valente para prevenção da doença pneumocócica em pacientes de risco gravíssimo, acima de cinco anos de idade. Considerou-se que a vacina apresenta eficácia, principalmente para o grupo de risco gravíssimo que apresenta maior vulnerabilidade, maior risco de adoecer e condições clínicas que, mesmo se houver imunidade de rebanho na população em geral, essa população mais vulnerável não seria beneficiada. Além disso, os pacientes de risco gravíssimo representam 75% da população de risco, o que já representa uma expansão importante para o PNI. CONSULTA PÚBLICA: Por meio da Consulta Pública nº 69/2018, realizada entre os dias 27/11/2018 e 17/12/2018, foram recebidas 100 contribuições, sendo 27 técnico-científicas e 73 de experiência ou opinião. A maioria das contribuições concordou totalmente com a recomendação preliminar da CONITEC, ressaltando a relevância da incorporação da vacina pneumocócica conjugada 13-valente no SUS. Entre as contribuições técnico-científicas, a empresa fabricante solicitou a inclusão do transplante de órgãos sólidos como uma comorbidade elegível para imunização, que constava no dossiê inicial apresentado e que está inserido no atual Manual dos Centros de Referência para Imunobiológicos Especiais do PNI/MS. A referida alteração foi aceita pelos membros do plenário. A CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação preliminar, a favor da incorporação no SUS da vacina pneumocócica conjugada 13-valente para prevenção da doença pneumocócica em pacientes de risco gravíssimo, acima de cinco anos de idade. RECOMENDAÇÃO FINAL: Os membros da CONITEC em 07/02/2019 deliberaram por unanimidade recomendar a incorporação, no SUS, da vacina pneumocócica conjugada 13-valente contra doenças pneumocócicas em pacientes de risco gravíssimo acima de 5 anos de idade nos Centros de Referência para Imunobiológicos Especiais - CRIE (pacientes que vivem com HIV/Aids, pacientes oncológicos e para indivíduos submetidos a transplante de medula óssea e de órgãos sólidos). DECISÃO: Incorporar a vacina pneumocócica conjugada 13-valente contra doenças pneumocócicas em pacientes de alto risco acima de 5 anos de idade nos Centros de Referência Imunobiológicos Especiais - CRIE (vivendo com HIV/AIDS, oncológicos, transplantados de médula óssea e de órgãos sólidos), no âmbito do Sistema Único de Saúde ­ SUS. Dada pela Portaria nº 14, publicada no Diário Oficial da União nº 44, seção 1, página 79, em 06 de março de 2019.

Application of pharmacokinetic/pharmacodynamic analysis to evaluate the adequacy of antimicrobial therapy for pediatric acute otitis media in Spain before and after the introduction of the PCV7 vaccine.

OBJECTIVE: To evaluate, by applying pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the change in antibiotic susceptibility after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Spain had any influence on the usefulness of the antimicrobials more frequently used as empirical treatment of pediatric acute otitis media (AOM). METHODS: PK parameters and susceptibility of Streptococcus pneumoniae and Haemophilus influenzae were obtained from bibliography. Monte Carlo simulation was used to estimate the cumulative fraction of response (CFR), understood as the expected probability of therapy success. For amoxicillin and amoxicillin/clavulanate, the target was free antibiotic concentration remaining above the minimum inhibitory concentration (MIC) for ≥50% of the dosing interval (fT>MIC≥50%), whereas for cefuroxime axetil and cefotaxime, the target was fT>MIC≥60%. CFR values ≥90% were considered successful. RESULTS: When all serotypes of S. pneumoniae are considered, amoxicillin and cefotaxime turned out to reach a high probability of success, and difference before and after vaccination was scarce. For H. influenzae, CFR values were higher with amoxicillin/clavulanate than with amoxicillin. For both microorganisms, cefuroxime axetil resulted in low probability of success in the two periods of study. CONCLUSIONS: We have shown that the introduction of the PCV7 vaccination did not lead to changes in the probability of success of the current empiric treatments of the AOM. Integrated PK/PD analysis has demonstrated to be a useful tool to identify changes in antimicrobial activity after the implantation of a vaccination program, providing complementary information to the simple assessment of MIC values.

Vacina pneumocócica conjugada 13-valente contra doenças pneumocócicas em pacientes de risco / 13-valent pneumococcal conjugate vaccine against pneumococcal diseases in at-risk patients

INTRODUÇÃO: A doença pneumocócica (DP) é causada pela bactéria Streptococcus pneumoniae, conhecida como pneumococo, sendo esta a causadora de doenças que atingem o trato respiratório e o cérebro. A DP pode ser classificada em dois tipos: a doença pneumocócica invasiva (DPI) ­ nos casos em que a bactéria invade a corrente sanguínea, e a doença pneumocócica não invasiva, sendo esta de menor gravidade, mas com maior recorrência e consequentemente maior peso econômico para o sistema de saúde. A infecção causada pelo pneumococo é uma das principais causas de morbimortalidade no mundo. Em 2005 a Organização Mundial de Saúde estimou a ocorrência de 1,6 milhão de mortes por ano por doença pneumocócica. Outros agravantes da situação são o aumento da resistência aos antibióticos pela bactéria e facilidade com que os sorotipos resistentes se disseminaram progressivamente pelo mundo. Atualmente, existem dois tipos de vacinas pneumocócicas, disponíveis no Sistema Único de Saúde (SUS), para prevenção das DPs: a vacina polissacarídica 23-valente (VPP-23) para pacientes de alto risco e a vacina conjugada 10-valente (VPC-10) para crianças de risco até os 5 anos de idade. TECNOLOGIA: Vacina pneumocócica conjugada 13-valente (Prevenar 13®). PERGUNTA: O uso da vacina pneumocócica conjugada 13-valente em combinação com a vacina pneumocócica polissacarídica 23-valente (VPC-13 + VPP-23) é eficaz e segura na prevenção de doença pneumocócica em pacientes de risco, acima de cinco anos de idade, de acordo com os critérios do Programa Nacional de Imunizações do Ministério da Saúde? EVIDÊNCIAS CIENTÍFICAS: Análise baseada em ensaios clínicos randomizados que avaliaram a sua aplicação em adultos/idosos com condição crônica preexistente (doenças cardiovasculares, pulmonares, hepáticas, distúrbios renais ou diabetes mellitus) e adultos HIV positivos. Para adultos/idosos com condição crônica preexistente, os resultados encontrados, de modo geral, evidenciaram que as médias geométricas dos títulos (MGTs) de AOP (atividade opsonofagocítica) da vacinação sequencial (VPC-13+VPP-23) foram não inferiores e/ou maiores, com significância estatística, para alguns dos 13 sorotipos, quando comparadas com as respostas da VPP-23 sozinha, ou combinada com ela mesma, a depender do intervalo de tempo entre as doses. Observa-se a vantagem potencial da administração inicial da VPC-13, que permite o estabelecimento de um estado imunológico que resulta em respostas de memória apropriadas para sorotipos em comum após a imunização subsequente com VPP-23. Tal resposta geral é consistentemente ausente quando a VPP-23 é administrada antes da VPC-13. Em adultos HIV positivos, com contagem de CD4>200 células/mm3, a combinação da VPC-13 com a VPP-23 obteve uma maior magnitude da resposta imunológica de IgG e de títulos da AOP em comparação com a VPP-23 isolada. A informação de eficácia é limitada a dados imunológicos (média geométrica dos títulos de atividade opsonofagocítica-MGT de AOP), faltando informações sobre a redução nas taxas de pneumonia (DPI) e outros resultados clínicos. AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-efetividade utilizando parâmetros extraídos da literatura e dados dos sistemas de informação do SUS e do IBGE, de forma combinada. Os resultados demonstraram que a vacinação sequencial (VPC-13 + VPP-23) proporcionou redução de custos com ganho em efetividade (cenário dominante) quando comparada à imunização com a VPP-23 isoladamente. Além disso, tanto os resultados da análise de sensibilidade univariada quanto da probabilística ratificaram o cenário de dominância da vacinação sequencial frente à VPP-23 isolada. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário foi calculado para 5 anos, 2019 a 2013, na perspectiva do SUS, considerando dois cenários: Cenário 1 ­pessoas, que são tratadas no SUS, com pelo menos uma das 17 condições clínicas de risco para as doenças pneumocócicas; Cenário 2 ­pessoas, que são tratadas no SUS, com pelo menos uma das 17 condições clínicas de risco para as doenças pneumocócicas estratificada segundo gravidade da condição clínica de risco: a)risco gravíssimo e b) risco grave. CONSIDERAÇÕES: Os achados da literatura apoiam as recomendações atuais de vacinação contra pneumococos nos Estados Unidos e na Europa para indivíduos infectados pelo HIV. A introdução da VPC-13 no esquema sequencial com a VPP-23, para populações de risco (pacientes que vivem com HIV/Aids, pacientes oncológicos e para indivíduos submetidos a transplante de medula óssea), foi recomendada pelo Comitê Técnico Assessor de Imunizações (CTAI) do Programa Nacional de Imunizações (PNI). Considera-se que a expansão do uso da vacina conjugada, em maiores de cinco anos de idade, para outros grupos, será tema abordado em revisões futuras. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário, na 72ª reunião ordinária, realizada no dia 07 de novembro de 2018, indicaram que o tema seja submetido à Consulta Pública com recomendação preliminar a favor da incorporação no SUS da vacina pneumocócica conjugada 13-valente para prevenção da doença pneumocócica em pacientes de risco gravíssimo, acima de cinco anos de idade. Considerou-se que a vacina apresenta eficácia, principalmente para o grupo de risco gravíssimo que apresenta maior vulnerabilidade, maior risco de adoecer e condições clínicas que, mesmo se houver imunidade de rebanho na população em geral, essa população mais vulnerável não seria beneficiada. Além disso, os pacientes de risco gravíssimo representam 75% da população de risco, o que já representa uma expansão importante para o PNI. CONSULTA PÚBLICA: Por meio da Consulta Pública nº 69/2018, realizada entre os dias 27/11/2018 e 17/11/2018, foram recebidas 100 contribuições, sendo 27 técnico-científicas e 73 de experiência ou opinião. A maioria das contribuições da incorporação da vacina pneumocócica conjugada 13-valente no SUS. Entre as contribuições técnico-científicas, a empresa fabricante solicitou a inclusão do transplante de órgãos sólidos como uma comorbidade elegível para imunização, que constava no dossiê inicial apresentado e que está inserido no atual Manual dos Centros de Referência para Imunobiológicos Especiais do PNI/MS. A referida alteração foi aceita pelos membros do plenário. A CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação preliminar, a favor da incorporação no SUS da vacina pneumocócica conjugada 13-valente para prevenção da doença pneumocócica em pacientes de risco gravíssimo, acima de cinco anos de idade. RECOMENDAÇÃO FINAL: Os membros da CONITEC em 07/02/2019 deliberaram por unanimidade recomendar a incorporação, no SUS, da vacina pneumocócica conjugada 13-valente contra doenças pneumocócicas em pacientes de risco gravíssimo acima de 5 anos de idade nos Centros de Referência para Imunobiológicos Especiais - CRIE (pacientes que vivem com HIV/Aids, pacientes oncológicos e para indivíduos submetidos a transplante de medula óssea e de órgãos sólidos).

Decline in Pneumococcal Disease Attenuated in Older Adults and Those With Comorbidities Following Universal Childhood PCV13 Immunization.

BACKGROUND: Following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, epidemiology of pneumococcal disease shifted such that disease incidence in the elderly exceeded that in children. We evaluated the impact of replacing PCV7 with PCV13 on disease burden in adults and identified age/risk-specific subgroups with the highest remaining disease burden. METHODS: A retrospective design and data from two US healthcare claims repositories were used. Study population included adults aged ≥18 years and was stratified by age (18-49, 50-64, 65-74, ≥75) and risk profile (healthy, at-risk, high-risk). Rate ratios comparing invasive pneumococcal disease (IPD), all-cause hospitalized pneumonia (ACHP), and pneumococcal pneumonia requiring hospitalization among at-risk and high-risk adults vs healthy counterparts were estimated for 2007-2010 (pre-PCV13), 2011-2012 (peri-PCV13), and 2013-2015 (post-PCV13). RESULTS: Across study periods, IPD and ACHP rates increased with age (2-27 times higher in persons ≥75 vs 18-49) and comorbidity (4-20 times higher in high-risk vs healthy). From pre- to post-PCV13 period, IPD rates declined 5%-48% and ACHP rates declined 4%-19% across age and risk groups (ACHP did not decline in persons ≥75). Decline in IPD and ACHP was attenuated among older adults and those with comorbidities. Accordingly, rate ratios among at-risk and high-risk persons (vs healthy counterparts) increased during the peri- and post-PCV13 periods compared with the pre-PCV13 period. CONCLUSIONS: The switch to PCV13 was associated with large declines in pneumococcal disease among US adults. However, the decline was attenuated with increasing age (and, for ACHP, was absent in persons ≥75) and in those with comorbidities.

Retrospective cost-effectiveness of the 23-valent pneumococcal polysaccharide vaccination program in Australia.

BACKGROUND: The Australian infant pneumococcal vaccination program was funded in 2005 using the 7-valent pneumococcal conjugate vaccine (PCV7) and the 13-valent conjugate vaccine (PCV13) in 2011. The PCV7 and PCV13 programs resulted in herd immunity effects across all age-groups, including older adults. Coincident with the introduction of the PCV7 program in 2005, 23-valent pneumococcal polysaccharide vaccine (PPV23) was funded for all Australian adults aged over 65 years. METHODS: A multi-cohort Markov model with a cycle length of one year was developed to retrospectively evaluate the cost-effectiveness of the PPV23 immunisation program from 2005 to 2015. The analysis was performed from the healthcare system perspective with costs and quality-adjusted life years discounted at 5% annually. The incremental cost-effectiveness ratio (ICER) for PPV23 doses provided from 2005 to 2015 was calculated separately for each year when compared to no vaccination. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis. RESULTS: It was estimated that PPV23 doses given out over the 11-year period from 2005 to 2015 prevented 771 hospitalisations and 99 deaths from invasive pneumococcal disease (IPD). However, the estimated IPD cases and deaths prevented by PPV23 declined by more than 50% over this period (e.g. from 12.9 deaths for doses given out in 2005 to 6.1 in 2015), likely driven by herd effects from infant PCV programs. The estimated ICER over the period 2005 to 2015 was approximately A$224,000/QALY gained compared to no vaccination. When examined per year, the ICER for each individual year worsened from $140,000/QALY in 2005 to $238,000/QALY in 2011 to $286,000/QALY in 2015. CONCLUSION: The cost-effectiveness of the PPV23 program in older Australians was estimated to have worsened over time. It is unlikely to have been cost-effective, unless PPV23 provided protection against non-invasive pneumococcal pneumonia and/or a low vaccine price was negotiated. A key policy priority should be to review of the future use of PPV23 in Australia, which is likely to be more cost-effective in certain high-risk groups.

[Treatment of stable chronic obstructive pulmonary disease].

In 2012, The Danish Society of Respiratory Medicine gave birth to their most recent guideline regarding chronic obstructive pulmonary disease (COPD). Much has happened since, and in late 2017 an update has been published. Chapters have been deleted, and new ones added. The major alteration has been in the section concerning treatment with inhalation medication - now aiming at an easy stepwise up-titration of long-acting medicine as well as a guide of how to down-titrate inhaled corticosteroids. This review mainly focuses on how to treat stable COPD according to The Danish Society of Respiratory Medicine.

Influence of pneumococcal conjugate vaccines on acute otitis media in Japan.

OBJECTIVE: This study investigated: (i) changes in the incidence of acute otitis media (AOM) following introduction of public funding for free inoculation with 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) and (ii) changes in the rate of myringotomies for AOM (MyfA) in children 1year following the publication of the first edition of the clinical practice guidelines for the diagnosis and management of AOM in children in Japan. METHODS: PCV7 was launched on the Japanese market in 2010 and gained public funding in 2011. PCV7 was replaced with PCV13 in November 2013. Using the Japan Medical Data Center Claims Database, an 11-year study conducted between January 2005 and December 2015 investigated the decline in the incidence of visits to medical institutions (VtMI) due to all-cause AOM in children <15years. The rate of MyfA from January 2007 to December 2015was also investigated and changes before and after introduction of public funding for PCV7 (pfPCV7) and PCV13 (pfPCV13) for children were examined. Statistical data for the age group between 10 years and <15years served as the control. An analysis was conducted to examine changes for each age group, from infants that had received PCVs to children <5years. Statistical analysis was performed using the chi-square test and Ryan's multiple comparison tests. Ryan's multiple comparison tests were applied at a 5% level of significance. Due to significant changes in the guidelines on the indications for myringotomy introduced in 2013, statistical analysis of the rate of MyfA was limited to the pre- and post-PCV7 period. RESULTS: After introduction of pfPCV7 and pfPCV13, no significant suppression of the incidence of VtMI was observed in any age group. There was a gradual decline in the rate of MyfA after 2011. Compared to the control group, significant differences in all age groups from infants to children <5years were observed (p<0.009, chi-square test). Within 2 years after the introduction of PCV7, a significant decline in the rate of MyfA was observed in 1- and 5-year-olds using Ryan's multiple comparison tests at a 5% level of significance. CONCLUSION: The preventative effect of PCVs on AOM was not established in this study. There was, however, a significant decline in the rate of MyfA among 1- and 5-year-olds. Taking into consideration past studies, PCV7 may play a role in preventing the aggravation of AOM in 1-year-olds. When evaluating the effectiveness of PCVs, measures to evaluate severity may be as important as evaluating disease prevention.

A Population-Based Assessment of the Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines on Macrolide-Resistant Invasive Pneumococcal Disease: Emergence and Decline of Streptococcus pneumoniae Serotype 19A (CC320) With Dual Macrolide Resistance Mechanisms.

BACKGROUND: Macrolide efflux encoded by mef(E)/mel and ribosomal methylation encoded by erm(B) confer most macrolide resistance in Streptococcus pneumoniae. Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000 reduced macrolide-resistant invasive pneumococcal disease (MR-IPD) due to PCV7 serotypes (6B, 9V, 14, 19F, and 23F). METHODS: In this study, the impact of PCV7 and PCV13 on MR-IPD was prospectively assessed. A 20-year study of IPD performed in metropolitan Atlanta, Georgia, using active, population-based surveillance formed the basis for this study. Genetic determinants of macrolide resistance were evaluated using established techniques. RESULTS: During the decade of PCV7 use (2000-2009), MR-IPD decreased rapidly until 2002 and subsequently stabilized until the introduction of PCV13 in 2010 when MR-IPD incidence decreased further from 3.71 to 2.45/100000 population. In 2003, serotype 19A CC320 isolates containing both mef(E)/mel and erm(B) were observed and rapidly expanded in 2005-2009, peaking in 2010 (incidence 1.38/100000 population), accounting for 36.1% of MR-IPD and 11.7% of all IPD isolates. Following PCV13 introduction, dual macrolide-resistant IPD decreased 74.1% (incidence 0.32/100000 in 2013). However, other macrolide-resistant serotypes (eg, 15A and 35B) not currently represented in PCV formulations increased modestly. CONCLUSIONS: The selective pressures of widespread macrolide use and PCV7 and PCV13 introductions on S. pneumoniae were associated with changes in macrolide resistance and the molecular basis over time in our population. Durable surveillance and programs that emphasize the judicious use of antibiotics need to continue to be a focus of public health strategies directed at S. pneumoniae.

Streptococcus pneumoniae serotype 19A: worldwide epidemiology.

INTRODUCTION: Streptococcus pneumoniae causes mucosal and invasive diseases with high morbidity and mortality. Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into routine infant immunization programs worldwide resulted in serotype 19A becoming a leading cause of the remaining pneumococcal disease burden in vaccinated and nonvaccinated individuals. This article reviews the impact of the latest generation PCVs (10-valent PCV, PCV10, and 13-valent PCV, PCV13) on serotype 19A. Areas covered: This article covers immune responses elicited by PCV7, PCV10 and PCV13 against serotype 19A and their impact on nasopharyngeal (NP) carriage and disease in vaccinated and unvaccinated populations using data from surveillance systems, randomized controlled trials, and observational studies. Expert commentary: As expected from a PCV containing serotype 19A, PCV13 elicits significantly higher functional immune responses against serotype 19A than PCV7 and PCV10. Higher responses are likely to be linked to both direct impact in vaccinated populations and reductions in 19A NP carriage in children, thus inducing herd protection and reducing 19A invasive pneumococcal disease (IPD) in nonvaccinated children and adults. In contrast, PCV7 and PCV10 have shown mixed evidence of direct short-lived cross-protection and little to no impact on 19A carriage, resulting in continued transmission and disease.

Long-term trends in invasive pneumococcal disease in Manitoba, Canada.

Invasive pneumococcal disease (IPD) remains a significant public health problem in Manitoba, Canada although publically-funded pneumococcal conjugate (PCV7 and PCV13) and polysaccharide (PPV23) vaccination programs exist. We analyzed routine surveillance and administrative health data to examine trends in IPD rates as these vaccines were introduced. Data on all individuals with a laboratory-confirmed diagnosis of IPD between 2001 and 2014 were obtained from the provincial Communicable Diseases Surveillance database and linked with Manitoba's provincial immunization registry and physician and hospital databases. We calculated IPD incidence rates overall, by serotype and for different population subgroups defined by socio-demographic and clinical (e.g., chronic diseases, immune status) characteristics. Annual IPD incidence (95%CI) was 8.6 (8.2-9.1)/100,000 people during the study period (n = 1092), and rates were higher in recent years and in regions with predominately indigenous populations. Reduction in the incidence of serotypes included in PCV7 have been offset by rising rates of PCV13-only serotypes in children, and more recently by rising rates of PPV-only serotypes and non-vaccine serotypes among young children and older adults (≥ 65 years). Rates were 3 times higher in those with a chronic disease and highest (> 175-fold) among alcoholics, organ-transplant, and chronic kidney failure patients. The case fatality rate was 12.0% within 30 d of diagnosis. Despite the introduction of several vaccination programs, overall rates of IPD have not declined in Manitoba in the last decade, due to increase in incidence of non-PCV7 serotypes. A disproportionately high burden of disease impacts indigenous communities and people with chronic disease.

Estimación de la Relación Costo-Efectividad de las Vacunas Neumocócicas Conjugadas Prevenar-13 y Synflorix®, Utilizadas en Los Programas de Vacunación de Población Infantil Mexicana.

OBJECTIVE: To estimate the cost effectiveness associated with the use of pneumococcal conjugated vaccines, Prevenar-13 and Synflorix®, in the Mexican pediatric population. METHODS: The cost-effectiveness ratio of instrumenting vaccination programs based upon the use of Prevenar-13 and Synflorix® in the Mexican pediatric population was estimated by using a Markov's simulation model. The robustness of the conclusions reached on cost-effectiveness for both vaccines was assayed through an univariate and probabilistic sensitivity analysis that included all of the parameters considered by the model. RESULTS: Synflorix® was dominant over Prevenar-13 in the cost-utility analysis; the former generated more quality-adjusted life years at a lower cost and with a lower incremental cost-utility ratio. Based on the cost-effective analysis, Prevenar-13 generated more life years gained but at a higher cost. The use of Prevenar-13 originated a higher incremental cost-effectiveness ratio and, therefore, it was not cost-effective as compared with Synflorix®. CONCLUSIONS: Even though the simulations for Prevenar-13 and Synflorix® revealed both of them to be cost-effective when used to instrument pediatric vaccination campaigns in Mexico, Synflorix® had a better cost-utility/effectiveness profile. In addition, although Prevenar-13 and Synflorix® produced equivalent health outcomes, the overall analysis predicted that Synflorix® would save 360 million Mexican pesos, as compared with Prevenar-13.

Cost-effectiveness analysis of pneumococcal vaccination for infants in China.

BACKGROUND: Although China has a high burden of pneumococcal disease among young children, the government does not administer publicly-funded pneumococcal conjugate vaccines (PCV) through its Expanded Program on Immunization (EPI). We evaluated the cost-effectiveness of publicly-funded PCV-7, PCV-10, and PCV-13 vaccination programs for infants in China. METHODS: Using a Markov model, we simulated a cohort of 16 million Chinese infants to estimate the impact of PCV-7, PCV-10, and PCV-13 vaccination programs from a societal perspective. We extrapolated health states to estimate the effects of the programs over the course of a lifetime of 75years. Parameters in the model were derived from a review of the literature. RESULTS: We found that PCV-7, PCV-10, and PCV-13 vaccination programs would be cost-effective compared to no vaccination. However, PCV-13 had the lowest incremental cost-effectiveness ratio ($11,464/QALY vs $16,664/QALY for PCV-10 and $18,224/QALY for PCV-7) due to a reduction in overall costs. Our sensitivity analysis revealed that the incremental cost-effectiveness ratios were most sensitive to the utility of acute otitis media, the cost of PCV-13, and the incidence of pneumonia and acute otitis media. CONCLUSIONS: The Chinese government should take steps to reduce the burden of pneumococcal diseases among young children through the inclusion of a pneumococcal conjugate vaccine in its EPI. Although all vaccinations would be cost-effective, PCV-13 would save more costs to the healthcare system and would be the preferred strategy.

Vaccine escape of piliated Streptococcus pneumoniae strains.

INTRODUCTION: Type1-pilus proteins were suggested as targets of future protein-based vaccines. Here we studied the effect of pneumococcal-conjugate vaccine (PCV7) implementation on the prevalence of piliated strains in a unique study setting which controls for typical confounders; the Palestinian-Israeli Collaborative Research (PICR). METHODS: Annual cross-sectional surveys of pneumococcal carriage were performed during 2009-2011 among two closely related population that live under different health policies (a) Palestinian-Authority (PA) (n=1773), where PCV7 was not yet introduced (b) East-Jerusalem (EJ) (n=983) where PCV7 was rapidly implemented. Clinical data were collected, pneumococci identified and characterized and the presence of Type1-pilus genes was determined by rrgC PCR. RESULTS: Following PCV7 implementation in EJ, overall carriage prevalence did not change (∼30%), but VT7 strains decreased from 61.5% to 33.8%. While prevalence of non-piliated-VT7 isolates decreased from 37% to 10%, p<0.001, the prevalence of piliated-VT7 strains persisted ∼25%. Additionally, piliated non-VT13 strains emerged (1-15%, p<0.001). These changes were not observed in PA. These dynamics were independent of the bacteria's resistance pattern. CONCLUSIONS: A differential effect of PCV7 was observed with a relative resistance of piliated strains to the vaccine. This suggests that Type1-pilus confers an intrinsic advantage for colonization and may be an attractive vaccine target.

A systematic review of the burden of vaccine preventable pneumococcal disease in UK adults.

BACKGROUND: Invasive pneumococcal disease (IPD) and pneumococcal pneumonia are common and carry a significant morbidity and mortality. Current strategies to prevent pneumococcal disease are under review in the United Kingdom (UK). We conducted a systematic review to evaluate the burden of vaccine type adult pneumococcal disease specifically in the UK. METHODS: A systematic review conducted and reported according to MOOSE guidelines. Relevant studies from 1990 to 2015 were included. The primary outcome was the incidence of vaccine type pneumococcal disease, focussing on the pneumococcal polysaccharide vaccine (PPSV), the 13-valent conjugate vaccine (PCV13) and the 7-valent conjugate vaccine (PCV7). RESULTS: Data from surveillance in England and Wales from 2013/14 shows an incidence of 6.85 per 100,000 population across all adult age groups for IPD, and an incidence of 20.58 per 100,000 population in those aged >65 years. The corresponding incidences for PCV13 serotype IPD were 1.4 per 100,000 and 3.72 per 100,000. The most recent available data for community-acquired pneumonia (CAP) including non-invasive disease showed an incidence of 20.6 per 100,000 for adult pneumococcal CAP and 8.6 per 100,000 population for PCV13 serotype CAP. Both IPD and CAP data sources in the UK suggest an ongoing herd protection effect from childhood PCV13 vaccination causing a reduction in the proportion of cases caused by PCV13 serotypes in adults. Despite this, applying the incidence rates to UK population estimates suggests more than 4000 patients annually will be hospitalised with PCV13 serotype CAP and more than 900 will be affected by IPD, although with a trend for these numbers to decrease over time. There was limited recent data on serotype distribution in high risk groups such as those with chronic respiratory or cardiac disease and no data available for vaccine type (VT) CAP managed in the community where there is likely to be a considerable unmeasured burden. CONCLUSION: The most recent available data suggests that VT pneumococcal disease continues to have a high burden in UK adults despite the impact of childhood PCV13 vaccination. IPD estimates represent only a fraction of the total burden of pneumococcal disease. STUDY REGISTRATION: PROSPERO CRD42015025043.