今日の臨床サポート

成人の予防接種

著者: 冲中敬二 国立がん研究センター東病院 総合内科

監修: 具芳明 東京医科歯科大学大学院医歯学総合研究科 統合臨床感染症学分野

著者校正/監修レビュー済:2020/10/14
参考ガイドライン:
  1. 日本呼吸器学会日本感染症学会:65歳以上の成人に対する肺炎球菌ワクチン接種に関する考え方 第3版
  1. 環境感染学会:医療関係者のためのワクチンガイドライン 第3版
  1. 米国感染症学会(IDSA):免疫不全者へのワクチン接種ガイドライン Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014 Feb;58(3):e44-100.

概要・推奨   

  1. ワクチン接種は接種した人を伝染性疾患から守るだけでなく、周囲の大切な人を守る役割も果たす。
-免疫不全のため十分なワクチン効果が期待できない人の周囲にいる人がワクチンを接種することによって間接的に免疫不全の人を守る、もしくはコミュニティ内の一定割合以上の人が接種して集団免疫を獲得することによってコミュニティ内での疾患流行を防ぐ。
  1. 健常成人および高齢者へのインフルエンザワクチンの効果:一定の有効性が示されている(推奨度1)。
  1. 高齢者におけるインフルエンザ高用量ワクチン:通常量よりも高い効果が期待できることが大規模研究で示されている(推奨度2)。
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  1. 閲覧に
  1. 2020年2月4日付けの厚生労働省健康局長通知によって、予防接種間隔の改訂がなされることとなった。具体的内容は2月28日の厚生労働省医薬・生活衛生局医薬安全対策課からの事務連絡に記載がある[1]。10月1日に定期接種実施要領が改正された。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
冲中敬二 : 特に申告事項無し[2021年]
監修:具芳明 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 65歳以上の成人に対する肺炎球菌ワクチン接種に関する考え方 第3版に基づき、高齢者への肺炎球菌ワクチン(PCV13)の推奨内容の修正を行った。
  1. 免疫不全者の項目で、免疫チェックポイント阻害剤投与患者におけるインフルエンザワクチンに関する記載を追記した。
  1. 医療関係者のためのワクチンガイドライン 第3版に基づき、各ワクチンの推奨事項の記載修正を行った。
  1. 2020年10月1日からワクチンの接種間隔が撤廃された。(生ワクチン[注射]を連続して接種する場合は除く)

病態・疫学・診察

まとめ  
  1. 医療の進歩に伴い、免疫不全を伴う患者が増加傾向にある。加えて、日本の高齢化が進むと2065年には約2.6人に1人が65歳以上、3.9人に1人が75歳以上となる[2]。市中の易感染者が増加するなか、このような易感染者を直接的もしくは間接的に守るためにもワクチンによる伝染性疾患の予防は今まで以上に重要となる。

各論

健常成人  
インフルエンザワクチン:
  1. 2015~16シーズンの米国ではワクチンによって以下の予防がなされたと試算されている[3]
  1. インフルエンザ関連疾患:510万件
  1. インフルエンザ関連受診:250万件
  1. インフルエンザ関連入院:7.1万件
  1. インフルエンザと肺炎による死亡:0.3万件
  1. 欧州では年間38,500例の死亡があり、その約9割が高齢者とされる[4]
  1. 年齢別の推定超過死亡率として、65歳未満が0.1-6.4/10万人、65~74歳が2.9-44.0/10万人、75歳以上が17.9-223.5/10万人と推定される[5]
  1. 65歳以上の高齢者はインフルエンザ罹患時の入院率が高いことが知られている。
 
米国における年齢ごとの入院率

65歳以上の入院率が非常に高いことが示されている。(情報元:CDCのMorbidity and Mortality Weekly Report)
*:流行の主流がA(H3N2)だった年を示す。

出典

img1:  Effective Immunization of Older Adults Against Seasonal Influenza.
 
 Am J Med. 2018 Aug;131(8):865-873. doi: ・・・
 
  1. また、ワクチン効果が劣る可能性のある人々を間接的に守るため(Herd Immunity)の接種意義もある。過去に日本で小児へのインフルエンザワクチン集団接種が中止になったことによって高齢者の超過死亡が増加したことが報告されている[6]
  1. 北半球では10月終わりまでに接種されることが推奨されるが、それ以降の接種でも意義はあるとされる[7]
  1. 1982-2018年までの36シーズンにおける流行のピークは2月が42%と最も多く、12月が19%、1月及び3月が17%であった[8]
  1. ワクチンの効果持続期間は6か月程度と考えられている[9]
  1. インフルエンザ関連合併症のリスクが高い人々が、ワクチン接種の対象者として重要と考えられる。
  1. 接種対象者:国内では65歳以上で推奨されている(心、腎臓、呼吸機能障害により身の回りの生活を極度に制限されたり、HIV感染に伴って日常生活が不可能な場合には60歳以上)。
  1. 米国では50歳以上のすべての人へ推奨されている。
  1. 50歳以下の年齢の人でも米国で接種が推奨されている代表例を以下にあげる。
  1. 慢性呼吸器、心、腎、肝、神経、血液、代謝性疾患の患者
  1. 免疫不全者
  1. インフルエンザシーズンに妊娠をする女性
  1. American Indians/Alaska Natives
  1. BMI≧40の肥満者
  1. 老人ホームや長期療養施設入所者
  1. 5歳未満の子供やリスクのある人の介護者や接触者
  1. 高齢者へのインフルエンザワクチンの副反応において大きな問題はなく、一定の効果を認めていることが示されており[10]、積極的な接種が推奨される。
  1. 医療従事者
  1. インフルエンザワクチンを毎年接種していると効果が下がる可能性が指摘されているが[11]、接種しないとその年のワクチン効果が得られないため、やはり毎年の接種が推奨される。
  1. 66歳以上を対象としたカナダでの検討では過去10シーズンに1度もワクチンを受けていない人のワクチン効果が34%であったのに対し、過去の接種回数に応じたワクチン効果は以下の通り。1-3回:26%、4-6回:24%、7-8回:13%、9-10回:7%。
  1. 原因は不明だが、過去のワクチン接種によって誘導された免疫反応とそのシーズンのウイルス抗原との交差反応による効果減弱などが疑われている[12]
 
  1. 健常成人および高齢者へのインフルエンザワクチンの効果:一定の有効性が示されている(推奨度1)。
  1. 健康な成人へのインフルエンザワクチンの効果に関し、2018年のDemicheliらのコクランレビューがある[13]。16~65歳の健康な成人に対して不活化インフルエンザワクチンを接種すると、プラセボまたは接種なしと比べたランダム化比較試験のメタ解析によるリスク比は以下の通りであった。
  1. インフルエンザ発症:0.41(2.3%→0.9%へ減、95%信頼区間〔CI〕:0.36-0.47、n=71,221、エビデンスの質Moderate)
  1. インフルエンザ様症状:0.84(21.5%→18.1%へ減、95%CI:0.75-0.95、n=25,795、エビデンスの質Moderate)
  1. 入院エピソード:0.96(14.7%→14.1%、95%CI:0.85-1.08、n=11,924、エビデンスの質Low)
  1. インフルエンザおよびインフルエンザ様症状を有意に減少させるという結果であるが、その減少幅は少なく、インフルエンザに対するNumber needed to vaccinate(NNV)は71で、インフルエンザ様症状は29であった。
  1. 高齢者においても、2018年のDemicheliらのコクランレビューによって検討されている[14]。65歳以上の高齢者に対して不活化インフルエンザワクチンを接種すると、プラセボまたは接種なしと比べたランダム化比較試験のメタ解析によるリスク比は以下の通りであった。
  1. インフルエンザ発症:0.42(6%→2.4%へ減、95%CI:0.27-0.66、n=2,217、エビデンスの質Low)
  1. インフルエンザ様症状:0.59(6%→3.5%へ減、95%CI:0.47-0.73、n=6,894、エビデンスの質Moderate)
  1. インフルエンザおよびインフルエンザ様症状を有意に減少させるという結果であり、インフルエンザに対するNNVは30、インフルエンザ様症状は42であった。ただ、研究ごとのインフルエンザ診断根拠に関する情報が限定されたため、エビデンスの質は低いと判断されている。
  1. インフルエンザで入院した患者での検討では、ICUへの入室を59%減少させた(調整オッズ比0.41、95%CI:0.18-0.96)と報告されている[15]
  1. また、A(H3N2)に対するワクチン効果は他の型よりもワクチン効果が劣る可能性が示されているが[16]、特にvariant A(H3N2)が流行する年の高齢者のワクチン効果は下がる可能性が別のメタ解析で報告されている[17]
  1. 18~64歳 46%(95%CI:30-61)
  1. 65歳以上 14%(95%CI:-3-30)
  1. 追記:ベースラインの発症頻度が数%と低くNNVは大きな数字となっているものの、リスク比は大きな減少を示しており、特に併存疾患の存在やインフルエンザによる合併症のリスクのある高齢者にはワクチンの接種を勧める根拠となると考えられる。
    2012年のLancet Infect Disの成人(18~64歳)におけるプラセボとのランダム化比較試験のメタ解析[18]でもワクチン効果は59%(2.7%→1.2%へ減、95%CI:0.51-0.67、n=31,892)との結果が報告されている。
    また、高齢者においても症例・対象研究(test-negative design)のメタ解析がLancet respire Medで報告[19]されており、流行シーズンではワクチンタイプと適合した場合の有効率が44.38%(95%CI:22.63-60.01)、ワクチンタイプと適合しない場合の有効率でも20.00%(95%CI:3.46-33.68)とある程度の効果が示されている。
 
成人への不活化インフルエンザワクチン接種のリスク比及び95%信頼区間

n=インフルエンザ症例数、N=登録例数
 
  1. Ohmit SE, Victor JC, Rotthoff JR et.al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med. 2006 Dec 14;355(24):2513-22. PubMed PMID: 17167134; PubMed Central PMCID: PMC2614682.
  1. Ohmit SE, Victor JC, Teich ER et.al. Prevention of symptomatic seasonal influenza in 2005-2006 by inactivated and live attenuated vaccines. J Infect Dis. 2008 Aug 1;198(3):312-7. doi: 10.1086/589885. PubMed PMID: 18522501; PubMed Central PMCID: PMC2613648.
  1. Beran J, Wertzova V, Honegr K et.al. Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example. BMC Infect Dis. 2009 Jan 17;9:2. doi: 10.1186/1471-2334-9-2. PubMed PMID: 19149900; PubMed Central PMCID: PMC2639595.
  1. Beran J, Vesikari T, Wertzova V et.al. Efficacy of inactivated split-virus influenza vaccine against culture-confirmed influenza in healthy adults: a prospective, randomized, placebo-controlled trial. J Infect Dis. 2009 Dec 15;200(12):1861-9. doi: 10.1086/648406. PubMed PMID: 19909082.
  1. Monto AS, Ohmit SE, Petrie JG et.al. Comparative efficacy of inactivated and live attenuated influenza vaccines. N Engl J Med. 2009 Sep 24;361(13):1260-7. doi: 10.1056/NEJMoa0808652. PubMed PMID: 19776407.
  1. Jackson LA, Gaglani MJ, Keyserling HL et.al. Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons. BMC Infect Dis. 2010 Mar 17;10:71. doi: 10.1186/1471-2334-10-71. PubMed PMID: 20236548; PubMed Central PMCID: PMC2845585.
  1. Frey S, Vesikari T, Szymczakiewicz-Multanowska A et.al. Clinical efficacy of cell culture–derived and egg‐derived inactivated subunit influenza vaccines in healthy adults. Clin Infect Dis. 2010 Nov 1;51(9):997-1004. doi: 10.1086/656578. PubMed PMID: 20868284.

出典

img1:  Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis.
 
 Lancet Infect Dis. 2012 Jan;12(1):36-44.・・・
 
  1. 高齢者におけるインフルエンザ高用量ワクチン:通常量よりも高い効果が期待できることが大規模研究で示されている(推奨度2)。
  1. 高齢者におけるワクチン効果の増強目的にワクチン含有量を増加させる研究が行われている。DiazGranadosらの代表的な研究[20]で、65歳以上31,989人へ4倍量のヘマグルチニンを接種したところ、検査で確定されたインフルエンザ症例は高用量群で1.4%、通常量群1.9%と24.2%の相対的ワクチン効果を認めた。(95%CI:9.7-36.5)一方、高用量化にともなう副反応の増加はみられなかった(8.3% vs 9.0%;相対リスク0.92、95%CI:0.85-0.99)。この研究を中心としたメタ解析[21]でも、リスク比は0.76(95%CI:0.65-0.90、n=41,141)と高用量の接種を支持している。
 
  1. 高齢者におけるインフルエンザ結合型ワクチン:従来型ワクチンよりも高い効果が期待できる可能性が示されている(推奨度2)。
  1. 高齢者におけるワクチン効果の増強目的に結合型ワクチンを用いた研究が行われているが、60歳以上を対象としたメタ解析の結果では、欧州医薬品庁の基準(接種後有効抗体価保持率≧60%、接種前後の幾何平均比≧2、抗体陽転化率≧30%)を満たすことが示されている[22]。また、他のメタ解析では肺炎やインフルエンザによる入院の抑制効果が51%(95%CI:31-69%)と有意な効果を認めたが、インフルエンザ(Laboratory-confirmed)抑制効果においては60.1%(95%CI:-1.3-84.3%)と有意差は示されなかった。しかし非結合型ワクチンと比較するとリスク比が肺炎/インフルエンザによる入院0.577(95%CI:0.334-0.999、n=3,183、I2=81%)、インフルエンザ(Laboratory-confirmed)0.412(95%CI:0.190-0.893、n=110、I2=0%)と有意な抑制効果を認めたことが示されている[23]
 
肺炎球菌ワクチン:
  1. 2013~2014年度の国内291例の侵襲性肺炎球菌感染症(IPD:血液や髄液など本来無菌環境である部位から検出された感染症)の検討によると、年齢中央値が70歳と高齢者が多く致死率が20%と高い[24]
  1. 侵襲性肺炎球菌感染症はワクチン予防可能疾患の中で最も致死率が高く(6.4~40%)、欧州28カ国で2014年に報告された侵襲性肺炎球菌感染症の死亡数は17,528例にのぼる[4]
  1. 2004年の米国における推定では肺炎球菌感染症による死亡は22,000例で、うち65歳以上が16,000例を占めるとされる[25]
  1. 肺炎球菌ワクチンにはポリサッカライドワクチン(ニューモバックス)と結合型ワクチン(プレベナー13)の2種類がある。
  1. ポリサッカライドワクチン(PPSV23):23種類の血清型をカバーしている。しかし、免疫原性では結合型ワクチンより劣るとされる。2歳以上が接種対象。65~100歳における定期B類に分類される。
  1. 結合型ワクチン(PCV13):13種類の血清型をカバーしている。免疫原性に優れ[26]、2歳以下でも有効性が示されており、6歳未満の定期A類に分類される。また、任意接種として65歳以上への接種も可能。
  1. 2010年に小児へのPCVの公費助成が始まり、その接種率は90%を超えている。これに伴う集団免疫効果によって高齢者のIPDも減少してきているが、IPDの起炎菌の血清型のうち非ワクチンタイプの血清型の占める割合が徐々に増加してきていること(血清型置換)が問題となっている。
  1. 日本や米国では65歳以上へのPCV13およびPPSV23の接種を推奨されてきたが、2019年以降、PPSV23は引き続き推奨されるものの、PCV13は症例ごとで検討する方針となった[27][28]。なお、欧州では英国やドイツなど以前より高齢者へはPPSV23のみを推奨している国も多い。フランスやポルトガル、スイスなどのようにそもそも高齢者への肺炎球菌ワクチンの推奨のない国もある[4]
  1. 米国では64歳以下であっても喫煙者、心・肺・肝機能障害、糖尿病患者にはPPSV23を、脾機能障害や免疫不全患者(HIV感染者や先天性免疫不全、悪性腫瘍患者、免疫抑制剤使用者、腎機能障害など)や髄液漏、人工内耳のある人へはPCV13およびPPSV23の接種を推奨している。
  1. 2014年10月より5年間の時限措置として65歳、70歳、75歳、80歳、85歳、90歳、95歳、100歳へのPPSV23の公費助成が行われたが、2019年からさらに5年間助成期間が延長された[29]。(100歳以上は2019年度のみ)しかし、2014-17年の接種率は30%台と低い[30]
  1. PCV13→PPSV23の接種間隔
  1. 日本呼吸器学会、日本感染症学会はPCV13接種6カ月から4年の間隔でのPPSV23の接種を推奨している。(図<図表>
  1. 米国では1年以上の間隔で接種することが推奨されているが、免疫不全者では8週間以上の間隔が推奨されている。
  1. 最初にPPSV23の接種を受けていて、その後にPCV13を接種する場合には1年以上の間隔をあけて接種することが推奨されている。
  1. 抗体価の減衰を懸念したPPSV23の再接種に関し、5年以上の間隔をあけた場合には効果低下[31][32][33]や副反応増強の影響が少ないとされており、PPSV23を再接種する場合は5年以上の間隔をあけて接種することが推奨されている[28]
 
65歳以上の成人に対する肺炎球菌ワクチン接種に関する考え方(第3版 2019-10-30)

日本呼吸器学会、日本感染症学会が2019年10月に発表した、国内における肺炎球菌ワクチン接種の推奨スケジュール。

 
  1. PPSV23の効果:死亡率は変わらないもののIPD、肺炎を減らすことが示されている(推奨度1)。
  1. 高齢者におけるPPSV23のワクチン効果に関するメタ解析として2017年に報告されたFalkenhorstらの報告がある[34]。これによるとランダム化比較試験によるリスク比は以下のとおりである。
  1. IPD:0.27(95%CI:0.08-0.90、n=43,590、I2=0%)
  1. 肺炎球菌肺炎:0.75(95%CI:0.35-1.62、n=43,590、I2=78%)
  1. 肺炎球菌肺炎:0.36(95%CI:0.20-0.65、n=3,887、I2=0%、バイアスが低い研究に限定)
  1. 死亡率を評価したメタ解析としてMoberleyらの2013年の報告があり[35]、有意差を持った効果は示されなかった。
  1. オッズ比0.90(95%CI:0.74-1.09、n=47,560、I2=69%)
  1. 国内で2011~2014年に実施された多施設前向き研究では、肺炎球菌肺炎に対するワクチン効果は27.4%(95%CI:3.2-45.6、n=2,036)で、ワクチンタイプの血清型では33.5%(95%CI:5.6-53.1)、非ワクチンタイプでは2.0%(95%CI:-78.9-46.3)であった[36]。この研究でも死亡率へは有意な影響はみられなかった(9.6%;95%CI:-218.4-74.3)。
  1. 追記:死亡率を改善させるデータではないが、IPDや肺炎を減らす効果が示されている。PCV13研究同様、血清型置換が起こっている現代における効果は変化している可能性はある。
 
  1. PCVの効果:死亡率は変わらないもののIPD、市中肺炎、非侵襲性肺炎を減らすことが示されている(推奨度1)。
  1. 高齢者へのPCV13研究ではBontenらの研究(CAPiTA)が最も有名である[37]。オランダにてPPSV23未接種の84,496人を対象にした大規模ランダム化比較試験結果が報告されており、ワクチン株に含まれる感染症におけるワクチン効果は以下のとおりである。
  1. 市中肺炎45.6%(95%CI:21.8-62.5%)
  1. 非侵襲性肺炎45.0%(95%CI:14.2-65.3%)
  1. IPD 75.0%(95%CI:41.4-90.8%)
  1. PCVの効果を示した大きな意味を持つ研究ではあるが、既にPPSV23接種を受けている人は除外されており、このような対象への効果が不明であることや、免疫不全者は対象に含まれていないこと、小児へのPCV13が導入され血清型置換が起こっている現代においても同等の効果があるかどうかは不明であること、などの複数のLimitationがある。
  1. 全生存率の改善はメタ解析では示されていない[38]
  1. PCV13 リスク比1.00(95%CI:0.95-1.05、n=86,263、I2=0%)
  1. PCV7 リスク比0.84(95%CI:0.53-1.33、n=46,890、I2=33.6%)
  1. 追記:PCV13はIPDを減少させることは示されている。血清型置換が起こってきている現状において効果の幅に変化がある可能性はある。
 
  1. PCV導入後の血清型置換(推奨度2)
  1. 米国をはじめ日本を含む世界各国で、小児へのPCVが導入された後に小児のIPDは劇的に減少した[39]。これに伴って、成人におけるIPDも減少している[40]。これは、以前から小児の鼻腔に保菌された肺炎球菌が成人への主要な肺炎球菌伝播経路と考えられていたが、PCVの効果によって小児の鼻腔の保菌が減少したからといわれている。ところが、ここ最近では市中のIPDを引き起こす肺炎球菌の血清型が非ワクチンタイプ(非PCV13タイプ)に移行してきていることが示されている。[24]、その一方で、市中に免疫不全者が増える中、IPD発症者における免疫不全者の占める割合が増加してきていることも示されている[41]。このため引き続き免疫不全者への肺炎球菌ワクチンの重要性は変わらないと思われる。2011-14年と2016-17年の肺炎球菌肺炎の前向き研究(成人438例)ではPCV13カバー率は53%から33%へ、PPSV23のカバー率は72%から51%への減少であった[42]。国内の肺炎球菌肺炎の後方視的研究(成人229例)ではPPSV23の非カバー率は2011年25.0%から2015年の44.4%と上昇しているものの、それ以降2017年47.1%と大きな上昇は来しておらず、PCV13も同様の傾向を示している[43]
  1. 追記:小児へのPCV導入後、IPDの疫学は変わってきており、今後の動向やワクチン推奨内容の変更にも注意が必要である。
 
帯状疱疹ワクチン:
  1. 近年、帯状疱疹の頻度が増えてきている[44]
  1. 特に50歳以上での発症頻度が高く、85歳時における生涯の罹患リスクは50%に達する[45]
  1. 帯状疱疹後神経痛は5~30%に合併するとされ、著しく生活の質を落とす危険性がある。
  1. 米国では帯状疱疹予防として生ワクチン(Zostavax)が60歳以上へ推奨されてきたが、2017年にサブユニットワクチン(Shingrix)がFDAに認可され、2018年から50歳以上への帯状疱疹ワクチンの第1選択薬として推奨されるようになった。
  1. 日本でも同様の力価の生ワクチン(乾燥弱毒生水痘ワクチン「ビケン」)があり、2016年3月に“50歳以上のものに対する帯状疱疹の予防“という効能効果が追加された。
  1. 生ワクチンでありステロイド等免疫抑制剤投与中の接種は禁忌である。
  1. サブユニットワクチンも2018年3月に50歳以上の成人を対象とした製造販売承認が得られている。
 
  1. 高齢者における帯状疱疹ワクチンは非常に高い効果を示しており、米国CDCの予防接種諮問機関であるACIPも、サブユニットワクチンが承認された翌年(2018年)から第1選択薬として推奨している。しかし、ワクチンの効果は100%ではない点についても患者には説明しておいた方がよいと思われる(推奨度2)。
  1. 生ワクチン(Oka/Merck VZVワクチン、力価中央値24,600pfu):
    60歳以上の38,501名を対象としたランダム化比較試験(修正ITT解析:同意撤回、接種30日内の帯状疱疹発症)
  1. 帯状疱疹へのワクチン効果61.1%(95%CI:51.1-69.1、5.42 vs 11.12/1000人・年)
  1. 70歳以上に限定55.4%(95%CI:39.9-66.9、7.18 vs 11.50/1000人・年)
  1. 帯状疱疹後神経痛(PHN)への効果66.5%(95%CI:47.5-79.2、0.46 vs 1.38/1000人・年)
  1. 接種部位の局所反応はプラセボよりも多かったが重篤な有害事象には差がなかった。
  1. N=69,916のメタ解析[46]でのワクチン効果(リスク比) 0.49(95%CI:0.43-0.56)
  1. サブユニットワクチン:
    50歳以上および70歳以上を対象としたGlobal Phase 3のランダム化比較試験(2カ月間隔で2回接種)が実施されている。
  1. 50歳以上n=15,411(ZOE-50:[47]):ワクチン効果97.2%(95%CI:93.7-99.0、0.3 vs 9.1/1000人・年)
  1. 70歳以上n=13,900(ZOE-70:[48]):ワクチン効果89.8%(95%CI:84.2-93.7、0.9 vs 9.2/1000人・年)
  1. 2つの研究の70歳以上の参加者16,594名
  1. ワクチン効果91.3%(95%CI:86.8-94.5、0.8 vs 9.3/1000人・年)
  1. 帯状疱疹後神経痛(PHN)への効果88.8%(95%CI:68.7-97.1)
  1. いずれの研究でも、接種部位の局所反応はプラセボよりも多かったが重篤な有害事象には差がなかった。
  1. 接種4年目のワクチン効果もZOE-50:93.1%、ZOE-70:87.9%と良好であった。
  1. PHN以外の帯状疱疹関連合併症への効果:50歳以上93.7%、70歳以上91.6%[49]
  1. 播種性疾患や神経疾患、眼科関連疾患、血管炎など
  1. 追記:非常に高い効果を示しており、米国CDCの予防接種諮問機関であるACIPも第1選択薬として推奨している[50]。効果は高いものの、予防接種を行った患者の中にも帯状疱疹を少数発症している点(ワクチンの効果は100%ではない)についても患者には説明しておいた方がよいと思われる。
 
百日咳ワクチン:
  1. 成人の百日咳は比較的症状が軽いものの、子供への伝播の感染源となり、罹患した小児(特に生後6カ月未満)が重症化する危険性が指摘されている。
  1. 精製百日咳ワクチン(Acellular pertussis vaccine)は発症防御能があるものの、感染防御効果が乏しい可能性が指摘されている[51]
  1. 欧米ではワクチンカバー率が高いにもかかわらず百日咳が近年再増加してきていることが示されており[52][53]、精製百日咳ワクチンは以前使用されていた全細胞ワクチンと比較すると免疫減衰が速い可能性が指摘されている[54]
  1. 成人への接種はドイツ、イタリア、フランスなどの欧州主要国や米国などで推奨されている。
  1. 米国では小児期の接種後、11~12歳でTdap(破傷風、減量ジフテリア、減量精製百日咳)の接種が推奨されている。もし19歳までにTdap未接種の場合にも追加接種を推奨している。また、妊婦への妊娠ごとの接種も推奨されている。
  1. ただし、成人への接種に用いるのはTdapで、小児向けのワクチン(DTaP)よりも百日咳ワクチンおよびジフテリアの抗原量を減らしたものが使われている。現在国内にTdapはなく、成人への追加免疫として3種混合ワクチン(沈降精製百日せきジフテリア破傷風混合ワクチン:トリビック)0.5mlの接種が承認され、2017年12月に添付文書に追加記載されている。これに伴い、2018年1月からDTaPの販売も再開されている。(国内では2016年3月以降製造中止されていた。)
  1. 2018年1月から百日咳は全数把握疾患となった。従来からの培養や血清学的検査に加えて、2016年11月から百日咳に対するLAMP法が保険収載されており、国内の疫学が明らかとなることを期待したい。
  1. 2018年に11190例が報告されている。5~15歳未満が全体の64%ともっとも多く、6カ月未満が5%、30~50代の成人では16%であった。もっとも多い5~15歳未満では発症者の81%が4回ワクチンを接種していた。また、重症化が懸念される6カ月未満の小児の感染源の多くが同胞(42%)であり、ついで両親(父親17%、母親14%)、祖父母が6%であった。この点からも成人への百日咳ワクチンの追加接種の重要性が示唆される[55][56]
  1. 5~15歳の学童期の発症者の大多数が百日咳ワクチン4回接種後である。現在第2期(11~13歳)にDTトキソイドの接種が定期接種として使用されている。日本小児科学会ではDTaPの接種をしてもよいとしている[57]が、任意接種となる。DTaPの追加接種は現在厚生科学審議会で検討中である。
 
麻疹ワクチン:
  1. 2015年に日本は世界保健機関西太平洋地域事務局より麻疹排除国認定を受けた。
  1. 2015年以降も定期的に輸入株を発端としたアウトブレイクが国内で散発している。
  1. 2019年の国内における麻疹の抗体保有状況調査では、麻疹あるいは修飾麻疹の発症予防の目安とされるPA抗体価1:128以上の抗体価の者は30~40代もほぼ90%前後まで改善してきているが、全年齢を通じ約1割前後はそれ以下の抗体価の者が存在することから、引き続き麻疹排除状態を維持するためにはワクチン接種が重要とされる[58]
  1. 成人において特に麻疹のリスクが高いのは大学生、医療関係者、国際旅行者とされる[59]
  1. 近年国内でも医療機関で生じた曝露による感染伝播の報告が複数ある[60][61]
  1. 自動車教習所や小学校の入学式、工場内など、それ以外の場所でも麻疹のアウトブレイクの報告があり、上記の高リスク者以外へも広くワクチンの接種が推奨される[62]
  1. 2019年4月に「麻疹に関する特定感染症予防指針」が改訂され、医療機関のほか、児童福祉施設及び学校等(幼稚園から大学、専修学校までの各種学校)の職員等への予防接種を強く推奨する必要があることが明記された[63]
 
風疹ワクチン:
  1. 日本は2020年度の風疹排除を目標として対策をすすめている。
  1. 2013年に14,000例を超える大流行となり、先天性風疹症候群の症例も大きな社会問題となった(2012年~2014年の報告は45例)[64]。2019年にも流行し、複数の先天性風疹症候群症例が報告されている。
  1. 妊娠出産年齢層の女性にワクチンを接種する場合は約1カ月間の避妊が推奨される(ワクチン株による先天性風疹症候群を懸念するため)。ただし、万が一妊娠していることに気が付かずワクチンを接種したとしても、そのリスクの低さから妊娠を中断する必要はないとされる。一方、男性は風疹ワクチン接種後の避妊は必要がないとされている。妊娠中に風疹抗体価が低いことが判明した場合は出産後早期の接種が望ましい[65]
  1. 2018年の国内における風疹の抗体保有状況調査では、抗体陽性と判定されるHI抗体価1:8以上の抗体保有率について、男性では40代~50代前半で80%前後の抗体保有率と低かったことが報告されている[66]
  1. 1962年4月2日から1979年4月1日生まれの男性に対し2019年から2022年3月まで風疹第5期定期接種(全額公費負担)が実施されている。
  1. 実際に2012~2013年の国内流行の主体は成人男性であり、職場における流行が目立ったことが知られているが2019年の流行でも30~40代の男性に多かった。一方、女性では出産年齢である20~30代に多かったことが示されている[67]
 
破傷風トキソイド:
  1. 2000年以降も年間100~130例前後の発症があり、ワクチン未接種である60~70歳代をピークとしている。
  1. 東日本大震災のような自然災害時にも高齢者を中心に10例の発症がみられている。2018年の中国地方の大豪雨でも高齢者2人が発症している。
  1. 2018年の国内調査では50歳代以降の抗体価保有率が低いことが示されている[68]
  1. ワクチン未接種者への接種や、日常生活で農作業や外傷のリスクを伴う活動を行う人への追加接種が特に推奨される。
  1. 欧米では10年ごとのTd(破傷風、減量ジフテリア)の追加接種が推奨されている。
  1. また、外傷時に国内で推奨されている接種方法は以下に示す。
 
外傷時のワクチン、ガンマグロブリン製剤の投与基準

  1. 外傷時の破傷風トキソイド追加接種基準
  1. 抗CD20抗体薬投与6カ月以内の場合は、免疫グロブリンの投与を行うことを推奨するガイドラインもある[1]
 
参考文献:
  1. van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, Emery P, Geborek P, Ioannidis JP, Jayne DR, Kallenberg CG, Müller-Ladner U, Shoenfeld Y, Stojanovich L, Valesini G, Wulffraat NM, Bijl M. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2011 Mar;70(3):414-22. doi: 10.1136/ard.2010.137216. Epub 2010 Dec 3. PubMed PMID: 21131643.

 
ジフテリアトキソイド:
  1. 現在国内での発生は1999年以降ないものの2017-2018年にかけてイエメンでの大流行やアメリカ大陸地域(ブラジル、ドミニカ共和国、ハイチ、ベネズエラ、コロンビア)をはじめ、海外では散発している。
  1. 致死率が5~10%と高く、欧米では10年ごとにTd(破傷風、ジフテリア)の接種が推奨されている。
 
B型肝炎ワクチン:
  1. 近年欧米に多く、慢性化率の高い遺伝子型AのB型肝炎ウイルスによる成人感染者の増加が問題となっている。
  1. B型肝炎の致死的な合併症として肝細胞癌がある。
  1. 2016年10月から小児への接種として定期A類に追加された。
 
妊娠時:
  1. 生ワクチンは妊娠時の接種が禁忌であり、妊娠前の接種が推奨される。
  1. もし妊婦が風疹ワクチン未接種と判明した場合は、出産後速やかに接種する。(もし夫が未接種なら、夫も接種する)
  1. 妊娠前の前に幼少期のワクチン接種歴を確認することが望ましい。(特に風疹ワクチン)
  1. 米国では不活化インフルエンザワクチンおよび成人用3種混合(Tdap:ジフテリア、破傷風、百日咳)の接種が推奨されている[69]。後者に関し日本国内ではDTaPが流通しているものの妊婦における安全性は確立していない点に注意が必要である。
 
大災害時:
  1. CDCはTdap、インフルエンザワクチン、および一般的な推奨者に対するPCV13/PPSV23の接種を推奨している[70]
  1. 東日本大震災時には海外からのジャーナリストを発端とした麻疹も問題となった。現場への派遣者へも一般的な医療従事者に準じたワクチン接種が推奨される。
免疫不全者  
免疫不全者へのワクチンにおける一般的注意事項:
  1. 疾患予防の程度をアウトカムとした臨床試験は非常に少なく、多くは抗体価をサロゲートマーカーとした研究である。しかし多くの病原体において、抗体価の濃度と疾患予防効果との相関性は未確立である。このためエキスパートオピニオンをもとにした推奨が多い。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
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文献 

著者: Susanna Esposito, Elisabetta Franco, Gaetan Gavazzi, Angel Gil de Miguel, Roland Hardt, George Kassianos, Isabelle Bertrand, Marie-Cécile Levant, Benoit Soubeyrand, Jose Antonio López Trigo
雑誌名: Vaccine. 2018 May 3;36(19):2523-2528. doi: 10.1016/j.vaccine.2018.03.053. Epub 2018 Apr 1.
Abstract/Text Longer life expectancy and decreasing fertility rates mean that the proportion of older people is continually increasing worldwide, and particularly in Europe. Ageing is associated with an increase in the risk and severity of infectious diseases. These diseases are also more difficult to diagnose and manage in seniors who often have at least one comorbid condition (60% of seniors have two or more conditions). Infectious diseases increase the risk of hospitalization, loss of autonomy and death in seniors. Effective vaccines are available in Europe for infectious diseases such as influenza, pneumococcal diseases, herpes zoster, diphtheria, tetanus and pertussis. Their effectiveness has been demonstrated in terms of reducing the rates of hospitalization, disability, dependency and death. The prevention of diseases in seniors also results in savings in healthcare and societal costs each year in Europe. Despite the availability of vaccines, vaccine-preventable diseases affect millions of European citizens annually, with the greatest burden of disease occurring in seniors, and the medical and economic benefits associated with are not being achieved. Vaccination coverage rates must be improved to achieve the full benefits of vaccination of seniors in Europe.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29615269  Vaccine. 2018 May 3;36(19):2523-2528. doi: 10.1016/j.va・・・
著者: A Danielle Iuliano, Katherine M Roguski, Howard H Chang, David J Muscatello, Rakhee Palekar, Stefano Tempia, Cheryl Cohen, Jon Michael Gran, Dena Schanzer, Benjamin J Cowling, Peng Wu, Jan Kyncl, Li Wei Ang, Minah Park, Monika Redlberger-Fritz, Hongjie Yu, Laura Espenhain, Anand Krishnan, Gideon Emukule, Liselotte van Asten, Susana Pereira da Silva, Suchunya Aungkulanon, Udo Buchholz, Marc-Alain Widdowson, Joseph S Bresee, Global Seasonal Influenza-associated Mortality Collaborator Network
雑誌名: Lancet. 2018 Mar 31;391(10127):1285-1300. doi: 10.1016/S0140-6736(17)33293-2. Epub 2017 Dec 14.
Abstract/Text BACKGROUND: Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000-500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999-2015.
METHODS: We estimated country-specific influenza-associated respiratory excess mortality rates (EMR) for 33 countries using time series log-linear regression models with vital death records and influenza surveillance data. To extrapolate estimates to countries without data, we divided countries into three analytic divisions for three age groups (<65 years, 65-74 years, and ≥75 years) using WHO Global Health Estimate (GHE) respiratory infection mortality rates. We calculated mortality rate ratios (MRR) to account for differences in risk of influenza death across countries by comparing GHE respiratory infection mortality rates from countries without EMR estimates with those with estimates. To calculate death estimates for individual countries within each age-specific analytic division, we multiplied randomly selected mean annual EMRs by the country's MRR and population. Global 95% credible interval (CrI) estimates were obtained from the posterior distribution of the sum of country-specific estimates to represent the range of possible influenza-associated deaths in a season or year. We calculated influenza-associated deaths for children younger than 5 years for 92 countries with high rates of mortality due to respiratory infection using the same methods.
FINDINGS: EMR-contributing countries represented 57% of the global population. The estimated mean annual influenza-associated respiratory EMR ranged from 0·1 to 6·4 per 100 000 individuals for people younger than 65 years, 2·9 to 44·0 per 100 000 individuals for people aged between 65 and 74 years, and 17·9 to 223·5 per 100 000 for people older than 75 years. We estimated that 291 243-645 832 seasonal influenza-associated respiratory deaths (4·0-8·8 per 100 000 individuals) occur annually. The highest mortality rates were estimated in sub-Saharan Africa (2·8-16·5 per 100 000 individuals), southeast Asia (3·5-9·2 per 100 000 individuals), and among people aged 75 years or older (51·3-99·4 per 100 000 individuals). For 92 countries, we estimated that among children younger than 5 years, 9243-105 690 influenza-associated respiratory deaths occur annually.
INTERPRETATION: These global influenza-associated respiratory mortality estimates are higher than previously reported, suggesting that previous estimates might have underestimated disease burden. The contribution of non-respiratory causes of death to global influenza-associated mortality should be investigated.
FUNDING: None.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29248255  Lancet. 2018 Mar 31;391(10127):1285-1300. doi: 10.1016/・・・
著者: T A Reichert, N Sugaya, D S Fedson, W P Glezen, L Simonsen, M Tashiro
雑誌名: N Engl J Med. 2001 Mar 22;344(12):889-96. doi: 10.1056/NEJM200103223441204.
Abstract/Text BACKGROUND: Influenza epidemics lead to increased mortality, principally among elderly persons and others at high risk, and in most developed countries, influenza-control efforts focus on the vaccination of this group. Japan, however, once based its policy for the control of influenza on the vaccination of schoolchildren. From 1962 to 1987, most Japanese schoolchildren were vaccinated against influenza. For more than a decade, vaccination was mandatory, but the laws were relaxed in 1987 and repealed in 1994; subsequently, vaccination rates dropped to low levels. When most schoolchildren were vaccinated, it is possible that herd immunity against influenza was achieved in Japan. If this was the case, both the incidence of influenza and mortality attributed to influenza should have been reduced among older persons.
METHODS: We analyzed the monthly rates of death from all causes and death attributed to pneumonia and influenza, as well as census data and statistics on the rates of vaccination for both Japan and the United States from 1949 through 1998. For each winter, we estimated the number of deaths per month in excess of a base-line level, defined as the average death rate in November.
RESULTS: The excess mortality from pneumonia and influenza and that from all causes were highly correlated in each country. In the United States, these rates were nearly constant over time. With the initiation of the vaccination program for schoolchildren in Japan, excess mortality rates dropped from values three to four times those in the United States to values similar to those in the United States. The vaccination of Japanese children prevented about 37,000 to 49,000 deaths per year, or about 1 death for every 420 children vaccinated. As the vaccination of schoolchildren was discontinued, the excess mortality rates in Japan increased.
CONCLUSIONS: The effect of influenza on mortality is much greater in Japan than in the United States and can be measured about equally well in terms of deaths from all causes and deaths attributed to pneumonia or influenza. Vaccinating schoolchildren against influenza provides protection and reduces mortality from influenza among older persons.

PMID 11259722  N Engl J Med. 2001 Mar 22;344(12):889-96. doi: 10.1056/・・・
著者: Joon Young Song, Hee Jin Cheong, In Sook Hwang, Won Suk Choi, Yu Mi Jo, Dae Won Park, Geum Joo Cho, Taik Gun Hwang, Woo Joo Kim
雑誌名: Vaccine. 2010 May 21;28(23):3929-35. doi: 10.1016/j.vaccine.2010.03.067. Epub 2010 Apr 13.
Abstract/Text The elderly have been considered as the priority group for influenza vaccination, but their influenza vaccine-induced antibody was believed to decline more rapidly. Long-term immunogenicity of the influenza vaccine among the elderly was evaluated as compared to young adults. Serum hemagglutinin inhibition (HI) titers were determined at pre- and post-vaccination periods (at 1, 6, and 12 months after vaccination). Of the 1018 subjects, 716 (70.3%) were followed up during a 12-month period. Seroprotection rates at 1 month post-vaccination ranged from 70.1% to 90.3% depending on the age group and influenza vaccine virus strain. At 6 months post-vaccination, seroprotection rates for all three strains had declined significantly in adults >or=65 years (P<0.01), but still met the EMEA criteria. Low pre-vaccination HI titer (<1:40) and advanced age were associated with early decline of HI titers, falling below seroprotective levels around 6 months after vaccination.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20394719  Vaccine. 2010 May 21;28(23):3929-35. doi: 10.1016/j.vac・・・
著者: William Schaffner, Wilbur H Chen, Robert H Hopkins, Kathleen Neuzil
雑誌名: Am J Med. 2018 Aug;131(8):865-873. doi: 10.1016/j.amjmed.2018.02.019. Epub 2018 Mar 12.
Abstract/Text The 2017-2018 influenza season reminds us that it is important for health care professionals to be prepared for the annual onslaught of this contagious respiratory disease associated with potentially serious complications. Vaccination is by far the best method to prevent and control influenza, reducing illness, hospitalizations, and mortality. The highest rates of influenza-associated morbidity and mortality are observed in older adults. The immune function of older adults decreases with increasing age, a phenomenon termed immunosenescence. Immunosenescence not only confers increased susceptibility to influenza disease, but also renders vaccination less effective. To address the need for improved vaccines that provide enhanced protection to this high-risk group, 2 formulations-a high-dose vaccine and an adjuvanted vaccine-have been approved in recent years specifically for people aged 65 years and over. Here we discuss: the challenges of influenza immunization in those 65 years and older; the recent advancements in vaccines targeted at this age group; and the latest influenza vaccine recommendations for the 2017-2018 influenza season in the United States.

Copyright © 2018 Elsevier Inc. All rights reserved.
PMID 29544989  Am J Med. 2018 Aug;131(8):865-873. doi: 10.1016/j.amjme・・・
著者: Jeffrey C Kwong, Hannah Chung, James Kh Jung, Sarah A Buchan, Aaron Campigotto, Michael A Campitelli, Natasha S Crowcroft, Jonathan B Gubbay, Timothy Karnauchow, Kevin Katz, Allison J McGeer, J Dayre McNally, David C Richardson, Susan E Richardson, Laura C Rosella, Kevin L Schwartz, Andrew Simor, Marek Smieja, George Zahariadis, On Behalf Of The Canadian Immunization Research Network Cirn Investigators
雑誌名: Euro Surveill. 2020 Jan;25(1). doi: 10.2807/1560-7917.ES.2020.25.1.1900245.
Abstract/Text IntroductionAnnual influenza vaccination is recommended for older adults, but evidence regarding the impact of repeated vaccination has been inconclusive.AimWe investigated vaccine effectiveness (VE) against laboratory-confirmed influenza and the impact of repeated vaccination over 10 previous seasons on current season VE among older adults.MethodsWe conducted an observational test-negative study in community-dwelling adults aged > 65 years in Ontario, Canada for the 2010/11 to 2015/16 seasons by linking laboratory and health administrative data. We estimated VE using multivariable logistic regression. We assessed the impact of repeated vaccination by stratifying by previous vaccination history.ResultsWe included 58,304 testing episodes for respiratory viruses, with 11,496 (20%) testing positive for influenza and 31,004 (53%) vaccinated. Adjusted VE against laboratory-confirmed influenza for the six seasons combined was 21% (95% confidence interval (CI): 18 to 24%). Patients who were vaccinated in the current season, but had received no vaccinations in the previous 10 seasons, had higher current season VE (34%; 95%CI: 9 to 52%) than patients who had received 1-3 (26%; 95%CI: 13 to 37%), 4-6 (24%; 95%CI: 15 to 33%), 7-8 (13%; 95%CI: 2 to 22%), or 9-10 (7%; 95%CI: -4 to 16%) vaccinations (trend test p = 0.001). All estimates were higher after correcting for misclassification of current season vaccination status. For patients who were not vaccinated in the current season, residual protection rose significantly with increasing numbers of vaccinations received previously.ConclusionsAlthough VE appeared to decrease with increasing numbers of previous vaccinations, current season vaccination likely provides some protection against influenza regardless of the number of vaccinations received over the previous 10 influenza seasons.

PMID 31937397  Euro Surveill. 2020 Jan;25(1). doi: 10.2807/1560-7917.E・・・
著者: Huong Q McLean, Mark G Thompson, Maria E Sundaram, Jennifer K Meece, David L McClure, Thomas C Friedrich, Edward A Belongia
雑誌名: Clin Infect Dis. 2014 Nov 15;59(10):1375-85. doi: 10.1093/cid/ciu680. Epub 2014 Sep 29.
Abstract/Text BACKGROUND: Recent studies suggest that influenza vaccination in the previous season may influence the effectiveness of current-season vaccination, but this has not been assessed in a single population over multiple years.
METHODS: Patients presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2012-2013 influenza seasons. Respiratory swabs were tested for influenza and vaccination dates obtained from a validated registry. Vaccination status was determined for the current, previous, and prior 5 seasons. Vaccine effectiveness (VE) was calculated for participants aged ≥9 years using logistic regression models with an interaction term for vaccination history.
RESULTS: There were 7315 enrollments during 8 seasons; 1056 (14%) and 650 (9%) were positive for influenza A(H3N2) and B, respectively. Vaccination during current only, previous only, or both seasons yielded similar protection against H3N2 (adjusted VE range, 31%-36%) and B (52%-66%). In the analysis using 5 years of historical vaccination data, current season VE against H3N2 was significantly higher among vaccinated individuals with no prior vaccination history (65%; 95% confidence interval [CI], 36%-80%) compared with vaccinated individuals with a frequent vaccination history (24%; 95% CI, 3%-41%; P = .01). VE against B was 75% (95% CI, 50%-87%) and 48% (95% CI, 29%-62%), respectively (P = .05). Similar findings were observed when analysis was restricted to adults 18-49 years.
CONCLUSIONS: Current- and previous-season vaccination generated similar levels of protection, and vaccine-induced protection was greatest for individuals not vaccinated during the prior 5 years. Additional studies are needed to understand the long-term effects of annual vaccination.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
PMID 25270645  Clin Infect Dis. 2014 Nov 15;59(10):1375-85. doi: 10.10・・・
著者: Vittorio Demicheli, Tom Jefferson, Eliana Ferroni, Alessandro Rivetti, Carlo Di Pietrantonj
雑誌名: Cochrane Database Syst Rev. 2018 Feb 1;2:CD001269. doi: 10.1002/14651858.CD001269.pub6. Epub 2018 Feb 1.
Abstract/Text BACKGROUND: The consequences of influenza in adults are mainly time off work. Vaccination of pregnant women is recommended internationally. This is an update of a review published in 2014. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated due to their lack of influence on the review conclusions.
OBJECTIVES: To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in healthy adults, including pregnant women.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12), MEDLINE (January 1966 to 31 December 2016), Embase (1990 to 31 December 2016), the WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017), and ClinicalTrials.gov (1 July 2017), as well as checking the bibliographies of retrieved articles.
SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy individuals aged 16 to 65 years. Previous versions of this review included observational comparative studies assessing serious and rare harms cohort and case-control studies. Due to the uncertain quality of observational (i.e. non-randomised) studies and their lack of influence on the review conclusions, we decided to update only randomised evidence. The searches for observational comparative studies are no longer updated.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We rated certainty of evidence for key outcomes (influenza, influenza-like illness (ILI), hospitalisation, and adverse effects) using GRADE.
MAIN RESULTS: We included 52 clinical trials of over 80,000 people assessing the safety and effectiveness of influenza vaccines. We have presented findings from 25 studies comparing inactivated parenteral influenza vaccine against placebo or do-nothing control groups as the most relevant to decision-making. The studies were conducted over single influenza seasons in North America, South America, and Europe between 1969 and 2009. We did not consider studies at high risk of bias to influence the results of our outcomes except for hospitalisation.Inactivated influenza vaccines probably reduce influenza in healthy adults from 2.3% without vaccination to 0.9% (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.36 to 0.47; 71,221 participants; moderate-certainty evidence), and they probably reduce ILI from 21.5% to 18.1% (RR 0.84, 95% CI 0.75 to 0.95; 25,795 participants; moderate-certainty evidence; 71 healthy adults need to be vaccinated to prevent one of them experiencing influenza, and 29 healthy adults need to be vaccinated to prevent one of them experiencing an ILI). The difference between the two number needed to vaccinate (NNV) values depends on the different incidence of ILI and confirmed influenza among the study populations. Vaccination may lead to a small reduction in the risk of hospitalisation in healthy adults, from 14.7% to 14.1%, but the CI is wide and does not rule out a large benefit (RR 0.96, 95% CI 0.85 to 1.08; 11,924 participants; low-certainty evidence). Vaccines may lead to little or no small reduction in days off work (-0.04 days, 95% CI -0.14 days to 0.06; low-certainty evidence). Inactivated vaccines cause an increase in fever from 1.5% to 2.3%.We identified one RCT and one controlled clinical trial assessing the effects of vaccination in pregnant women. The efficacy of inactivated vaccine containing pH1N1 against influenza was 50% (95% CI 14% to 71%) in mothers (NNV 55), and 49% (95% CI 12% to 70%) in infants up to 24 weeks (NNV 56). No data were available on efficacy against seasonal influenza during pregnancy. Evidence from observational studies showed effectiveness of influenza vaccines against ILI in pregnant women to be 24% (95% CI 11% to 36%, NNV 94), and against influenza in newborns from vaccinated women to be 41% (95% CI 6% to 63%, NNV 27).Live aerosol vaccines have an overall effectiveness corresponding to an NNV of 46. The performance of one- or two-dose whole-virion 1968 to 1969 pandemic vaccines was higher (NNV 16) against ILI and (NNV 35) against influenza. There was limited impact on hospitalisations in the 1968 to 1969 pandemic (NNV 94). The administration of both seasonal and 2009 pandemic vaccines during pregnancy had no significant effect on abortion or neonatal death, but this was based on observational data sets.
AUTHORS' CONCLUSIONS: Healthy adults who receive inactivated parenteral influenza vaccine rather than no vaccine probably experience less influenza, from just over 2% to just under 1% (moderate-certainty evidence). They also probably experience less ILI following vaccination, but the degree of benefit when expressed in absolute terms varied across different settings. Variation in protection against ILI may be due in part to inconsistent symptom classification. Certainty of evidence for the small reductions in hospitalisations and time off work is low. Protection against influenza and ILI in mothers and newborns was smaller than the effects seen in other populations considered in this review.Vaccines increase the risk of a number of adverse events, including a small increase in fever, but rates of nausea and vomiting are uncertain. The protective effect of vaccination in pregnant women and newborns is also very modest. We did not find any evidence of an association between influenza vaccination and serious adverse events in the comparative studies considered in this review. Fifteen included RCTs were industry funded (29%).

PMID 29388196  Cochrane Database Syst Rev. 2018 Feb 1;2:CD001269. doi:・・・
著者: Vittorio Demicheli, Tom Jefferson, Carlo Di Pietrantonj, Eliana Ferroni, Sarah Thorning, Roger E Thomas, Alessandro Rivetti
雑誌名: Cochrane Database Syst Rev. 2018 Feb 1;2:CD004876. doi: 10.1002/14651858.CD004876.pub4. Epub 2018 Feb 1.
Abstract/Text BACKGROUND: The consequences of influenza in the elderly (those age 65 years or older) are complications, hospitalisations, and death. The primary goal of influenza vaccination in the elderly is to reduce the risk of death among people who are most vulnerable. This is an update of a review published in 2010. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated because of their lack of influence on the review conclusions.
OBJECTIVES: To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in the elderly.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 11), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register; MEDLINE (1966 to 31 December 2016); Embase (1974 to 31 December 2016); Web of Science (1974 to 31 December 2016); CINAHL (1981 to 31 December 2016); LILACS (1982 to 31 December 2016); WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017); and ClinicalTrials.gov (1 July 2017).
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. We considered any influenza vaccine given independently, in any dose, preparation, or time schedule, compared with placebo or with no intervention. Previous versions of this review included 67 cohort and case-control studies. The searches for these trial designs are no longer updated.
DATA COLLECTION AND ANALYSIS: Review authors independently assessed risk of bias and extracted data. We rated the certainty of evidence with GRADE for the key outcomes of influenza, ILI, complications (hospitalisation, pneumonia), and adverse events. We have presented aggregate control group risks to illustrate the effect in absolute terms. We used them as the basis for calculating the number needed to vaccinate to prevent one case of each event for influenza and ILI outcomes.
MAIN RESULTS: We identified eight RCTs (over 5000 participants), of which four assessed harms. The studies were conducted in community and residential care settings in Europe and the USA between 1965 and 2000. Risk of bias reduced our certainty in the findings for influenza and ILI, but not for other outcomes.Older adults receiving the influenza vaccine may experience less influenza over a single season compared with placebo, from 6% to 2.4% (risk ratio (RR) 0.42, 95% confidence interval (CI) 0.27 to 0.66; low-certainty evidence). We rated the evidence as low certainty due to uncertainty over how influenza was diagnosed. Older adults probably experience less ILI compared with those who do not receive a vaccination over the course of a single influenza season (3.5% versus 6%; RR 0.59, 95% CI 0.47 to 0.73; moderate-certainty evidence). These results indicate that 30 people would need to be vaccinated to prevent one person experiencing influenza, and 42 would need to be vaccinated to prevent one person having an ILI.The study providing data for mortality and pneumonia was underpowered to detect differences in these outcomes. There were 3 deaths from 522 participants in the vaccination arm and 1 death from 177 participants in the placebo arm, providing very low-certainty evidence for the effect on mortality (RR 1.02, 95% CI 0.11 to 9.72). No cases of pneumonia occurred in one study that reported this outcome (very low-certainty evidence). No data on hospitalisations were reported. Confidence intervaIs around the effect of vaccines on fever and nausea were wide, and we do not have enough information about these harms in older people (fever: 1.6% with placebo compared with 2.5% after vaccination (RR 1.57, 0.92 to 2.71; moderate-certainty evidence)); nausea (2.4% with placebo compared with 4.2% after vaccination (RR 1.75, 95% CI 0.74 to 4.12; low-certainty evidence)).
AUTHORS' CONCLUSIONS: Older adults receiving the influenza vaccine may have a lower risk of influenza (from 6% to 2.4%), and probably have a lower risk of ILI compared with those who do not receive a vaccination over the course of a single influenza season (from 6% to 3.5%). We are uncertain how big a difference these vaccines will make across different seasons. Very few deaths occurred, and no data on hospitalisation were reported. No cases of pneumonia occurred in one study that reported this outcome. We do not have enough information to assess harms relating to fever and nausea in this population.The evidence for a lower risk of influenza and ILI with vaccination is limited by biases in the design or conduct of the studies. Lack of detail regarding the methods used to confirm the diagnosis of influenza limits the applicability of this result. The available evidence relating to complications is of poor quality, insufficient, or old and provides no clear guidance for public health regarding the safety, efficacy, or effectiveness of influenza vaccines for people aged 65 years or older. Society should invest in research on a new generation of influenza vaccines for the elderly.

PMID 29388197  Cochrane Database Syst Rev. 2018 Feb 1;2:CD004876. doi:・・・
著者: Mark G Thompson, Nevil Pierse, Q Sue Huang, Namrata Prasad, Jazmin Duque, E Claire Newbern, Michael G Baker, Nikki Turner, Colin McArthur, SHIVERS investigation team
雑誌名: Vaccine. 2018 Sep 18;36(39):5916-5925. doi: 10.1016/j.vaccine.2018.07.028. Epub 2018 Aug 1.
Abstract/Text BACKGROUND: Little is known about inactivated influenza vaccine effectiveness (IVE) in preventing very severe disease, including influenza-associated intensive care unit (ICU) admissions.
METHODS: The Southern Hemisphere Influenza and Vaccine Effectiveness Research and Surveillance (SHIVERS) project enrolled adults (aged ≥ 18 years) with acute respiratory illness (ARI) in general ward (GW) hospital settings (n = 3034) and ICUs (n = 101) during 2012-2015. IVE was assessed using a test-negative design comparing the odds of influenza vaccination among influenza positives vs. negatives (confirmed by real-time reverse transcription polymerase chain reaction). All models were adjusted for season, weeks from season peak, and a vaccination propensity score.
RESULTS: Influenza virus infection was confirmed in 28% of GW hospital and 41% of ICU patients; influenza vaccination was documented for 56% and 41%, respectively. Across seasons, IVE was 37% (95% confidence intervals [CI] = 23-48%) among GW patients and 82% (95% CI = 45-94%) among ICU patients. IVE point estimates were > 70% against ICU influenza and consistently higher than IVE against GW influenza when stratified by season, by virus (sub)types, and for adults with or without chronic medical conditions and for both adults aged <65 and ≥65 years old. Among hospitalized influenza positives, influenza vaccination was associated with a 59% reduction in the odds of ICU admission (aOR = 0.41, 95% CI = 0.18-0.96) and with shorter ICU lengths of stay (LOS), but not with radiograph-confirmed pneumonia or GW hospital LOS.
CONCLUSION: Inactivated influenza vaccines prevented influenza-associated ICU admissions, may have higher effectiveness in ICU than GW hospital settings, and appeared to reduce the risk of severe disease among those who are infected despite vaccination.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 30077480  Vaccine. 2018 Sep 18;36(39):5916-5925. doi: 10.1016/j.v・・・
著者: Edward A Belongia, Melissa D Simpson, Jennifer P King, Maria E Sundaram, Nicholas S Kelley, Michael T Osterholm, Huong Q McLean
雑誌名: Lancet Infect Dis. 2016 Aug;16(8):942-51. doi: 10.1016/S1473-3099(16)00129-8. Epub 2016 Apr 6.
Abstract/Text BACKGROUND: Influenza vaccine effectiveness (VE) can vary by type and subtype. Over the past decade, the test-negative design has emerged as a valid method for estimation of VE. In this design, VE is calculated as 100% × (1 - odds ratio) for vaccine receipt in influenza cases versus test-negative controls. We did a systematic review and meta-analysis to estimate VE by type and subtype.
METHODS: In this systematic review and meta-analysis, we searched PubMed and Embase from Jan 1, 2004, to March 31, 2015. Test-negative design studies of influenza VE were eligible if they enrolled outpatients on the basis of predefined illness criteria, reported subtype-level VE by season, used PCR to confirm influenza, and adjusted for age. We excluded studies restricted to hospitalised patients or special populations, duplicate reports, interim reports superseded by a final report, studies of live-attenuated vaccine, and studies of prepandemic seasonal vaccine against H1N1pdm09. Two reviewers independently assessed titles and abstracts to identify articles for full review. Discrepancies in inclusion and exclusion criteria and VE estimates were adjudicated by consensus. Outcomes were VE against H3N2, H1N1pdm09, H1N1 (pre-2009), and type B. We calculated pooled VE using a random-effects model.
FINDINGS: We identified 3368 unduplicated publications, selected 142 for full review, and included 56 in the meta-analysis. Pooled VE was 33% (95% CI 26-39; I(2)=44·4) for H3N2, 54% (46-61; I(2)=61·3) for type B, 61% (57-65; I(2)=0·0) for H1N1pdm09, and 67% (29-85; I(2)=57·6) for H1N1; VE was 73% (61-81; I(2)=31·4) for monovalent vaccine against H1N1pdm09. VE against H3N2 for antigenically matched viruses was 33% (22-43; I(2)=56·1) and for variant viruses was 23% (2-40; I(2)=55·6). Among older adults (aged >60 years), pooled VE was 24% (-6 to 45; I(2)=17·6) for H3N2, 63% (33-79; I(2)=0·0) for type B, and 62% (36-78; I(2)=0·0) for H1N1pdm09.
INTERPRETATION: Influenza vaccines provided substantial protection against H1N1pdm09, H1N1 (pre-2009), and type B, and reduced protection against H3N2. Vaccine improvements are needed to generate greater protection against H3N2 than with current vaccines.
FUNDING: None.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27061888  Lancet Infect Dis. 2016 Aug;16(8):942-51. doi: 10.1016/・・・
著者: Marc Rondy, Nathalie El Omeiri, Mark G Thompson, Alain Levêque, Alain Moren, Sheena G Sullivan
雑誌名: J Infect. 2017 Nov;75(5):381-394. doi: 10.1016/j.jinf.2017.09.010. Epub 2017 Sep 18.
Abstract/Text OBJECTIVES: Summary evidence of influenza vaccine effectiveness (IVE) against hospitalized influenza is lacking. We conducted a meta-analysis of studies reporting IVE against laboratory-confirmed hospitalized influenza among adults.
METHODS: We searched Pubmed (January 2009 to November 2016) for studies that used test-negative design (TND) to enrol patients hospitalized with influenza-associated conditions. Two independent authors selected relevant articles. We calculated pooled IVE against any and (sub)type specific influenza among all adults, and stratified by age group (18-64 and 65 years and above) using random-effects models.
RESULTS: We identified 3411 publications and 30 met our inclusion criteria. Between 2010-11 and 2014-15, the pooled seasonal IVE was 41% (95%CI:34;48) for any influenza (51% (95%CI:44;58) among people aged 18-64y and 37% (95%CI:30;44) among ≥65 years). IVE was 48% (95%CI:37;59),37% (95%CI:24;50) and 38% (95%CI:23;53) against influenza A(H1N1)pdm09, A(H3N2) and B, respectively. Among persons aged ≥65 year, IVE against A(H3N2) was 43% (95%CI:33;53) in seasons when circulating and vaccine strains were antigenically similar and 14% (95%CI:-3;30) when A(H3N2) variant viruses predominated.
CONCLUSIONS: Influenza vaccines provided moderate protection against influenza-associated hospitalizations among adults. They seemed to provide low protection among elderly in seasons where vaccine and circulating A(H3N2) strains were antigenically variant.

Copyright © 2017 The British Infection Association. All rights reserved.
PMID 28935236  J Infect. 2017 Nov;75(5):381-394. doi: 10.1016/j.jinf.2・・・
著者: Michael T Osterholm, Nicholas S Kelley, Alfred Sommer, Edward A Belongia
雑誌名: Lancet Infect Dis. 2012 Jan;12(1):36-44. doi: 10.1016/S1473-3099(11)70295-X. Epub 2011 Oct 25.
Abstract/Text BACKGROUND: No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza.
METHODS: We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups).
FINDINGS: We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51-67] in adults aged 18-65 years). No such trials met inclusion criteria for children aged 2-17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69-91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8-17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60-93).
INTERPRETATION: Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality.
FUNDING: Alfred P Sloan Foundation.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22032844  Lancet Infect Dis. 2012 Jan;12(1):36-44. doi: 10.1016/S・・・
著者: Maryam Darvishian, Edwin R van den Heuvel, Ange Bissielo, Jesus Castilla, Cheryl Cohen, Helene Englund, Giedre Gefenaite, Wan-Ting Huang, Sacha la Bastide-van Gemert, Iván Martinez-Baz, Johanna M McAnerney, Genevie M Ntshoe, Motoi Suzuki, Nikki Turner, Eelko Hak
雑誌名: Lancet Respir Med. 2017 Mar;5(3):200-211. doi: 10.1016/S2213-2600(17)30043-7. Epub 2017 Feb 9.
Abstract/Text BACKGROUND: Several aggregate data meta-analyses have provided estimates of the effectiveness of influenza vaccination in community-dwelling elderly people. However, these studies ignored the effects of patient-level confounders such as sex, age, and chronic diseases that could bias effectiveness estimates. We aimed to assess the confounder-adjusted effectiveness of influenza vaccines on laboratory-confirmed influenza among elderly people by conducting a global individual participant data meta-analysis.
METHODS: In this individual participant data meta-analysis, we considered studies included in a previously conducted aggregate data meta-analysis that included test-negative design case-control studies published up to July 13, 2014. We contacted all authors of the included studies on Dec 1, 2014, to request individual participant data. Patients were excluded if their unique identifier was missing, their vaccination status was unknown, their outcome status was unknown, or they had had suspected influenza infection more than once in the same influenza season. Cases were patients with influenza-like illness symptoms who tested positive for at least one of A H1N1, A H1N1 pdm09, A H3N2, or B viruses; controls were patients with influenza-like illness symptoms who tested negative for these virus types or subtypes. Influenza vaccine effectiveness against overall and subtype-specific laboratory-confirmed influenza were the primary and secondary outcomes. We used a generalised linear mixed model to calculate adjusted vaccine effectiveness according to vaccine match to the circulating strains of influenza virus and intensity of the virus activity (epidemic or non-epidemic). Vaccine effectiveness was defined as the relative reduction in risk of laboratory-confirmed influenza in vaccinated patients compared with unvaccinated patients. We did subgroup analyses to estimate vaccine effectiveness according to hemisphere, age category, and health status.
FINDINGS: We received 23 of the 53 datasets included in the aggregate data meta-analysis. Furthermore, six additional datasets were provided by data collaborators, which resulted in individual participant data for a total of 5210 participants. A total of 4975 patients had the required data for analysis. Of these, 3146 (63%) were controls and 1829 (37%) were cases. Influenza vaccination was significantly effective during epidemic seasons irrespective of vaccine match status (matched adjusted vaccine effectiveness 44·38%, 95% CI 22·63-60·01; mismatched adjusted vaccine effectiveness 20·00%, 95% CI 3·46-33·68; analyses in the imputed dataset). Seasonal influenza vaccination did not show significant effectiveness during non-epidemic seasons. We found substantial variation in vaccine effectiveness across virus types and subtypes, with the highest estimate for A H1N1 pdm09 (53·19%, 10·25-75·58) and the lowest estimate for B virus types (-1·52%, -39·58 to 26·16). Although we observed no significant differences between subgroups in each category (hemisphere, age, and health status), influenza vaccination showed a protective effect among elderly people with cardiovascular disease, lung disease, or aged 75 years and younger.
INTERPRETATION: Influenza vaccination is moderately effective against laboratory-confirmed influenza in elderly people during epidemic seasons. More research is needed to investigate factors affecting vaccine protection (eg, brand-specific or type-specific vaccine effectiveness and repeated annual vaccination) in elderly people.
FUNDING: University Medical Center Groningen.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28189522  Lancet Respir Med. 2017 Mar;5(3):200-211. doi: 10.1016/・・・
著者: Carlos A DiazGranados, Andrew J Dunning, Murray Kimmel, Daniel Kirby, John Treanor, Avi Collins, Richard Pollak, Janet Christoff, John Earl, Victoria Landolfi, Earl Martin, Sanjay Gurunathan, Richard Nathan, David P Greenberg, Nadia G Tornieporth, Michael D Decker, H Keipp Talbot
雑誌名: N Engl J Med. 2014 Aug 14;371(7):635-45. doi: 10.1056/NEJMoa1315727.
Abstract/Text BACKGROUND: As compared with a standard-dose vaccine, a high-dose, trivalent, inactivated influenza vaccine (IIV3-HD) improves antibody responses to influenza among adults 65 years of age or older. This study evaluated whether IIV3-HD also improves protection against laboratory-confirmed influenza illness.
METHODS: We conducted a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial to compare IIV3-HD (60 μg of hemagglutinin per strain) with standard-dose trivalent, inactivated influenza vaccine (IIV3-SD [15 μg of hemagglutinin per strain]) in adults 65 years of age or older. Assessments of relative efficacy, effectiveness, safety (serious adverse events), and immunogenicity (hemagglutination-inhibition [HAI] titers) were performed during the 2011-2012 (year 1) and the 2012-2013 (year 2) northern-hemisphere influenza seasons.
RESULTS: A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada (15,991 were randomly assigned to receive IIV3-HD, and 15,998 to receive IIV3-SD). In the intention-to-treat analysis, 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol-defined influenza-like illness (relative efficacy, 24.2%; 95% confidence interval [CI], 9.7 to 36.5). At least one serious adverse event during the safety surveillance period was reported by 1323 (8.3%) of the participants in the IIV3-HD group, as compared with 1442 (9.0%) of the participants in the IIV3-SD group (relative risk, 0.92; 95% CI, 0.85 to 0.99). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥ 1:40) were significantly higher in the IIV3-HD group. Conclusions: Among persons 65 years of age or older, IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01427309.).

PMID 25119609  N Engl J Med. 2014 Aug 14;371(7):635-45. doi: 10.1056/N・・・
著者: Krista Wilkinson, Yichun Wei, Andrea Szwajcer, Rasheda Rabbani, Ryan Zarychanski, Ahmed M Abou-Setta, Salaheddin M Mahmud
雑誌名: Vaccine. 2017 May 15;35(21):2775-2780. doi: 10.1016/j.vaccine.2017.03.092. Epub 2017 Apr 18.
Abstract/Text INTRODUCTION: Older adults are prioritized for influenza vaccination but also have lowered antibody responses to the vaccine. Higher-doses of influenza antigen may increase immune response and thus be more effective. Our objectives were to compare the efficacy and safety of the high-dose influenza vaccine to the standard-dose influenza vaccine in the elderly (age>65).
METHODS: Data sources: Randomized trials (RCTs) from Medline (Ovid), EMBASE (Ovid), Cochrane Library (Wiley), ClinicalTrials.gov, reference lists of relevant articles, and gray literature.
STUDY SELECTION: Two reviewers independently identified RCTs comparing high-dose influenza vaccine (60μg of hemagglutinin per strain) to standard-dose influenza vaccine (15μg of hemagglutinin per strain) in adults over the age of 65years.
DATA EXTRACTION: Two reviewers independently extracted trial-level data including population characteristics, interventions, outcomes, and funding sources. Risk of bias was assessed using the Cochrane Risk of Bias tool.
RESULTS: We included seven eligible trials; all were categorized as having a low (n=3) or unclear (n=4) risk of bias. Patients receiving the high-dose vaccine had significantly less risk of developing laboratory-confirmed influenza infections (Relative Risk 0.76, 95%CI 0.65 to 0.90; I2 0%, 2 trials, 41,141 patients). Post-vaccination geometric mean titres and seroprotection rates were also higher in high-dose vaccine recipients. There were no protocol-defined serious adverse events in the included trials in either group.
CONCLUSIONS: In elderly adults, the high-dose influenza vaccine was well-tolerated, more immunogenic, and more efficacious in preventing influenza infections than the standard-dose vaccine. Further pragmatic trials are needed to determine if the higher efficacy translates into higher vaccine effectiveness in adults over the age of 65.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28431815  Vaccine. 2017 May 15;35(21):2775-2780. doi: 10.1016/j.v・・・
著者: Barbara Camilloni, Michela Basileo, Stefano Valente, Emilia Nunzi, Anna Maria Iorio
雑誌名: Hum Vaccin Immunother. 2015;11(3):553-63. doi: 10.1080/21645515.2015.1011562.
Abstract/Text Because of the age-related immune system decline, 2 potentiated influenza vaccines were specifically licensed for the elderly: Fluad(®), an MF59-adjuvanted vaccine administered intramuscularly (IM-MF59), and Intanza 15 mcg(®), a non adjuvanted vaccine administered intradermally (ID). The objective of this paper was to conduct a systematic review of studies that evaluated antibody responses in the elderly following immunization with IM-MF59 or ID vaccines. The two potentiated vaccines induced immune responses satisfying, in most instances, the European Medicine Agency immunogenicity criteria, both against vaccine antigens and heterovariant drifted strains. Considering pooled data reported in the articles analyzed and papers directly comparing the 2 vaccines, the antibody responses elicited by IM-MF59 and ID were found to be generally comparable. The use of IM-MF59 and ID vaccines can be proposed as an appropriate strategy for elderly seasonal influenza vaccination although further studies are required for a more complete characterization of the 2 vaccines.

PMID 25714138  Hum Vaccin Immunother. 2015;11(3):553-63. doi: 10.1080/・・・
著者: Alexander Domnich, Lucia Arata, Daniela Amicizia, Joan Puig-Barberà, Roberto Gasparini, Donatella Panatto
雑誌名: Vaccine. 2017 Jan 23;35(4):513-520. doi: 10.1016/j.vaccine.2016.12.011. Epub 2016 Dec 23.
Abstract/Text BACKGROUND: In the elderly, traditional influenza inactivated vaccines are often only modestly immunogenic, owing to immunosenescence. Given that adjuvantation is a means of enhancing the immune response, the trivalent inactivated vaccine adjuvanted with MF59 (MF59-TIV) was specifically designed to overcome this problem. Considering that, for ethical reasons, the absolute effectiveness of an influenza vaccine in the elderly cannot be demonstrated in placebo-controlled studies, the present study aimed to assess the effectiveness of MF59-TIV in preventing influenza-related outcomes in the elderly.
METHODS: We conducted a systematic review of observational studies aimed at evaluating the effectiveness of MF59-TIV against influenza-related outcomes. Results of single studies were pooled whenever possible.
RESULTS: Of the 1993 papers screened, 11 (6 case-control, 3 cohort and 2 prospective case-control) studies were identified. Hospitalization due to pneumonia/influenza and laboratory-confirmed influenza were reported in more than one study, while other outcomes (influenza-like illness, cardio- and cerebrovascular accidents) were investigated only by one study each. Pooled analysis of four case-control studies showed an adjusted MF59-TIV effectiveness of 51% (95% CI: 39-61%) against hospitalizations for pneumonia/influenza among community-dwelling seniors. Pooled results of the adjusted vaccine effectiveness against laboratory-confirmed influenza were also high (60.1%), although the 95% CI passed through zero (-1.3 to 84.3%). Other single community-based studies showed very high effectiveness of MF59-TIV in preventing hospitalizations for acute coronary [87% (95% CI: 35-97%)] and cerebrovascular [93% (95% CI: 52-99%)] events. MF59-TIV proved highly effective [94% (95% CI: 47-100%] in reducing influenza-like illness among institutionalized elderly. Furthermore, MF59-TIV displayed greater efficacy than non-adjuvanted vaccines in preventing hospitalizations due to pneumonia/influenza [adjusted risk ratio 0.75 (95% CI: 0.57-0.98)] and laboratory-confirmed influenza [adjusted odds ratio 0.37 (0.14-0.96)].
CONCLUSIONS: Our results suggest that MF59-TIV is effective in reducing several influenza-related outcomes among the elderly, especially hospitalizations due to influenza-related complications.

Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
PMID 28024956  Vaccine. 2017 Jan 23;35(4):513-520. doi: 10.1016/j.vacc・・・
著者: Munehisa Fukusumi, Bin Chang, Yoshinari Tanabe, Kengo Oshima, Takaya Maruyama, Hiroshi Watanabe, Koji Kuronuma, Kei Kasahara, Hiroaki Takeda, Junichiro Nishi, Jiro Fujita, Tetsuya Kubota, Tomimasa Sunagawa, Tamano Matsui, Kazunori Oishi, Adult IPD Study Group
雑誌名: BMC Infect Dis. 2017 Jan 3;17(1):2. doi: 10.1186/s12879-016-2113-y. Epub 2017 Jan 3.
Abstract/Text BACKGROUND: In Japan, the clinical characteristics and recent serotype distribution among adult patients of invasive pneumococcal disease (IPD) have not been fully investigated since the introduction of the pneumococcal conjugate vaccine (PCV) in children. From November 2010, PCV7 was encouraged by an official program, funded by government, subsequently included in the routine schedule in April 2013, and replaced with a PCV13 in November 2013.
METHODS: Between April 2013 and March 2015, patients with IPD older than 15 years were evaluated based on the enhanced national surveillance in ten prefectures of Japan. The serotype distribution of the isolates was analyzed in these patients.
RESULTS: The analysis included 291 patients: 107 patients (37%) were female and the median age was 70 years. Of 281 patients with available data, 202 (72%) had underlying diseases, including 107 patients (38%) with immunocompromised status. The case fatality proportion for all case was 20%. In subgroup analysis, the case fatality proportion (29%) in immunocompromised patients was much higher than that (0-16%) in each age group of nonimmunocompromised patients (15-39 years, 40-64 years, and ≥ 65 years). While the proportion of bacteremia without any focus (27%) was higher than that (8-10%) in nonimmunocompromised patients, the proportions of vaccine types (PCV13, 32%; PPSV23, 51%) of the causative isolates were lower than those in each age group of nonimmunocompromised patients. Among 291 isolates, the most frequent serotypes were 3 (17%), 19A (13%), and 22F (10%). Twelve percent of the isolates were PCV7 serotypes, 46% were PCV13 serotypes, and 66% were PPSV23 serotypes.
CONCLUSIONS: The majority of adult patients of IPD had underlying diseases, including immunocompromised conditions. A low proportion (12%) of PCV7-type IPD was observed in this population where PCV7 for children had been included in the routine immunization schedule.

PMID 28049447  BMC Infect Dis. 2017 Jan 3;17(1):2. doi: 10.1186/s12879・・・
著者: Susan S Huang, Kristen M Johnson, G Thomas Ray, Peter Wroe, Tracy A Lieu, Matthew R Moore, Elizabeth R Zell, Jeffrey A Linder, Carlos G Grijalva, Joshua P Metlay, Jonathan A Finkelstein
雑誌名: Vaccine. 2011 Apr 18;29(18):3398-412. doi: 10.1016/j.vaccine.2011.02.088. Epub 2011 Mar 11.
Abstract/Text BACKGROUND: Streptococcus pneumoniae continues to cause a variety of common clinical syndromes, despite vaccination programs for both adults and children. The total U.S. burden of pneumococcal disease is unknown.
METHODS: We constructed a decision tree-based model to estimate U.S. healthcare utilization and costs of pneumococcal disease in 2004. Data were obtained from the 2004-2005 National (Hospital) Ambulatory Medical Care Surveys (outpatient visits, antibiotics) and the National Hospital Discharge Survey (hospitalization rates), and CDC surveillance data. Other assumptions regarding the incidence of each syndrome due to pneumococcus, expected health outcomes, and healthcare utilization were derived from literature and expert opinion. Healthcare and time costs used 2007 dollars.
RESULTS: We estimate that, in 2004, pneumococcal disease caused 4.0 million illness episodes, 22,000 deaths, 445,000 hospitalizations, 774,000 emergency department visits, 5.0 million outpatient visits, and 4.1 million outpatient antibiotic prescriptions. Direct medical costs totaled $3.5 billion. Pneumonia (866,000 cases) accounted for 22% of all cases and 72% of pneumococcal costs. In contrast, acute otitis media and sinusitis (1.5 million cases each) comprised 75% of cases but only 16% of direct medical costs. Patients ≥ 65 years old, accounted for most serious cases and the majority of direct medical costs ($1.8 billion in healthcare costs annually). In this age group, pneumonia caused 242,000 hospitalizations, 1.4 million hospital days, 194,000 emergency department visits, 374,000 outpatient visits, and 16,000 deaths. However, if work loss and productivity are considered, the cost of pneumococcal disease among younger working adults (18-<50) nearly equaled those ≥ 65.
CONCLUSIONS: Pneumococcal disease remains a substantial cause of morbidity and mortality even in the era of routine pediatric and adult vaccination. Continued efforts are warranted to reduce serious pneumococcal disease, especially adult pneumonia.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21397721  Vaccine. 2011 Apr 18;29(18):3398-412. doi: 10.1016/j.va・・・
著者: Nirma Khatri Vadlamudi, Kamalpreet Parhar, Kim Lorenzo Altre Malana, Amy Kang, Fawziah Marra
雑誌名: Vaccine. 2019 Feb 14;37(8):1021-1029. doi: 10.1016/j.vaccine.2019.01.014. Epub 2019 Jan 23.
Abstract/Text BACKGROUND: Despite the use of 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults there is substantial morbidity and mortality in the elderly due to pneumococcal infections. Since 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) is in use for infant immunization programs to reduce rates of pneumococcal disease, but is not routinely used in adults. Recent literature suggests PCV13 may be used in adult vaccination programs as well.
OBJECTIVE: To determine the immunogenicity and safety of PCV13 compared with the PPV23 in adults.
DESIGN: Systematic review and meta-analysis.
SETTING: Randomized controlled trials evaluating immunogenicity of a single dose of PCV13 and PPV23 in adults by the opsonophagocytic assay (OPA) geometric mean titer (GMT) response at 1-month post-vaccination were considered for inclusion.
RESULTS: Five randomized trials were included with 4561 subjects ranging 50-95.5 years, consisting of 51% females. The pooled OPA GMT ratio (GMTR) in the PCV13 arm was significantly higher for 10 of 13 serotypes (1, 4, 5, 6A, 6B, 9V, 18C, 19A, 19F and 23F) compared with the PPV23 arm. Overall, pooled risk ratios (RR) for local and systemic reactions did not differ between PCV13 and PPV23. Pneumococcal naïve subjects experienced significantly higher local reactions in the PCV13 arm compared with the PPV23 arm (RR: 1.15, 95%CI: 1.05-1.26, p = 0.0025).
CONCLUSION: A single dose of PCV13 elicits a better immune response among adults compared with PPV23, while having a similar safety profile to PPV23.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30685252  Vaccine. 2019 Feb 14;37(8):1021-1029. doi: 10.1016/j.va・・・
著者: Almea Matanock, Grace Lee, Ryan Gierke, Miwako Kobayashi, Andrew Leidner, Tamara Pilishvili
雑誌名: MMWR Morb Mortal Wkly Rep. 2019 Nov 22;68(46):1069-1075. doi: 10.15585/mmwr.mm6846a5. Epub 2019 Nov 22.
Abstract/Text Two pneumococcal vaccines are currently licensed for use in adults in the United States: a 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Pfizer, Inc.]) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax 23, Merck and Co., Inc.]). In 2014, the Advisory Committee on Immunization Practices (ACIP)* recommended routine use of PCV13 in series with PPSV23 for all adults aged ≥65 years based on demonstrated PCV13 safety and efficacy against PCV13-type pneumonia among adults aged ≥65 years (1). At that time, ACIP recognized that there would be a need to reevaluate this recommendation because it was anticipated that PCV13 use in children would continue to reduce disease burden among adults through reduced carriage and transmission of vaccine serotypes from vaccinated children (i.e., PCV13 indirect effects). On June 26, 2019, after having reviewed the evidence accrued during the preceding 3 years (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html), ACIP voted to remove the recommendation for routine PCV13 use among adults aged ≥65 years and to recommend administration of PCV13 based on shared clinical decision-making for adults aged ≥65 years who do not have an immunocompromising condition,† cerebrospinal fluid (CSF) leak, or cochlear implant, and who have not previously received PCV13. ACIP recognized that some adults aged ≥65 years are potentially at increased risk for exposure to PCV13 serotypes, such as persons residing in nursing homes or other long-term care facilities and persons residing in settings with low pediatric PCV13 uptake or traveling to settings with no pediatric PCV13 program, and might attain higher than average benefit from PCV13 vaccination. When patients and vaccine providers§ engage in shared clinical decision-making for PCV13 use to determine whether PCV13 is right for a particular person, considerations might include both the person's risk for exposure to PCV13 serotypes and their risk for developing pneumococcal disease as a result of underlying medical conditions. All adults aged ≥65 years should continue to receive 1 dose of PPSV23. If the decision is made to administer PCV13, it should be given at least 1 year before PPSV23. ACIP continues to recommend PCV13 in series with PPSV23 for adults aged ≥19 years with an immunocompromising condition, CSF leak, or cochlear implant (2).

PMID 31751323  MMWR Morb Mortal Wkly Rep. 2019 Nov 22;68(46):1069-1075・・・
著者: Katherine L O'Brien, Michael Hochman, David Goldblatt
雑誌名: Lancet Infect Dis. 2007 Sep;7(9):597-606. doi: 10.1016/S1473-3099(07)70210-4.
Abstract/Text Streptococcus pneumoniae is a major cause of morbidity and mortality in children less than 5 years of age. Prevention of pneumococcal disease and death in children in the developing world through vaccination with recently developed, highly efficacious pneumococcal conjugate vaccines (PCVs) is now possible. Schedules combining PCV with 23-valent pneumococcal polysaccharide vaccine (PPV23) have been studied and proposed as a means to expand disease protection against serotypes not included in the PCVs. Studies of group A and C meningococcal polysaccharide vaccine and repeated doses of PPV23 in adults and children have shown that a state of immune tolerance, or hyporesponsiveness, can develop to repeated polysaccharide vaccine antigen exposures. In this Review, we describe the evidence for and against this hyporesponsiveness and explore the possible mechanisms for such an occurrence.

PMID 17714673  Lancet Infect Dis. 2007 Sep;7(9):597-606. doi: 10.1016/・・・
著者: Laura L Hammitt, Lisa R Bulkow, Rosalyn J Singleton, J Pekka Nuorti, Kim Boyd Hummel, Karen M Miernyk, Carolyn Zanis, Melissa Whaley, Sandra Romero-Steiner, Jay C Butler, Karen Rudolph, Thomas W Hennessy
雑誌名: Vaccine. 2011 Mar 9;29(12):2287-95. doi: 10.1016/j.vaccine.2011.01.029. Epub 2011 Jan 19.
Abstract/Text BACKGROUND: Older adults are at highest risk of invasive pneumococcal disease (IPD) and are recommended to receive vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23). Antibody concentrations decline following vaccination. We evaluated the immunogenicity and reactogenicity of revaccination and repeat revaccination.
METHODS: Adults aged 55-74 years were vaccinated with a 1st to 4th dose of PPV23. Participants were eligible for revaccination if a minimum of 6 years had passed since their last dose of PPV23. Blood collected on the day of vaccination and 30 days later was analyzed by ELISA for IgG to five serotypes. Functional antibody activity was measured using an opsonophagocytic killing (OPK) assay. Reactions to vaccination were documented.
RESULTS: Subjects were vaccinated with a 1st dose (n=123), 2nd dose (n=121), or 3rd or 4th dose (n=71) of PPV23. The post-vaccination IgG geometric mean concentrations (GMCs) were similar among first-time vaccinees and re-vaccinees for all serotypes with the exception of a lower GMC for serotype 1 in re-vaccinees. The post-vaccination OPK geometric mean titers (GMTs) were similar among first-time vaccinees and re-vaccinees with the exception of a higher GMT for serotype 6B in re-vaccinees. Compared to first-time vaccinees, re-vaccinees reported more joint pain (p=0.004), fatigue (p=0.019), headache (p=0.014), swelling (p=0.006), and moderate limitation in arm movement (p=0.025).
CONCLUSIONS: Repeat revaccination with PPV23, administered 6 or more years after the prior dose, was immunogenic and generally well tolerated.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21255685  Vaccine. 2011 Mar 9;29(12):2287-95. doi: 10.1016/j.vacc・・・
著者: Susan B Manoff, Charles Liss, Michael J Caulfield, Rocio D Marchese, Jeffrey Silber, John Boslego, Sandra Romero-Steiner, Gowrisankar Rajam, Nina E Glass, Cynthia G Whitney, George M Carlone
雑誌名: J Infect Dis. 2010 Feb 15;201(4):525-33. doi: 10.1086/651131.
Abstract/Text BACKGROUND: Older adults are at high risk of developing invasive pneumococcal disease, but the optimal timing and number of vaccine doses needed to prevent disease among this group are unknown. We compared revaccination with 23-valent pneumococcal polysaccharide vaccine (PN23) with primary vaccination for eliciting initial and persistent functional antibody responses.
METHODS: Subjects aged > or = 65 years were enrolled. Functional (opsonic) and total immunoglobulin (Ig) G antibody levels were measured following either PN23 primary vaccination (n = 60) or revaccination 3-5 years after receiving a first PN23 vaccination (n = 60). Antibody against vaccine serotypes 4, 14, and 23F was measured at prevaccination (day 0), 30 days after vaccination, and 5 years after vaccination.
RESULTS: By day 30, both primary vaccination and revaccination induced significant increases in opsonic and IgG antibody levels. Day 30 levels following revaccination were slightly lower but not significantly different than those after primary vaccination. Year 5 levels were similar in both groups and remained significantly higher than prevaccination levels for primary vaccination subjects. There was good agreement between postvaccination opsonic and IgG antibody levels.
CONCLUSIONS: Revaccination of older adults with PN23 was comparable to primary vaccination for inducing elevated and persistent functional and IgG antibody responses.

PMID 20088694  J Infect Dis. 2010 Feb 15;201(4):525-33. doi: 10.1086/6・・・
著者: Gerhard Falkenhorst, Cornelius Remschmidt, Thomas Harder, Eva Hummers-Pradier, Ole Wichmann, Christian Bogdan
雑誌名: PLoS One. 2017;12(1):e0169368. doi: 10.1371/journal.pone.0169368. Epub 2017 Jan 6.
Abstract/Text BACKGROUND: Routine vaccination of elderly people against pneumococcal diseases is recommended in many countries. National guidelines differ, recommending either the 23-valent polysaccharide vaccine (PPV23), the 13-valent conjugate vaccine (PCV13) or both. Considering the ongoing debate on the effectiveness of PPV23, we performed a systematic literature review and meta-analysis of the vaccine efficacy/effectiveness (VE) of PPV23 against invasive pneumococcal disease (IPD) and pneumococcal pneumonia in adults aged ≥60 years living in industrialized countries.
METHODS: We searched for pertinent clinical trials and observational studies in databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. We assessed the risk of bias of individual studies using the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. We rated the overall quality of the evidence by GRADE criteria. We performed meta-analyses of studies grouped by outcome and study design using random-effects models. We applied a sensitivity analysis excluding studies with high risk of bias.
RESULTS: We identified 17 eligible studies. Pooled VE against IPD (by any serotype) was 73% (95%CI: 10-92%) in four clinical trials, 45% (95%CI: 15-65%) in three cohort studies, and 59% (95%CI: 35-74%) in three case-control studies. After excluding studies with high risk of bias, pooled VE against pneumococcal pneumonia (by any serotype) was 64% (95%CI: 35-80%) in two clinical trials and 48% (95%CI: 25-63%) in two cohort studies. Higher VE estimates in trials (follow-up ~2.5 years) than in observational studies (follow-up ~5 years) may indicate waning protection. Unlike previous meta-analyses, we excluded two trials with high risk of bias regarding the outcome pneumococcal pneumonia, because diagnosis was based on serologic methods with insufficient specificity.
CONCLUSIONS: Our meta-analysis revealed significant VE of PPV23 against both IPD and pneumococcal pneumonia by any serotype in the elderly, comparable to the efficacy of PCV13 against vaccine-serotype disease in a recent clinical trial in elderly people. Due to its broader serotype coverage and the decrease of PCV13 serotypes among adults resulting from routine infant immunization with PCV13, PPV23 continues to play an important role for protecting adults against IPD and pneumococcal pneumonia.

PMID 28061505  PLoS One. 2017;12(1):e0169368. doi: 10.1371/journal.pon・・・
著者: Sarah Moberley, John Holden, David Paul Tatham, Ross M Andrews
雑誌名: Cochrane Database Syst Rev. 2013 Jan 31;1:CD000422. doi: 10.1002/14651858.CD000422.pub3. Epub 2013 Jan 31.
Abstract/Text BACKGROUND: Diseases caused by Streptococcus pneumoniae (S. pneumoniae) continue to cause substantial morbidity and mortality globally. Whilst pneumococcal polysaccharide vaccines (PPVs) have the potential to prevent disease and death, the degree of protection afforded against various clinical endpoints and within different populations is uncertain.
OBJECTIVES: To assess the efficacy and effectiveness of PPVs in preventing pneumococcal disease or death in adults. We did not assess adverse events.
SEARCH METHODS: We searched CENTRAL 2012, Issue 6, MEDLINE (January 1966 to June Week 2, 2012) and EMBASE (1974 to June 2012).
SELECTION CRITERIA: We considered randomised controlled trials (RCTs) in adults, provided the study outcome met the definition of the outcome considered in the review. We also considered non-RCTs in adults, where the study assessed PPV effectiveness against culture-confirmed invasive pneumococcal disease (IPD), provided the study controlled for important confounding factors.
DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality of RCTs and three review authors extracted the data. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. Two review authors assessed study quality and extracted data for non-RCTs. We calculated ORs and 95% CIs using a random-effects model following the conversion of each study outcome to a log OR and standard error (SE).
MAIN RESULTS: Twenty-five studies met our inclusion criteria (18 RCTs involving 64,852 participants and seven non-RCTs involving 62,294 participants). Meta-analysis of the RCTs found strong evidence of PPV efficacy against IPD with no statistical heterogeneity (OR 0.26, 95% CI 0.14 to 0.45; random-effects model, I(2) statistic = 0%). There was efficacy against all-cause pneumonia in low-income (OR 0.54, 95% CI 0.43 to 0.67, I(2) statistic = 19%) but not high-income countries in either the general population (OR 0.71, 95% CI 0.45 to 1.12, I(2) statistic = 93%) or in adults with chronic illness (OR 0.93, 95% CI 0.73 to 1.19, I(2) statistic = 10%). PPV was not associated with substantial reductions in all-cause mortality (OR 0.90, 95% CI 0.74 to 1.09; random-effects model, I(2) statistic = 69%). Vaccine efficacy against primary outcomes appeared poorer in adults with chronic illness. Non-RCTs provided evidence for protection against IPD in populations for whom the vaccine is currently utilised (OR 0.48, 95% CI 0.37 to 0.61; random-effects model, I(2) statistic = 31%). This review did not consider adverse events as it was outside the scope of the review.
AUTHORS' CONCLUSIONS: This meta-analysis provides evidence supporting the recommendation for PPV to prevent IPD in adults. The evidence from RCTs is less clear with respect to adults with chronic illness. This might be because of lack of effect or lack of power in the studies. The meta-analysis does not provide evidence to support the routine use of PPV to prevent all-cause pneumonia or mortality.

PMID 23440780  Cochrane Database Syst Rev. 2013 Jan 31;1:CD000422. doi・・・
著者: Motoi Suzuki, Bhim Gopal Dhoubhadel, Tomoko Ishifuji, Michio Yasunami, Makito Yaegashi, Norichika Asoh, Masayuki Ishida, Sugihiro Hamaguchi, Masahiro Aoshima, Koya Ariyoshi, Konosuke Morimoto, Adult Pneumonia Study Group-Japan (APSG-J)
雑誌名: Lancet Infect Dis. 2017 Mar;17(3):313-321. doi: 10.1016/S1473-3099(17)30049-X. Epub 2017 Jan 24.
Abstract/Text BACKGROUND: The serotype-specific effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPV23) against pneumococcal pneumonia has not been established in people aged 65 years or older. We assessed the effectiveness of PPV23 in this population.
METHODS: For this multicentre, prospective study, we enrolled all individuals aged 65 years or older with community-onset pneumonia who visited four study hospitals in Japan between Sept 28, 2011, and Aug 23, 2014. Streptococcus pneumoniae was isolated from sputum and blood samples, and serotyped by the capsular Quellung method. Sputum samples were further tested by PCR assay to identify pneumococcal DNA, and positive samples were examined for 50 serotypes by a nanofluidic real-time PCR assay. Urine samples were tested by a urinary antigen test. Serotype-specific vaccine effectiveness was estimated using the test-negative design.
FINDINGS: 2621 eligible patients visited the study hospitals, of whom 585 did not have sputum samples available and were excluded from our analysis. 419 (21%) of 2036 patients were positive for pneumococcal infection (232 by sputum culture, 317 by sputum PCR, 197 by urinary antigen test, and 14 by blood culture). 522 (26%) patients were judged to be vaccinated in the analyses. Effectiveness of PPV23 was 27·4% (95% CI 3·2 to 45·6) against all pneumococcal pneumonia, 33·5% (5·6 to 53·1) against PPV23 serotypes, and 2·0% (-78·9 to 46·3) against non-PPV23 serotypes. Although no significant differences between subgroups were seen, higher protection was noted in people younger than 75 years, women, and individuals with lobar pneumonia or health-care-associated pneumonia.
INTERPRETATION: PPV23 showed low to moderate effectiveness against vaccine serotype pneumococcal pneumonia in people aged 65 years or older. To improve the current pneumococcal vaccination programme, the variability of PPV23 effectiveness in different groups of older people must be further investigated.
FUNDING: Pfizer and Nagasaki University.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28126327  Lancet Infect Dis. 2017 Mar;17(3):313-321. doi: 10.1016・・・
著者: Marc J M Bonten, Susanne M Huijts, Marieke Bolkenbaas, Chris Webber, Scott Patterson, Samantha Gault, Cornelis H van Werkhoven, Anna M M van Deursen, Elisabeth A M Sanders, Theo J M Verheij, Michael Patton, Anne McDonough, Anita Moradoghli-Haftvani, Helen Smith, Tracey Mellelieu, Michael W Pride, Graham Crowther, Beate Schmoele-Thoma, Daniel A Scott, Kathrin U Jansen, Rita Lobatto, Bas Oosterman, Nils Visser, Esther Caspers, Andre Smorenburg, Emilio A Emini, William C Gruber, Diederick E Grobbee
雑誌名: N Engl J Med. 2015 Mar 19;372(12):1114-25. doi: 10.1056/NEJMoa1408544.
Abstract/Text BACKGROUND: Pneumococcal polysaccharide conjugate vaccines prevent pneumococcal disease in infants, but their efficacy against pneumococcal community-acquired pneumonia in adults 65 years of age or older is unknown.
METHODS: In a randomized, double-blind, placebo-controlled trial involving 84,496 adults 65 years of age or older, we evaluated the efficacy of 13-valent polysaccharide conjugate vaccine (PCV13) in preventing first episodes of vaccine-type strains of pneumococcal community-acquired pneumonia, nonbacteremic and noninvasive pneumococcal community-acquired pneumonia, and invasive pneumococcal disease. Standard laboratory methods and a serotype-specific urinary antigen detection assay were used to identify community-acquired pneumonia and invasive pneumococcal disease.
RESULTS: In the per-protocol analysis of first episodes of infections due to vaccine-type strains, community-acquired pneumonia occurred in 49 persons in the PCV13 group and 90 persons in the placebo group (vaccine efficacy, 45.6%; 95.2% confidence interval [CI], 21.8 to 62.5), nonbacteremic and noninvasive community-acquired pneumonia occurred in 33 persons in the PCV13 group and 60 persons in the placebo group (vaccine efficacy, 45.0%; 95.2% CI, 14.2 to 65.3), and invasive pneumococcal disease occurred in 7 persons in the PCV13 group and 28 persons in the placebo group (vaccine efficacy, 75.0%; 95% CI, 41.4 to 90.8). Efficacy persisted throughout the trial (mean follow-up, 3.97 years). In the modified intention-to-treat analysis, similar efficacy was observed (vaccine efficacy, 37.7%, 41.1%, and 75.8%, respectively), and community-acquired pneumonia occurred in 747 persons in the PCV13 group and 787 persons in placebo group (vaccine efficacy, 5.1%; 95% CI, -5.1 to 14.2). Numbers of serious adverse events and deaths were similar in the two groups, but there were more local reactions in the PCV13 group.
CONCLUSIONS: Among older adults, PCV13 was effective in preventing vaccine-type pneumococcal, bacteremic, and nonbacteremic community-acquired pneumonia and vaccine-type invasive pneumococcal disease but not in preventing community-acquired pneumonia from any cause. (Funded by Pfizer; CAPITA ClinicalTrials.gov number NCT00744263.).

PMID 25785969  N Engl J Med. 2015 Mar 19;372(12):1114-25. doi: 10.1056・・・
著者: Hannah Ewald, Matthias Briel, Danielle Vuichard, Veronika Kreutle, Andriy Zhydkov, Viktoria Gloy
雑誌名: Dtsch Arztebl Int. 2016 Mar 4;113(9):139-46. doi: 10.3238/arztebl.2016.0139.
Abstract/Text BACKGROUND: Streptococcus pneumoniae is responsible for approximately 1.6 million yearly deaths worldwide. An up-to-date evidence base on the effects of pneumococcal conjugate vaccines (PCVs) on infectious diseases and mortality in any population or setting regardless of age or health status is currently lacking.
METHODS: We systematically searched MEDLINE and EMBASE for pertinent randomized controlled trials (RCTs). Two reviewers independently screened 9498 titles/abstracts and 430 full-text papers for eligible trials. The outcomes of our meta-analysis were pooled using relative risks (RRs) with a random effects model or Peto's odds ratios (ORs) if event rates were :lt;1%.
RESULTS: 21 RCTs comprising 361 612 individuals were included. PCVs reduced the risk for invasive pneumococcal disease (odds ratio [OR]: 0.43, 95% confidence interval [CI]: [0.36; 0.51]), all-cause acute otitis media (AOM) (RR: 0.93, 95% CI: [0.86; 1.00]), pneumococcal AOM (RR: 0.57, 95% CI: [0.39; 0.83]), allcause pneumonia (RR: 0.93, 95% CI: [0.89; 0.97]), and pneumococcal pneumonia (RR: 0.78, 95% CI: [0.62; 0.97]). We found no significant effect of PCVs on all-cause mortality (RR: 0.95, 95% CI: [0.88; 1.03]) or recurrent AOM (RR: 0.87, 95% CI: [0.72; 1.05]).
CONCLUSION: PCVs are associated with large risk reductions for pneumococcal infectious diseases, smaller risk reductions for infectious diseases from any cause, and no significant effect on all-cause mortality.

PMID 26987462  Dtsch Arztebl Int. 2016 Mar 4;113(9):139-46. doi: 10.32・・・
著者: Shigeru Suga, Bin Chang, Kazutoyo Asada, Hideki Akeda, Junichiro Nishi, Kenji Okada, Hiroshi Wakiguchi, Akihiko Maeda, Megumi Oda, Naruhiko Ishiwada, Akihiko Saitoh, Tomohiro Oishi, Mitsuaki Hosoya, Takehiro Togashi, Kazunori Oishi, Toshiaki Ihara
雑誌名: Vaccine. 2015 Nov 9;33(45):6054-60. doi: 10.1016/j.vaccine.2015.07.069. Epub 2015 Jul 31.
Abstract/Text BACKGROUND: In Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013.
METHODS: The effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008-2013 in 10 prefectures in Japan.
RESULTS: 1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction.
CONCLUSIONS: Our data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26235372  Vaccine. 2015 Nov 9;33(45):6054-60. doi: 10.1016/j.vacc・・・
著者: Tamara Pilishvili, Catherine Lexau, Monica M Farley, James Hadler, Lee H Harrison, Nancy M Bennett, Arthur Reingold, Ann Thomas, William Schaffner, Allen S Craig, Philip J Smith, Bernard W Beall, Cynthia G Whitney, Matthew R Moore, Active Bacterial Core Surveillance/Emerging Infections Program Network
雑誌名: J Infect Dis. 2010 Jan 1;201(1):32-41. doi: 10.1086/648593.
Abstract/Text BACKGROUND: Changes in invasive pneumococcal disease (IPD) incidence were evaluated after 7 years of 7-valent pneumococcal conjugate vaccine (PCV7) use in US children.
METHODS: Laboratory-confirmed IPD cases were identified during 1998-2007 by 8 active population-based surveillance sites. We compared overall, age group-specific, syndrome-specific, and serotype group-specific IPD incidence in 2007 with that in 1998-1999 (before PCV7) and assessed potential serotype coverage of new conjugate vaccine formulations.
RESULTS: Overall and PCV7-type IPD incidence declined by 45% (from 24.4 to 13.5 cases per 100,000 population) and 94% (from 15.5 to 1.0 cases per 100,000 population), respectively (P< .01 all age groups). The incidence of IPD caused by serotype 19A and other non-PCV7 types increased from 0.8 to 2.7 cases per 100,000 population and from 6.1 to 7.9 cases per 100,000 population, respectively (P< .01 for all age groups). The rates of meningitis and invasive pneumonia caused by non-PCV7 types increased for all age groups (P< .05), whereas the rates of primary bacteremia caused by these serotypes did not change. In 2006-2007, PCV7 types caused 2% of IPD cases, and the 6 additional serotypes included in an investigational 13-valent conjugate vaccine caused 63% of IPD cases among children <5 years-old.
CONCLUSIONS: Dramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later. IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV7-type IPD.

PMID 19947881  J Infect Dis. 2010 Jan 1;201(1):32-41. doi: 10.1086/648・・・
著者: Riyadh D Muhammad, Reena Oza-Frank, Elizabeth Zell, Ruth Link-Gelles, K M Venkat Narayan, William Schaffner, Ann Thomas, Catherine Lexau, Nancy M Bennett, Monica M Farley, Lee H Harrison, Arthur Reingold, James Hadler, Bernard Beall, Keith P Klugman, Matthew R Moore
雑誌名: Clin Infect Dis. 2013 Mar;56(5):e59-67. doi: 10.1093/cid/cis971. Epub 2012 Nov 15.
Abstract/Text BACKGROUND: Certain chronic diseases increase risk for invasive pneumococcal disease (IPD) and are indications for receipt of 23-valent pneumococcal polysaccharide vaccine (PPV23). Since the pediatric introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in 2000, incidence of IPD among adults has declined. The relative magnitude of these indirect effects among persons with and without PPV23 indications is unknown.
METHODS: We evaluated IPD incidence among adults with and without PPV23 indications using population- and laboratory-based data collected during 1998-2009 and estimates of the denominator populations with PPV23 indications from the National Health Interview Survey. We compared rates before and after PCV7 use by age, race, PPV23 indication, and serotype.
RESULTS: The proportion of adult IPD cases with PPV23 indications increased from 51% before to 61% after PCV7 introduction (P < .0001). PCV7-serotype IPD declined among all race, age, and PPV23 indication strata, ranging from 82% to 97%. Overall IPD rates declined in most strata, by up to 65%. However, incidence remained highest among adults with PPV23 indications compared with those without (34.9 vs 8.8 cases per 100 000 population, respectively). Apart from age ≥65 years, diabetes is now the most common indication for PPV23 (20% of all cases vs 10% of cases in 1998-1999).
CONCLUSIONS: Although IPD rates have declined among adults, adults with underlying conditions remain at increased risk of IPD and comprise a larger proportion of adult IPD cases in 2009 compared with 2000. A continued increase in the prevalence of diabetes among US adults could lead to increased burden of pneumococcal disease.

PMID 23155149  Clin Infect Dis. 2013 Mar;56(5):e59-67. doi: 10.1093/ci・・・
著者: Eiichiro Sando, Motoi Suzuki, Akitsugu Furumoto, Norichika Asoh, Makito Yaegashi, Masahiro Aoshima, Masayuki Ishida, Sugihiro Hamaguchi, Yoshihito Otsuka, Konosuke Morimoto
雑誌名: Vaccine. 2019 May 6;37(20):2687-2693. doi: 10.1016/j.vaccine.2019.04.009. Epub 2019 Apr 8.
Abstract/Text BACKGROUND: The pediatric 13-valent pneumococcal conjugate vaccine (PCV13) was included in the pediatric immunization programme in Japan in late 2013. The impact of vaccination on the serotype distribution and clinical characteristics of pneumococcal pneumonia has not been described.
METHODS: The first phase of this multicentre prospective study was conducted at community-based hospitals in Japan from 2011 to 2014. The second phase was conducted from 2016 to 2017. Pneumococcal isolates and clinical data were collected from patients with community-acquired pneumonia who were ≥15 years of age. Patients were classified by pneumococcal serotype to PCV13 serotype, 23-valent pneumococcal polysaccharide vaccine (PPV23) non-PCV13 serotype, and non-vaccine serotype.
RESULTS: A total of 484 patients were enrolled, 241 in the first phase and 243 in the second. The proportion of PCV13 serotypes decreased from 53% to 33% (p < 0.001), whereas PPV23 non-PCV13 serotypes did not change (p = 0.754). PCV13 serotypes were associated with increased risk of elevated blood urea nitrogen (adjusted odds ratio 2.49; 95% confidence interval: 1.49-4.16) and hospitalization (adjusted odds ratio 1.74; 95% confidence interval: 1.02-2.95). These associations were not observed in patients with PPV23 non-PCV13 serotypes.
CONCLUSIONS: The occurrence of pneumococcal pneumonia caused by vaccine-covered serotypes dramatically decreased following the introduction of pediatric PCV13. The PCV13 serotypes were associated with pneumonia severity.

Copyright © 2019. Published by Elsevier Ltd.
PMID 30975569  Vaccine. 2019 May 6;37(20):2687-2693. doi: 10.1016/j.va・・・
著者: Shingo Noguchi, Kazuhiro Yatera, Kentaro Akata, Bin Chang, Hiroaki Ikegami, Ryosuke Hata, Kei Yamasaki, Toshinori Kawanami, Hiroshi Mukae
雑誌名: J Infect Chemother. 2019 Nov;25(11):925-929. doi: 10.1016/j.jiac.2019.07.007. Epub 2019 Jul 24.
Abstract/Text In 2014, vaccinations with 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13) were implemented in Japan for all adults aged ≥65 years. We previously clarified reductions in the proportions of PCV7-, PCV13-, and PPSV23-covered serotypes in patients with pneumococcal pneumonia after the initiation of PCV7 and PCV13 vaccinations for Japanese children; however, information about the annual changes in the proportion of Streptococcus pneumoniae serotypes in patients with pneumococcal pneumonia after the initiation of routine PPSV23 vaccinations remains unclear. We retrospectively studied 229 adults with pneumococcal pneumonia which S. pneumoniae was cultured from their lower respiratory tract samples between 2011 and 2017 and investigated the annual changes in the proportion of S. pneumoniae serotypes. The proportion of PPSV23-covered serotypes decreased from 71.4% in 2011 to 52.2% in 2014, but it remained essentially unchanged from 2015 to 2017. The proportions of PCV7-covered serotypes decreased from 46.4% in 2011 to 4.3% in 2014; however, this rate increased beginning in 2015 and reached 20.6% in 2017. Among the PCV7-covered serotypes, the proportion of the 19F serotype increased from 2015 to 2017. In conclusion, there were no obvious changes in the proportion of PPSV23-covered and PCV13-covered serotypes in patients with pneumococcal pneumonia after the initiation of routine PPSV23 vaccinations.

Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
PMID 31350184  J Infect Chemother. 2019 Nov;25(11):925-929. doi: 10.10・・・
著者: T Tanaka, K Katou, S Kimata, S Hosoda, K Hirosawa
雑誌名: Jpn Circ J. 1989 Feb;53(2):155-64.
Abstract/Text In a normal man sitting upright, pulmonary perfusion is several times greater in the lower lung zone than in the upper zone. This pattern may sometimes be reversed in patients with cardiac disease. Tc99m-macro-aggregated albumin pulmonary perfusion images were computerized to isocounts area images (digital perfusion images; DPI). DPI were applied to various types of cardiac disease and patterns of DPI were divided into 4 classes according to amount of nonperfused pulmonary vascular bed. C-0; normal perfusion. C-1; decrease of nonperfused pulmonary vascular bed. C-2; disappearance of nonperfused pulmonary vascular bed. C-3; decrease of pulmonary vascular bed. In 71 patients with mitral stenosis relationships between pulmonary hemodynamics during exercise and distribution of pulmonary perfusion were studied, i.e. at rest (n = 71, mean pulmonary arterial pressure; 23 mmHg-cardiac index; 2.4 L/m) and during exercise C-0 (n = 13, 41 mmHg-5.4 L/m), C-1 (n = 17, 52 mmHg-5.2 L/m), C-2 (n = 27, 52 mmHg-4.5 L/m) and C-3 (n = 14, 65 mmHg-3.6 L/m) respectively. In patients with congestive heart failure cardiac status was classified to 4 classes according to ejection fraction and DPI. Patients with EF less than 30% and DPI more than C-2 showed high morbidity and mortality (two years mortality 47%; 27/40). Pulmonary venous pressure increases to maintain the cardiac index (Starling's law) in cases of decline in cardiac function or mitral stenosis. It was shown that increases in pulmonary venous pressure cause changes in distribution of pulmonary perfusion, which in turn works to depress the cardiac index. A decline in cardiac function and changes in the distribution of pulmonary perfusion coexist, mediated by pulmonary venous pressure and cardiac index. The distribution of pulmonary perfusion reflects the severity of cardiac failure itself, so by using DPI the severity of cardiac failure can be easily evaluated.

PMID 2716177  Jpn Circ J. 1989 Feb;53(2):155-64.
著者: Amrita R John, David H Canaday
雑誌名: Infect Dis Clin North Am. 2017 Dec;31(4):811-826. doi: 10.1016/j.idc.2017.07.016.
Abstract/Text Herpes zoster (HZ) is the result of reactivation of latent varicella zoster virus (VZV) and occurs most frequently in older adults. Classically, HZ presents as a unilateral, selflimited, dermatomal rash. Postherpetic neuralgia (PHN) is a common sequela, presenting as severe pain that persists after the rash has resolved. In the elderly, PHN can be debilitating and requires a prompt diagnosis, treatment with antivirals, and adequate pain control. A longer-term pain management strategy is required if PHN occurs. A modestly effective vaccine exists and is recommended for older individuals.

Copyright © 2017 Elsevier Inc. All rights reserved.
PMID 29079160  Infect Dis Clin North Am. 2017 Dec;31(4):811-826. doi: ・・・
著者: Anna M Z Gagliardi, Brenda N G Andriolo, Maria R Torloni, Bernardo G O Soares
雑誌名: Cochrane Database Syst Rev. 2016 Mar 3;3:CD008858. doi: 10.1002/14651858.CD008858.pub3. Epub 2016 Mar 3.
Abstract/Text BACKGROUND: Herpes zoster, also known as 'shingles', is a neurocutaneous disease characterised by the reactivation of the latent varicella zoster virus (VZV), the virus that causes chickenpox when immunity to VZV declines. It is an extremely painful condition that can last many weeks or months and it can significantly compromise the quality of life of affected individuals. The natural process of aging is associated with a reduction in cellular immunity and this predisposes older people to herpes zoster. Vaccination with an attenuated form of VZV activates specific T cell production avoiding viral reactivation. The Food and Drug Administration has approved a herpes zoster vaccine with an attenuated active virus for clinical use among older adults, which has been tested in large populations. A new adjuvanted recombinant VZV subunit zoster vaccine has also been tested. It consists of recombinant VZV glycoprotein E and a liposome-based AS01B adjuvant system. This new vaccine is not yet available for clinical use.
OBJECTIVES: To evaluate the effectiveness and safety of vaccination for preventing herpes zoster in older adults.
SEARCH METHODS: For this 2015 update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9), MEDLINE (1948 to the 3rd week of October 2015), EMBASE (2010 to October 2015), CINAHL (1981 to October 2015) and LILACS (1982 to October 2015).
SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing zoster vaccine with placebo or no vaccine, to prevent herpes zoster in older adults (mean age > 60 years).
DATA COLLECTION AND ANALYSIS: Two review authors independently collected and analysed data using a data extraction form. They also performed 'Risk of bias' assessment.
MAIN RESULTS: We identified 13 studies involving 69,916 participants. The largest study included 38,546 participants. All studies were conducted in high-income countries and included only healthy Caucasian individuals ≥ 60 years of age without immunosuppressive comorbidities. Ten studies used live attenuated varicella zoster virus (VZV) vaccines. Three studies tested a new type of vaccine not yet available for clinical use. We judged five of the included studies to be at low risk of bias.The incidence of herpes zoster, at up to three years of follow-up, was lower in participants who received the vaccine than in those who received a placebo: risk ratio (RR) 0.49; 95% confidence interval (CI) 0.43 to 0.56, risk difference (RD) 2%, number needed to treat to benefit (NNTB) 50; GRADE: moderate quality evidence. The vaccinated group had a higher incidence of mild to moderate intensity adverse events. These date came from one large study that included 38,546 people aged 60 years or older.A study including 8122 participants compared the new vaccine (not yet available) to the placebo; the group that received the new vaccine had a lower incidence of herpes zoster at 3.2 years of follow-up: RR 0.04, 95% CI 0.02 to 0.10, RD 3%, NNTB 33; GRADE: moderate quality evidence. The vaccinated group had a higher incidence of adverse events but most them were of mild to moderate intensity.All studies received funding from the pharmaceutical industry.
AUTHORS' CONCLUSIONS: Herpes zoster vaccine is effective in preventing herpes zoster disease and this protection can last three years. In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse events of mild to moderate intensity.There are studies of a new vaccine (with a VZV glycoproteic fraction plus adjuvant), which is currently not yet available for clinical use.

PMID 26937872  Cochrane Database Syst Rev. 2016 Mar 3;3:CD008858. doi:・・・
著者: Himal Lal, Anthony L Cunningham, Olivier Godeaux, Roman Chlibek, Javier Diez-Domingo, Shinn-Jang Hwang, Myron J Levin, Janet E McElhaney, Airi Poder, Joan Puig-Barberà, Timo Vesikari, Daisuke Watanabe, Lily Weckx, Toufik Zahaf, Thomas C Heineman, ZOE-50 Study Group
雑誌名: N Engl J Med. 2015 May 28;372(22):2087-96. doi: 10.1056/NEJMoa1501184. Epub 2015 Apr 28.
Abstract/Text BACKGROUND: In previous phase 1-2 clinical trials involving older adults, a subunit vaccine containing varicella-zoster virus glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response.
METHODS: We conducted a randomized, placebo-controlled, phase 3 study in 18 countries to evaluate the efficacy and safety of HZ/su in older adults (≥50 years of age), stratified according to age group (50 to 59, 60 to 69, and ≥70 years). Participants received two intramuscular doses of the vaccine or placebo 2 months apart. The primary objective was to assess the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster in older adults.
RESULTS: A total of 15,411 participants who could be evaluated received either the vaccine (7698 participants) or placebo (7713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1000 person-years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P<0.001). Vaccine efficacy was between 96.6% and 97.9% for all age groups. Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group. There were solicited or unsolicited reports of grade 3 symptoms in 17.0% of vaccine recipients and 3.2% of placebo recipients. The proportions of participants who had serious adverse events or potential immune-mediated diseases or who died were similar in the two groups.
CONCLUSIONS: The HZ/su vaccine significantly reduced the risk of herpes zoster in adults who were 50 years of age or older. Vaccine efficacy in adults who were 70 years of age or older was similar to that in the other two age groups. (Funded by GlaxoSmithKline Biologicals; ZOE-50 ClinicalTrials.gov number, NCT01165177.).

PMID 25916341  N Engl J Med. 2015 May 28;372(22):2087-96. doi: 10.1056・・・
著者: Anthony L Cunningham, Himal Lal, Martina Kovac, Roman Chlibek, Shinn-Jang Hwang, Javier Díez-Domingo, Olivier Godeaux, Myron J Levin, Janet E McElhaney, Joan Puig-Barberà, Carline Vanden Abeele, Timo Vesikari, Daisuke Watanabe, Toufik Zahaf, Anitta Ahonen, Eugene Athan, Jose F Barba-Gomez, Laura Campora, Ferdinandus de Looze, H Jackson Downey, Wayne Ghesquiere, Iris Gorfinkel, Tiina Korhonen, Edward Leung, Shelly A McNeil, Lidia Oostvogels, Lars Rombo, Jan Smetana, Lily Weckx, Wilfred Yeo, Thomas C Heineman, ZOE-70 Study Group
雑誌名: N Engl J Med. 2016 Sep 15;375(11):1019-32. doi: 10.1056/NEJMoa1603800.
Abstract/Text BACKGROUND: A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70).
METHODS: This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50.
RESULTS: In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups.
CONCLUSIONS: In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.gov numbers, NCT01165177 and NCT01165229 .).

PMID 27626517  N Engl J Med. 2016 Sep 15;375(11):1019-32. doi: 10.1056・・・
著者: Martina Kovac, Himal Lal, Anthony L Cunningham, Myron J Levin, Robert W Johnson, Laura Campora, Antonio Volpi, Thomas C Heineman, ZOE-50/70 Study Group
雑誌名: Vaccine. 2018 Mar 14;36(12):1537-1541. doi: 10.1016/j.vaccine.2018.02.029. Epub 2018 Feb 17.
Abstract/Text BACKGROUND: An adjuvanted herpes zoster (HZ) subunit vaccine, HZ/su, demonstrated high efficacy against HZ and postherpetic neuralgia (PHN) in two randomized, observer-blind, placebo-controlled trials in adults aged ≥50 and ≥70 years (ZOE-50 and ZOE-70, respectively).
METHODS: Data from ZOE-50 and ZOE-70 trials were analyzed to evaluate the efficacy of HZ/su against mortality, hospitalizations, and non-PHN complications of HZ including HZ-associated vasculitis, stroke, and disseminated, ophthalmic, neurologic, and visceral diseases.
RESULTS: In the pooled ZOE-50/ZOE-70 analysis, 1 of 32 HZ/su recipients (3.1%) and 16 of 477 placebo recipients (3.4%) with a confirmed HZ episode had complications other than PHN. Efficacy against HZ-related complications was 93.7% (95% confidence interval, 59.5-99.9%) in adults aged ≥50 years and 91.6% (43.3-99.8%) in adults ≥70 years. Five HZ-related hospitalizations, all in placebo recipients, and no HZ-related deaths were reported.
CONCLUSIONS: HZ/su reduces the risk of HZ-associated complications in older adults (NCT01165177; NCT01165229).

Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.
PMID 29463421  Vaccine. 2018 Mar 14;36(12):1537-1541. doi: 10.1016/j.v・・・
著者: Kathleen L Dooling, Angela Guo, Manisha Patel, Grace M Lee, Kelly Moore, Edward A Belongia, Rafael Harpaz
雑誌名: MMWR Morb Mortal Wkly Rep. 2018 Jan 26;67(3):103-108. doi: 10.15585/mmwr.mm6703a5. Epub 2018 Jan 26.
Abstract/Text On October 20, 2017, Zoster Vaccine Recombinant, Adjuvanted (Shingrix, GlaxoSmithKline, [GSK] Research Triangle Park, North Carolina), a 2-dose, subunit vaccine containing recombinant glycoprotein E in combination with a novel adjuvant (AS01B), was approved by the Food and Drug Administration for the prevention of herpes zoster in adults aged ≥50 years. The vaccine consists of 2 doses (0.5 mL each), administered intramuscularly, 2-6 months apart (1). On October 25, 2017, the Advisory Committee on Immunization Practices (ACIP) recommended the recombinant zoster vaccine (RZV) for use in immunocompetent adults aged ≥50 years.

PMID 29370152  MMWR Morb Mortal Wkly Rep. 2018 Jan 26;67(3):103-108. d・・・
著者: Jason M Warfel, Lindsey I Zimmerman, Tod J Merkel
雑誌名: Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):787-92. doi: 10.1073/pnas.1314688110. Epub 2013 Nov 25.
Abstract/Text Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis. Pertussis rates in the United States have been rising and reached a 50-y high of 42,000 cases in 2012. Although pertussis resurgence is not completely understood, we hypothesize that current acellular pertussis (aP) vaccines fail to prevent colonization and transmission. To test our hypothesis, infant baboons were vaccinated at 2, 4, and 6 mo of age with aP or whole-cell pertussis (wP) vaccines and challenged with B. pertussis at 7 mo. Infection was followed by quantifying colonization in nasopharyngeal washes and monitoring leukocytosis and symptoms. Baboons vaccinated with aP were protected from severe pertussis-associated symptoms but not from colonization, did not clear the infection faster than naïve animals, and readily transmitted B. pertussis to unvaccinated contacts. Vaccination with wP induced a more rapid clearance compared with naïve and aP-vaccinated animals. By comparison, previously infected animals were not colonized upon secondary infection. Although all vaccinated and previously infected animals had robust serum antibody responses, we found key differences in T-cell immunity. Previously infected animals and wP-vaccinated animals possess strong B. pertussis-specific T helper 17 (Th17) memory and Th1 memory, whereas aP vaccination induced a Th1/Th2 response instead. The observation that aP, which induces an immune response mismatched to that induced by natural infection, fails to prevent colonization or transmission provides a plausible explanation for the resurgence of pertussis and suggests that optimal control of pertussis will require the development of improved vaccines.

PMID 24277828  Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):787-92. do・・・
著者: Tami H Skoff, Joan Baumbach, Paul R Cieslak
雑誌名: Emerg Infect Dis. 2015 Sep;21(9):1568-73. doi: 10.3201/eid2109.150023.
Abstract/Text Despite high coverage with pertussis-containing vaccines, pertussis remains endemic to the United States. There have been increases in reported cases in recent years, punctuated by striking epidemics and shifting epidemiology, both of which raise questions about current policies regarding its prevention and control. Limited data on pertussis reported through the National Notifiable Disease Surveillance System have proved insufficient to answer these questions. To address shortcomings of national pertussis data, the Emerging Infections Program at the US Centers for Disease Control and Prevention launched Enhanced Pertussis Surveillance (EPS), which is characterized by systematic case ascertainment, augmented data collection, and collection of Bordetella pertussis isolates. Data collected through EPS have been instrumental in understanding the rapidly evolving epidemiology and molecular epidemiology of pertussis and have contributed essential information regarding pertussis vaccines. EPS also serves as a platform for conducting critical and timely evaluations of pertussis prevention and control strategies, including targeting of vaccinations and antimicrobial prophylaxis.

PMID 26291475  Emerg Infect Dis. 2015 Sep;21(9):1568-73. doi: 10.3201/・・・
著者: Tina Tan, Tine Dalby, Kevin Forsyth, Scott A Halperin, Ulrich Heininger, Daniela Hozbor, Stanley Plotkin, Rolando Ulloa-Gutierrez, Carl Heinz Wirsing von König
雑誌名: Pediatr Infect Dis J. 2015 Sep;34(9):e222-32. doi: 10.1097/INF.0000000000000795.
Abstract/Text Pertussis has reemerged as a problem across the world. To better understand the nature of the resurgence, we reviewed recent epidemiologic data and we report disease trends from across the world. Published epidemiologic data from January 2000 to July 2013 were obtained via PubMed searches and open-access websites. Data on vaccine coverage and reported pertussis cases from 2000 through 2012 from the 6 World Health Organization regions were also reviewed. Findings are confounded not only by the lack of systematic and comparable observations in many areas of the world but also by the cyclic nature of pertussis with peaks occurring every 3-5 years. It appears that pertussis incidence has increased in school-age children in North America and western Europe, where acellular pertussis vaccines are used, but an increase has also occurred in some countries that use whole-cell vaccines. Worldwide, pertussis remains a serious health concern, especially for infants, who bear the greatest disease burden. Factors that may contribute to the resurgence include lack of booster immunizations, low vaccine coverage, improved diagnostic methods, and genetic changes in the organism. To better understand the epidemiology of pertussis and optimize disease control, it is important to improve surveillance worldwide, irrespective of pertussis vaccine types and schedules used in each country.

PMID 26376316  Pediatr Infect Dis J. 2015 Sep;34(9):e222-32. doi: 10.1・・・
著者: Juventila Liko, Steve G Robison, Paul R Cieslak
雑誌名: N Engl J Med. 2013 Feb 7;368(6):581-2. doi: 10.1056/NEJMc1212006.
Abstract/Text
PMID 23388023  N Engl J Med. 2013 Feb 7;368(6):581-2. doi: 10.1056/NEJ・・・
国立感染症研究所:麻しんに関する特定感染症予防指針の改正について IASR Vol. 34 p. 39-40: 2013年2月号、日本国立研究所HP、2013(2020年6月閲覧).
著者: Lucy A McNamara, Nadav Topaz, Xin Wang, Susan Hariri, LeAnne Fox, Jessica R MacNeil
雑誌名: MMWR Morb Mortal Wkly Rep. 2017 Jul 14;66(27):734-737. doi: 10.15585/mmwr.mm6627e1. Epub 2017 Jul 14.
Abstract/Text Use of eculizumab (Soliris, Alexion Pharmaceuticals), a terminal complement inhibitor, is associated with a 1,000-fold to 2,000-fold increased incidence of meningococcal disease (1). Administration of meningococcal vaccines is recommended for patients receiving eculizumab before beginning treatment (2,3). Sixteen cases of meningococcal disease were identified in eculizumab recipients in the United States during 2008-2016; among these, 11 were caused by nongroupable Neisseria meningitidis. Fourteen patients had documentation of receipt of at least 1 dose of meningococcal vaccine before disease onset. Because eculizumab recipients remain at risk for meningococcal disease even after receipt of meningococcal vaccines, some health care providers in the United States as well as public health agencies in other countries recommend antimicrobial prophylaxis for the duration of eculizumab treatment; a lifelong course of treatment is expected for many patients. Heightened awareness, early care seeking, and rapid treatment of any symptoms consistent with meningococcal disease are essential for all patients receiving eculizumab treatment, regardless of meningococcal vaccination or antimicrobial prophylaxis status.

PMID 28704351  MMWR Morb Mortal Wkly Rep. 2017 Jul 14;66(27):734-737. ・・・
著者: Phillip S Blanchette, Hannah Chung, Kathleen I Pritchard, Craig C Earle, Michael A Campitelli, Sarah A Buchan, Kevin L Schwartz, Natasha S Crowcroft, Jonathan B Gubbay, Timothy Karnauchow, Kevin Katz, Allison J McGeer, James D McNally, David C Richardson, Susan E Richardson, Laura C Rosella, Andrew Simor, Marek Smieja, George Zahariadis, Aaron Campigotto, Jeffrey C Kwong
雑誌名: J Clin Oncol. 2019 Oct 20;37(30):2795-2804. doi: 10.1200/JCO.19.00354. Epub 2019 Aug 29.
Abstract/Text PURPOSE: Seasonal influenza vaccination is recommended for patients with cancer despite concerns of disease or treatment-associated immunosuppression. The objective of this study was to evaluate vaccine effectiveness (VE) against laboratory-confirmed influenza for patients with cancer.
PATIENTS AND METHODS: We conducted an observational test-negative design study of previously diagnosed patients with cancer 18 years of age and older who underwent influenza testing during the 2010-2011 to 2015-2016 influenza seasons in Ontario, Canada. We linked individual-level cancer registry, respiratory virus testing, and health administrative data to identify the study population and outcomes. Vaccination status was determined from physician and pharmacist billing claims. We used multivariable logistic regression to estimate VE, adjusting for age, sex, rurality, income quintile, cancer characteristics, chemotherapy exposure, comorbidities, previous health care use, influenza season, and calendar time.
RESULTS: We identified 26,463 patients with cancer who underwent influenza testing, with 4,320 test-positive cases (16%) and 11,783 (45%) vaccinated. Mean age was 70 years, 52% were male, mean time since diagnosis was 6 years, 69% had solid tumor malignancies, and 23% received active chemotherapy. VE against laboratory-confirmed influenza was 21% (95% CI, 15% to 26%), and VE against laboratory-confirmed influenza hospitalization was 20% (95% CI, 13% to 26%). For patients with solid tumor malignancies, VE was 25% (95% CI, 18% to 31%), compared with 8% (95% CI, -5% to 19%) for patients with hematologic malignancies (P = .015). Active chemotherapy usage did not significantly affect VE, especially among patients with solid tumor cancer.
CONCLUSION: Our results support recommendations for influenza vaccination for patients with cancer. VE was decreased for patients with hematologic malignancies, and there was no significant difference in VE among patients with solid tumor cancer receiving active chemotherapy. Strategies to optimize influenza prevention among patients with cancer are warranted.

PMID 31465264  J Clin Oncol. 2019 Oct 20;37(30):2795-2804. doi: 10.120・・・
著者: Bhumsuk Keam, Chang Kyung Kang, Kang Il Jun, Song Mi Moon, Koung Jin Suh, Dae-Won Lee, Chan-Young Ock, Miso Kim, Yunhee Choi, Yoojoo Lim, Kyung-Hun Lee, Se Hyun Kim, Tae Min Kim, Tae-Yong Kim, Do-Youn Oh, Dong-Wan Kim, Seock-Ah Im, Jong Seok Lee, Eu Suk Kim, Hong Bin Kim, Nam-Joong Kim, Yu Jung Kim, Wan Beom Park, Myoung-Don Oh
雑誌名: Clin Infect Dis. 2020 Jul 11;71(2):422-425. doi: 10.1093/cid/ciz1092.
Abstract/Text Among prospectively enrolled adult patients with cancer receiving immune checkpoint inhibitors (ICIs; n = 46) or cytotoxic agents (n = 90), seroprotection and seroconversion rates after seasonal quadrivalent influenza vaccinations were higher with ICI than with cytotoxic chemotherapy. These results support annual influenza vaccinations for cancer patients receiving ICIs. Clinical Trials Registration clinicaltrials.gov (NCT03590808).

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
PMID 31680143  Clin Infect Dis. 2020 Jul 11;71(2):422-425. doi: 10.109・・・
著者: Dirk H Wijn, Geert H Groeneveld, Albert M Vollaard, Mirte Muller, Jacco Wallinga, Hans Gelderblom, Egbert F Smit
雑誌名: Eur J Cancer. 2018 Nov;104:182-187. doi: 10.1016/j.ejca.2018.09.012. Epub 2018 Oct 24.
Abstract/Text BACKGROUND: Influenza vaccination is recommended in patients with cancer to reduce influenza-related complications. Recently, more immune-related adverse events (irAEs) were demonstrated in patients with lung cancer who were vaccinated with the trivalent seasonal influenza vaccine during anti-programmed death receptor 1 (PD-1) immunotherapy. Confirmation of these findings is essential before recommendations on influenza vaccination may be revoked.
METHODS: In this cohort study in patients with lung cancer receiving nivolumab 3 mg/kg every 2 weeks during two influenza seasons (2015/16-2016/17), irAEs have been monitored. Incidence, timing and severity of irAEs were compared between vaccinated patients and non-vaccinated patients.
FINDINGS: In a compassionate use programme, 127 patients with lung cancer had been treated with at least one dose of nivolumab during two national influenza vaccination campaigns from September until December of 2015 and 2016. Forty-two patients had received the influenza vaccine, and 85 patients were not vaccinated. Median follow-up period was 118 days (interquartile range 106-119). Mean age was 64 years (range 46-83). In vaccinated and non-vaccinated patients, the incidence of irAEs was 26% and 22%, respectively, rate ratio 1.20 (95% confidence interval [CI] 0.51-2.65). The incidence of serious irAEs was 7% and 4%, respectively, rate ratio 2.07 (95% CI 0.28-15.43). Influenza vaccination while receiving nivolumab did not result in significant differences in the rates of discontinuation, death, clinical deterioration or tumour response between the groups.
INTERPRETATION: Influenza vaccination in patients with lung cancer receiving anti-PD-1 immunotherapy does not induce irAEs in our cohort. With this result, influenza vaccination should not be deterred from this group of patients.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 30368069  Eur J Cancer. 2018 Nov;104:182-187. doi: 10.1016/j.ejca・・・
著者: Curtis R Chong, Vivian J Park, Bevin Cohen, Michael A Postow, Jedd D Wolchok, Mini Kamboj
雑誌名: Clin Infect Dis. 2020 Jan 2;70(2):193-199. doi: 10.1093/cid/ciz202.
Abstract/Text BACKGROUND: Cancer patients are at a higher risk for developing influenza (flu)- related complications. It is unclear if the flu vaccine exacerbates immune events in patients treated with immune checkpoint inhibitors (ICIs).
METHODS: We conducted an institutional review board-IRB-approved retrospective review of advanced cancer patients on ICIs who received the flu vaccine during three 3 consecutive seasons: 2014-2015, 2015-2016, and 2016-2017. The primary outcome assessed was any "new onset" immune-related adverse event (IRAE). A subset analysis of vaccinated patients newly treated with anti-programmed cell death protein 1 (PD-1) agents (nivolumab or pembrolizumab) was conducted to assess overall IRAE rates for comparison with published clinical trials.
RESULTS: During the three 3 seasons, 370 patients met criteria for ICI and vaccination within ~ twoapproximately 2 months (65 days). The most common underlying cancers were lung (46%) and melanoma (19%); 61% of patients received an anti-PD-1 agent only. In the entire cohort, 20% experienced an IRAE (any grade); incidence of grade 3 or 4 toxicity was 8%. No grade 5 events occurred. In the subset of 170 patients newly treated with anti-PD-1 agents, the overall IRAE rate was 18% and, grade 3/4 events occurred in 7.6%. Influenza was diagnosed in 2 patients.
CONCLUSIONS: No increase in incidence or severity of IRAEs was detected in patients on ICIs who received the inactivated influenza vaccine within ~ approximately 2 months of ICI. For newly treated patients on anti-PDI-1 agents, IRAE rates were comparable to those from published clinical trials and did not vary with order of administration. Routine seasonal flu vaccination is encouraged in patients on ICIs.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
PMID 30874791  Clin Infect Dis. 2020 Jan 2;70(2):193-199. doi: 10.1093・・・
著者: L Danzinger-Isakov, D Kumar, AST Infectious Diseases Community of Practice
雑誌名: Am J Transplant. 2009 Dec;9 Suppl 4:S258-62. doi: 10.1111/j.1600-6143.2009.02917.x.
Abstract/Text
PMID 20070687  Am J Transplant. 2009 Dec;9 Suppl 4:S258-62. doi: 10.11・・・
著者: P Ljungman, C Cordonnier, H Einsele, J Englund, C M Machado, J Storek, T Small, Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, European Blood and Marrow Transplant Group, American Society of Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Disease Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Diseases Canada, Centers for Disease Control and Prevention
雑誌名: Bone Marrow Transplant. 2009 Oct;44(8):521-6. doi: 10.1038/bmt.2009.263.
Abstract/Text
PMID 19861986  Bone Marrow Transplant. 2009 Oct;44(8):521-6. doi: 10.1・・・
著者: Per Ljungman, Rafael de la Camara, Christine Robin, Roberto Crocchiolo, Hermann Einsele, Joshua A Hill, Petr Hubacek, David Navarro, Catherine Cordonnier, Katherine N Ward, 2017 European Conference on Infections in Leukaemia group
雑誌名: Lancet Infect Dis. 2019 Aug;19(8):e260-e272. doi: 10.1016/S1473-3099(19)30107-0. Epub 2019 May 29.
Abstract/Text Cytomegalovirus is one of the most important infections to occur after allogeneic haematopoietic stem cell transplantation (HSCT), and an increasing number of reports indicate that cytomegalovirus is also a potentially important pathogen in patients treated with recently introduced drugs for hematological malignancies. Expert recommendations have been produced by the 2017 European Conference on Infections in Leukaemia (ECIL 7) after a review of the literature on the diagnosis and management of cytomegalovirus in patients after HSCT and in patients receiving other types of therapy for haematological malignancies. These recommendations cover diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management of cytomegalovirus disease. Antiviral drugs including maribavir and letermovir are in development and prospective clinical trials have recently been completed. However, management of patients with resistant or refractory cytomegalovirus infection or cytomegalovirus disease is a challenge. In this Review we summarise the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31153807  Lancet Infect Dis. 2019 Aug;19(8):e260-e272. doi: 10.10・・・
著者: Malgorzata Mikulska, Simone Cesaro, Hugues de Lavallade, Roberta Di Blasi, Sigrun Einarsdottir, Giuseppe Gallo, Christina Rieger, Dan Engelhard, Thomas Lehrnbecher, Per Ljungman, Catherine Cordonnier, European Conference on Infections in Leukaemia group
雑誌名: Lancet Infect Dis. 2019 Jun;19(6):e188-e199. doi: 10.1016/S1473-3099(18)30601-7. Epub 2019 Feb 8.
Abstract/Text Patients with haematological malignancies are at high risk of infection because of various mechanisms of humoral and cell-mediated immune deficiencies, which mainly depend on underlying disease and specific therapies. Some of these infections are vaccine preventable. However, these malignancies are different from each other, and the treatment approaches are diverse and rapidly evolving, so it is difficult to have a common programme for vaccination in a haematology ward. Additionally, because of insufficient training about the topic, vaccination is an area often neglected by haematologists, and influenced by cultural differences, even among health-care workers, in compliance to vaccines. Several issues are encountered when addressing vaccination in haematology: the small size of the cohorts that makes it difficult to show the clinical benefits of vaccination, the subsequent need to rely on biological parameters, their clinical pertinence not being established in immunocompromised patients, scarcity of clarity on the optimal timing of vaccination in complex treatment schedules, and the scarcity of data on long-term protection in patients receiving treatments. Moreover, the risk of vaccine-induced disease with live-attenuated vaccines strongly limits their use. Here we summarise guidelines for patients without transplantations, and address the issue by the haematological group-myeloid and lymphoid-of diseases, with a special consideration for children with acute leukaemia.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30744964  Lancet Infect Dis. 2019 Jun;19(6):e188-e199. doi: 10.10・・・
著者: Baldassarre Martire, Chiara Azzari, Raffaele Badolato, Clementina Canessa, Emilia Cirillo, Vera Gallo, Simona Graziani, Tiziana Lorenzini, Cinzia Milito, Raffaella Panza, Viviana Moschese, with Italian Network for Primary Immunodeficiencies (IPINET)
雑誌名: Vaccine. 2018 Jun 7;36(24):3541-3554. doi: 10.1016/j.vaccine.2018.01.061. Epub 2018 Feb 6.
Abstract/Text Infectious complications are a major cause of morbidity and mortality in patients with primary or secondary immunodeficiency. Prevention of infectious diseases by vaccines is among the most effective healthcare measures mainly for these subjects. However immunocompromised people vary in their degree of immunosuppression and susceptibility to infection and, therefore, represent a heterogeneous population with regard to immunization. To date there is no well- established evidence for use of vaccines in immunodeficient patients, and indications are not clearly defined even in high-quality reviews and in most of the guidelines prepared to provide recommendations for the active vaccination of immunocompromised hosts. The aim of this document is to issue recommendations based on published literature and the collective experience of the Italian primary immunodeficiency centers, about how and when vaccines can be used in immunocompromised patients, in order to facilitate physician decisions and to ensure the best immune protection with the lowest risk to the health of the patient.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29426658  Vaccine. 2018 Jun 7;36(24):3541-3554. doi: 10.1016/j.va・・・
著者: Medical Advisory Committee of the Immune Deficiency Foundation, William T Shearer, Thomas A Fleisher, Rebecca H Buckley, Zuhair Ballas, Mark Ballow, R Michael Blaese, Francisco A Bonilla, Mary Ellen Conley, Charlotte Cunningham-Rundles, Alexandra H Filipovich, Ramsay Fuleihan, Erwin W Gelfand, Vivian Hernandez-Trujillo, Steven M Holland, Richard Hong, Howard M Lederman, Harry L Malech, Stephen Miles, Luigi D Notarangelo, Hans D Ochs, Jordan S Orange, Jennifer M Puck, John M Routes, E Richard Stiehm, Kathleen Sullivan, Troy Torgerson, Jerry Winkelstein
雑誌名: J Allergy Clin Immunol. 2014 Apr;133(4):961-6. doi: 10.1016/j.jaci.2013.11.043. Epub 2014 Feb 28.
Abstract/Text The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine-derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.

Published by Mosby, Inc.
PMID 24582311  J Allergy Clin Immunol. 2014 Apr;133(4):961-6. doi: 10.・・・
著者: Sharmeel K Wasan, Stacey E Baker, Paul R Skolnik, Francis A Farraye
雑誌名: Am J Gastroenterol. 2010 Jun;105(6):1231-8. doi: 10.1038/ajg.2009.733. Epub 2010 Jan 26.
Abstract/Text The increasing use of corticosteroids, immune modulators, and biologics as a mainstay of therapy in certain Crohn's disease and ulcerative colitis patients have placed these inflammatory bowel disease (IBD) patients at increased risk for a variety of infections, many of which are preventable by prior vaccination. This article provides a review of the issues surrounding immunizations in the IBD patient and a practical guide for clinicians regarding the appropriate vaccinations to administer both before and during immunosuppressive therapy.

PMID 20104218  Am J Gastroenterol. 2010 Jun;105(6):1231-8. doi: 10.103・・・
著者: Lara Wine-Lee, Sara C Keller, Marissa B Wilck, Stephen J Gluckman, Abby S Van Voorhees
雑誌名: J Am Acad Dermatol. 2013 Dec;69(6):1003-13. doi: 10.1016/j.jaad.2013.06.046. Epub 2013 Sep 26.
Abstract/Text Patients with moderate to severe psoriasis often require systemic immunomodulatory medications that place them at risk for infection. Vaccination is a proven strategy to reduce infections. However, vaccination rates among patients with inflammatory autoimmune conditions, including psoriasis, remain low. We review the literature regarding vaccine-preventable illness and vaccinations commonly used in the United States in patients older than 18 years on immunosuppressive therapies that are used in the treatment of psoriasis. The medical board of the National Psoriasis Foundation recommends that dermatologists counsel patients on updating vaccinations in accordance with recommendations of the Advisory Committee for Immunization Practices as any measures taken to prevent infection can increase the safety of immunomodulatory therapies.

Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
PMID 24075223  J Am Acad Dermatol. 2013 Dec;69(6):1003-13. doi: 10.101・・・
著者: Jasvinder A Singh, Kenneth G Saag, S Louis Bridges, Elie A Akl, Raveendhara R Bannuru, Matthew C Sullivan, Elizaveta Vaysbrot, Christine McNaughton, Mikala Osani, Robert H Shmerling, Jeffrey R Curtis, Daniel E Furst, Deborah Parks, Arthur Kavanaugh, James O'Dell, Charles King, Amye Leong, Eric L Matteson, John T Schousboe, Barbara Drevlow, Seth Ginsberg, James Grober, E William St Clair, Elizabeth Tindall, Amy S Miller, Timothy McAlindon
雑誌名: Arthritis Rheumatol. 2016 Jan;68(1):1-26. doi: 10.1002/art.39480. Epub 2015 Nov 6.
Abstract/Text OBJECTIVE: To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA).
METHODS: We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.
RESULTS: The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional.
CONCLUSION: This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

© 2015, American College of Rheumatology.
PMID 26545940  Arthritis Rheumatol. 2016 Jan;68(1):1-26. doi: 10.1002/・・・
著者: S van Assen, N Agmon-Levin, O Elkayam, R Cervera, M F Doran, M Dougados, P Emery, P Geborek, J P A Ioannidis, D R W Jayne, C G M Kallenberg, U Müller-Ladner, Y Shoenfeld, L Stojanovich, G Valesini, N M Wulffraat, M Bijl
雑誌名: Ann Rheum Dis. 2011 Mar;70(3):414-22. doi: 10.1136/ard.2010.137216. Epub 2010 Dec 3.
Abstract/Text OBJECTIVES: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD).
METHODS: A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I-IV, the strength of recommendations was graded in categories A-D and Delphi voting was applied to determine the level of agreement between the experts of the task force.
RESULTS: Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed.
CONCLUSION: Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.

PMID 21131643  Ann Rheum Dis. 2011 Mar;70(3):414-22. doi: 10.1136/ard.・・・
著者: A M Geretti, BHIVA Immunization Writing Committee, Gary Brook, Claire Cameron, David Chadwick, Robert S Heyderman, Eithne MacMahon, Anton Pozniak, Mary Ramsay, M Schuhwerk
雑誌名: HIV Med. 2008 Nov;9(10):795-848. doi: 10.1111/j.1468-1293.2008.00637.x.
Abstract/Text
PMID 18983477  HIV Med. 2008 Nov;9(10):795-848. doi: 10.1111/j.1468-12・・・
著者:
雑誌名: Am J Surg Pathol. 1990 Aug;14(8):791.
Abstract/Text
PMID 2198814  Am J Surg Pathol. 1990 Aug;14(8):791.
著者: Kudzai Kanhutu, Penelope Jones, Allen C Cheng, Louise Grannell, Emma Best, Denis Spelman
雑誌名: Intern Med J. 2017 Aug;47(8):848-855. doi: 10.1111/imj.13348.
Abstract/Text People with asplenia/hyposplenism are at increased risk of fulminant sepsis, which carries a high mortality rate. A range of preventive measures is recommended although there is ongoing evidence that knowledge of and adherence to these strategies is poor. There have been significant changes in recommended vaccinations since the previously published recommendations in 2008. We provide current recommendations to help Australian and New Zealand clinicians in the prevention of sepsis in patients with asplenia and hyposplenia. The guideline includes Australian epidemiological data, preferred diagnostic techniques and recommendations for optimal antimicrobial prophylaxis and vaccination protocols.

© 2017 Royal Australasian College of Physicians.
PMID 27925427  Intern Med J. 2017 Aug;47(8):848-855. doi: 10.1111/imj.・・・
著者: Faruque Ahmed, Megan C Lindley, Norma Allred, Cindy M Weinbaum, Lisa Grohskopf
雑誌名: Clin Infect Dis. 2014 Jan;58(1):50-7. doi: 10.1093/cid/cit580. Epub 2013 Sep 17.
Abstract/Text BACKGROUND: Influenza vaccination of healthcare personnel (HCP) is recommended in >40 countries. However, there is controversy surrounding the evidence that HCP vaccination reduces morbidity and mortality among patients. Key factors for developing evidence-based recommendations include quality of evidence, balance of benefits and harms, and values and preferences.
METHODS: We conducted a systematic review of randomized trials, cohort studies, and case-control studies published through June 2012 to evaluate the effect of HCP influenza vaccination on mortality, hospitalization, and influenza cases in patients of healthcare facilities. We pooled trial results using meta-analysis and assessed evidence quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
RESULTS: We identified 4 cluster randomized trials and 4 observational studies conducted in long-term care or hospital settings. Pooled risk ratios across trials for all-cause mortality and influenza-like illness were 0.71 (95% confidence interval [CI], .59-.85) and 0.58 (95% CI, .46-.73), respectively; pooled estimates for all-cause hospitalization and laboratory-confirmed influenza were not statistically significant. The cohort and case-control studies indicated significant protective associations for influenza-like illness and laboratory-confirmed influenza. No studies reported harms to patients. Using GRADE, the quality of the evidence for the effect of HCP vaccination on mortality and influenza cases in patients was moderate and low, respectively. The evidence quality for the effect of HCP vaccination on patient hospitalization was low. The overall evidence quality was moderate.
CONCLUSIONS: The quality of evidence is higher for mortality than for other outcomes. HCP influenza vaccination can enhance patient safety.

PMID 24046301  Clin Infect Dis. 2014 Jan;58(1):50-7. doi: 10.1093/cid/・・・

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