JP5232006B2 - B型肝炎ウイルス表面抗原および界面活性剤の両方を含むワクチンの製造 - Google Patents
B型肝炎ウイルス表面抗原および界面活性剤の両方を含むワクチンの製造 Download PDFInfo
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- JP5232006B2 JP5232006B2 JP2008539536A JP2008539536A JP5232006B2 JP 5232006 B2 JP5232006 B2 JP 5232006B2 JP 2008539536 A JP2008539536 A JP 2008539536A JP 2008539536 A JP2008539536 A JP 2008539536A JP 5232006 B2 JP5232006 B2 JP 5232006B2
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Description
抗原を精製した後に非イオン性界面活性剤を抗原に添加する[3、4]のではなく、本発明は抗原の精製中に非イオン性界面活性剤を使用する。したがって、この界面活性剤は最終組み合わせワクチンにおいてその機能を果たすことができるが、汚染のリスク(したがって、調製後の組み合わせワクチン全体の損失のリスクも)は低下する。
本発明は、様々な非イオン性界面活性剤[5]、詳細にはワクチン製剤において見られる非イオン性界面活性剤を使用することができる。有機界面活性剤が好ましい。これらは典型的には、アルキレンオキシド(例えば、エチレンオキシド)と、高級アルコール、脂肪酸、アルキルフェノール、アルキルアミン、または少なくとも1つの活性水素原子を有する他の適切な化合物との反応生成物である。大部分の界面活性剤に関して、最も一般的なアルコール、アミンおよび酸はC8〜C18の範囲の炭素鎖長を有する。最も一般的なアルキルフェノールは、ノニルフェノールおよびオクチルフェノールである。ポリ(オキシエテン)残基を含む界面活性剤が特に好ましい。
B型肝炎ウイルス(HBV)は、ウイルス肝炎を引き起こす既知の因子の1つである。HBVビリオンは外側タンパク質コートまたはカプシドに囲まれた内部コアからなり、ウイルスコアはウイルスDNAゲノムを含む。カプシドの主な成分は、典型的には約24kDaの分子量を有する226アミノ酸ポリペプチドである、HBV表面抗原、またはより一般的に「HBsAg」として知られるタンパク質である。HBsAgを含むすべての既存のB型肝炎ワクチンは、この抗原を通常なワクチンに投与すると、それはHBV感染に対して防御する抗HBsAg抗体の産生を刺激する。
本発明の免疫原性組成物は、少なくとも1つの非HBV病原体由来の少なくとも1つの防御抗原を含む。非HBV病原体はウイルス性および/または細菌性であってよい。
− HBsAg、D、T
− HBsAg、D、T、Pw
− HBsAg、D、T、Pw、Hib
− HBsAg、D、T、Pw、Hib、MenA、MenC
− HBsAg、D、T、Pw、Hib、MenA、MenC、MenW135
− HBsAg、D、T、Pw、Hib、MenA、MenC、MenY
− HBsAg、D、T、Pw、Hib、MenA、MenC、MenW135、MenY
− HBsAg、D、T、Pa
− HBsAg、D、T、Pa、Hib
− HBsAg、D、T、Pa、ポリオウイルス
− HBsAg、D、T、Pa、ポリオウイルス、Hib
− HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC
− HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenA
− HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenY
− HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenW135
− HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenA、MenW135、MenY
− HBsAg、Hib
− HBsAg、A型肝炎ウイルス。
本発明の好ましい免疫原性組成物はアジュバントを含み、このアジュバントは1つまたは複数のアルミニウム塩、および特にリン酸アルミニウムアジュバントおよび/または水酸化アルミニウムアジュバントを含むことが好ましい。
本発明の方法は、精製HBsAgを少なくとも1つの非HBV病原体の由来の少なくとも1つの抗原と合わせるステップを含む。
本発明の組成物は(a)抗原成分、および(b)非抗原成分を含むことができる。抗原成分は前に記載した抗原を含むか、あるいはそれらからなってよい。非抗原成分は、以下でさらに詳細に記載するように、担体、アジュバント、賦形剤、バッファーなどを含むことができる。これらの非抗原成分は様々な供給源を有し得る。例えばそれらは、製造中に使用する、あるいはこれらの成分と別に加えることができる抗原またはアジュバント物質の1つ中に存在する可能性がある。
HBsAgとアジュバントを組み合わせた後、本発明の方法は容器に混合物の0.5mlサンプルを抽出およびパッケージするステップを含むことができる。多用量の状況に関しては、多用量を抽出し、1つの容器に一緒にパッケージするはずである。
− 前に記載したように水性組み合わせワクチンを調製するが、ただし前記1つまたは複数の抗原が複合体被膜糖抗原を含まないステップ、
− 第1の容器(例えばシリンジ)中で前記組み合わせワクチンをパッケージするステップ、
− 複合体被膜糖抗原を凍結乾燥形に調製するステップ、
− 前記凍結乾燥抗原を第2の容器(例えばバイアル)中でパッケージするステップ、および
− 第1の容器と第2の容器をキットに1つにパッケージするステップを含む方法を提供する。
本発明の組成物はヒト患者への投与に適しており、本発明は、本発明の組成物を患者に投与するステップを含む、患者における免疫応答を増大させる方法を提供する。
本発明の特異的な多価免疫原性組成物は以下の組成物を含む:
・ HBsAg、D、T、PaおよびIPVを含む5価組成物。ワクチンは水性形態である。それは水酸化アルミニウムアジュバントとリン酸アルミニウムアジュバントの両方を含む。HBsAgはリン酸アルミニウムに吸着する。D、TおよびPaは水酸化アルミニウムに吸着する。1ml当たりの量:約50Lfのジフテリアトキソイド;約20Lfの破傷風トキソイド;約50μgのPT;約50μgのFHA;約16μgのペルタクチン;約20μgのHBsAg;約80DUの1型ポリオウイルス;約16DUの2型ポリオウイルス;約64DUの3型ポリオウイルス。用量:約0.5ml。予め充填したシリンジ中に存在してよい。
・ 本発明によるHBsAgの精製;HBsAgのリン酸アルミニウムアジュバントへの吸着;チメロサールを含まない水酸化アルミニウムアジュバントとの2価D−T混合物の入手;Pa成分用のPT、FHAおよびペルタクチンの入手;好ましくはアルミニウム塩アジュバントを含まない型1、2および3としてプールするIPV抗原の入手;最終的な5価混合を得るための任意の順序でのD−T、Pa、IPVおよびHBsAgの組合せ;場合によってはシリンジへのパッケージ。
複合体糖抗原は、糖がそれに直接、あるいはリンカーを介して共有結合する担体タンパク質を含む。結合技法に関する一般的な情報は参考文献45において見ることができる。
用語「comprising」は「including」ならびに「consisting」を包含し、例えば、Xを「含む(comprising)」組成物はXのみからなる可能性があるか、あるいは他の何かを含む、例えばX+Yである可能性がある。
HBsAg発現および精製
HBsAgをコードするH.ポリモルファ酵母菌宿主[107、108]を調製した。300リットルの発酵槽中で100リットルの培地を調製し、酵母菌を接種した。100グラム/リットルで細胞が存在するまで発酵を続けた。この段階で、宿主がメチロトローフ酵母菌であるので、メタノールを加え、発酵を停止させた。最終培養物の体積は160〜170リットルであった。遠心分離によって培養培地から細胞を採取した。
酵母菌発現型HBsAg、ジフテリアトキソイド、破傷風トキソイドおよび完全細胞百日咳抗原を、アルミニウム塩アジュバントの懸濁液に加えた。混合物のpHを調節し、それがアルミニウムアジュバントに吸着した状態にならないようにHib−CRM197複合体を次いで加えた。この方法によって、以下の組成を有する5価ワクチンを得た:
3つの抗原成分を以下のように回収する:
− 3価D−T−Pw成分:水酸化アルミニウムアジュバントに吸着したジフテリアトキソイド、さらに水酸化アルミニウムアジュバントに吸着した破傷風トキソイド、および完全細胞百日咳抗原を含むD−T−Pw成分を調製した。D−T−Pw成分はリン酸アルミニウムアジュバントも含む。この成分はチメロサールを含むが、2−フェノキシエタノールは含まない。
Claims (24)
- 組み合わせワクチンを調製するためのプロセスであって、該ワクチンが(i)非イオン性界面活性剤、(ii)リン酸アルミニウムアジュバントに吸着されたB型肝炎ウイルス(HBV)表面抗原(HBsAg)、および(iii)少なくとも1つの非HBV病原体由来の抗原を含み、該プロセスが、
(a)組換え酵母細胞からHBsAg粒子を精製することであって、該精製は、該酵母細胞が該非イオン性界面活性剤の存在下で破壊して精製HBsAg成分を得るステップを含み、該プロセスは、HBsAg精製後に別個の成分として該非イオン性界面活性剤を添加するステップを含まないことと、
(b)該精製HBsAg成分を非HBV病原体由来の少なくとも1つの他の抗原と合わせて、該組み合わせワクチンを得ることを含む、プロセス。 - 組み合わせワクチンを調製するためのプロセスであって、該ワクチンが(i)非イオン性界面活性剤、(ii)リン酸アルミニウムアジュバントに吸着されたB型肝炎ウイルス(HBV)表面抗原(HBsAg)、および(iii)少なくとも1つの非HBV病原体由来の抗原を含み、該プロセスが、精製HBsAgを非HBV病原体由来の少なくとも1つの他の抗原と合わせて、組み合わせワクチンを得るステップを含み、該HBsAgは、
(a)HBsAg発現組換え酵母細胞を該非イオン性界面活性剤の存在下で破壊するプロセスによって調製され、該非イオン性界面活性剤は、該HBsAgの粒子中に保持され、該プロセスは、HBsAg精製後に別個の成分として該非イオン性界面活性剤を添加するステップを含まず、
(b)該リン酸アルミニウムに予め吸着される、
プロセス。 - 前記非イオン性界面活性剤がポリ(オキシエテン)残基を含む、請求項1または2に記載のプロセス。
- 前記非イオン性界面活性剤がポリオキシエチレンソルビタンエステルである、請求項3に記載のプロセス。
- 前記非イオン性界面活性剤がポリソルベート20である、請求項4に記載のプロセス。
- 前記非イオン性界面活性剤が30μg/ml以下で最終産物中に存在する、請求項1から5のいずれかに記載のプロセス。
- 前記非イオン性界面活性剤がHBsAg各100μgに対して50μg以下で最終産物中に存在する、請求項1から6のいずれかに記載のプロセス。
- (i)前記少なくとも1つの非HBV病原体がジフテリア菌および破傷風菌を含み、(ii)これら2つの病原体由来の該抗原がジフテリアトキソイドおよび破傷風トキソイドであり、かつ(iii)該ジフテリアトキソイドと該破傷風トキソイドがポリソルベート20を含まない混合された形態で最初に存在する、請求項1から7のいずれかに記載のプロセス。
- 前記HBV表面抗原がグリコシル化されていない、請求項1から8のいずれかに記載のプロセス。
- 前記HBV表面抗原が、リン脂質を含む脂質マトリクスを含む粒子の形態である、請求項1から9のいずれかに記載のプロセス。
- 前記HBV表面抗原がHBV亜型adw2に由来する、請求項1から10のいずれかに記載のプロセス。
- 前記HBV表面抗原が用量当たり約10μgで最終組成物中に存在する、請求項1から11のいずれかに記載のプロセス。
- 前記ワクチンがHib複合体、髄膜炎菌複合体、および/または肺炎球菌複合体を含む、請求項1から12のいずれかに記載のプロセス。
- 前記最終組成物が
3価HBsAg、D、T組成物;
4価HBsAg、D、T、Pw組成物;
5価HBsAg、D、T、Pw、Hib組成物;
7価HBsAg、D、T、Pw、Hib、MenA、MenC組成物;
8価HBsAg、D、T、Pw、Hib、MenA、MenC、MenW135組成物;8価HBsAg、D、T、Pw、Hib、MenA、MenC、MenY組成物;
9価HBsAg、D、T、Pw、Hib、MenA、MenC、MenW135、MenY組成物;
4価HBsAg、D、T、Pa組成物;
5価HBsAg、D、T、Pa、Hib組成物;
5価HBsAg、D、T、Pa、ポリオウイルス組成物;
6価HBsAg、D、T、Pa、ポリオウイルス、Hib組成物;
7価HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC組成物;
8価HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenA組成物;8価HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenY組成物;8価HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenW135組成物;
10価HBsAg、D、T、Pa、ポリオウイルス、Hib、MenC、MenA、MenW135、MenY組成物;
2価HBsAg、Hib組成物;および
2価HBsAg、A型肝炎ウイルス組成物
から選択される、請求項1から13のいずれかに記載のプロセス。 - 前記最終組成物がリン酸アルミニウムアジュバントと水酸化アルミニウムアジュバントの両方を含む、請求項1から14のいずれかに記載のプロセス。
- 前記最終組成物中のAl3+の濃度が5mg/ml以下である、請求項15に記載のプロセス。
- 予め混合したD−T成分を加えることを含む、請求項1から16のいずれかに記載のプロセス。
- 予め混合したD−T−Pw成分を加えることを含む、請求項1から16のいずれかに記載のプロセス。
- 前記予め混合したD−T−Pw成分がリン酸アルミニウムアジュバントと水酸化アルミニウムアジュバントの両方を含む、請求項18に記載のプロセス。
- 2容器の組み合わせワクチンを調製するためのプロセスであって、
− 請求項1〜19のいずれか1項に記載のプロセスによって水性組み合わせワクチンを調製するステップであって、ただし該ワクチンが複合体被膜糖抗原を含まないステップ、
− 第1の容器に該組み合わせワクチンをパッケージするステップ、
− 複合体被膜糖抗原を凍結乾燥形に調製するステップ、
− 該凍結乾燥抗原を第2の容器にパッケージするステップ、および
− 該第1の容器と該第2の容器を一緒にキットにパッケージするステップ
を含む、プロセス。 - 請求項1〜12のいずれか1項に記載のプロセスであって、
組み換え酵母細胞からHBsAgを精製するステップであって、該精製は、該酵母細胞を前記非イオン性界面活性剤の存在下で破壊して、精製HBsAg成分を得ることを含むステップ、
HBsAgをリン酸アルミニウムアジュバントに吸着するステップ;
チメロサールを含まない水酸化アルミニウムアジュバントとの2価D−T混合物の入手するステップ;
Pa成分用のPT、FHAおよびペルタクチンを入手するステップ;
好ましくはアルミニウム塩アジュバントを含まない型1、2および3としてプールするIPV抗原を入手するステップ;
任意の順序でD−T、Pa、IPVおよびHBsAgを組合せて、最終的な5価混合物を得るステップ;ならびに
場合によってはシリンジへパッケージするステップ
を含む、プロセス。 - 請求項1〜12のいずれか1項に記載のプロセスであって、
組み換え酵母細胞からHBsAgを精製するステップであって、該精製は、該酵母細胞を前記非イオン性界面活性剤の存在下で破壊して、精製HBsAg成分を得ることを含むステップ、
HBsAgをリン酸アルミニウムアジュバントに吸着するステップ;
2−フェノキシエタノールを含まずチメロサールを含む水酸化アルミニウムアジュバントおよびリン酸アルミニウムアジュバントとの3価D−T−Pw混合物を入手するステップ;
D−T−PwとHBsAgを組合せて、最終的な4価混合物を得るステップ;
場合によってはシリンジへパッケージするステップ;
場合によっては凍結乾燥複合体成分と組み合わせてパッケージするステップ
を含む、プロセス。 - 請求項1〜13のいずれか1項に記載のプロセスであって、
組み換え酵母細胞からHBsAgを精製するステップであって、該精製は、該酵母細胞を前記非イオン性界面活性剤の存在下で破壊して、精製HBsAg成分を得ることを含むステップ、
HBsAgをリン酸アルミニウムアジュバントに吸着するステップ;
2−フェノキシエタノールを含まずチメロサールを含む水酸化アルミニウムアジュバントおよびリン酸アルミニウムアジュバントとの3価D−T−Pw混合物を入手するステップ;
凍結乾燥Hib−T複合体を入手するステップ;
D−T−PwとHBsAgを組合せて水性4価成分を得るステップ;
水性4価成分をガラスバイアルへパッケージするステップ;
凍結乾燥Hib−Tをガラスバイアルへパッケージするステップ;
該2つのバイアルを組合せて水戻し用の単一キット中に存在させ、5価組み合わせワクチンを得るステップ
を含む、プロセス。 - 請求項1〜12のいずれか1項に記載のプロセスであって、
組み換え酵母細胞からHBsAgを精製するステップであって、該精製は、該酵母細胞を前記非イオン性界面活性剤の存在下で破壊して、精製HBsAg成分を得ることを含むステップ、
HBsAgをリン酸アルミニウムアジュバントに吸着するステップ;
2−フェノキシエタノールを含まずチメロサールを含む水酸化アルミニウムアジュバントおよびリン酸アルミニウムアジュバントとの3価D−T−Pw混合物を入手するステップ;
好ましくはアルミニウム塩アジュバントを含まない型1、2および3としてプールするIPV抗原を入手するステップ;
任意の順序でのD−T−Pw、IPVおよびHBsAgを組合せて最終的な5価混合物を得るステップ;
場合によってはシリンジへパッケージするステップ;
場合によっては凍結乾燥複合体成分と組み合わせてパッケージするステップ
を含む、プロセス。
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- 2006-11-07 JP JP2008539536A patent/JP5232006B2/ja not_active Expired - Fee Related
- 2006-11-07 US US12/084,753 patent/US20090155305A1/en not_active Abandoned
- 2006-11-07 EP EP06831744A patent/EP1948233A2/en not_active Withdrawn
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US9534845B2 (en) | 2011-05-27 | 2017-01-03 | Sgl Carbon Se | Method for manufacturing a refractory for an inner lining of a blast furnace and blast furnace having the inner lining |
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CN101330927A (zh) | 2008-12-24 |
CN101330927B (zh) | 2012-08-29 |
WO2007054820A2 (en) | 2007-05-18 |
GB0522765D0 (en) | 2005-12-14 |
WO2007054820A3 (en) | 2007-08-09 |
BRPI0618359A2 (pt) | 2011-08-23 |
US8802111B2 (en) | 2014-08-12 |
US20090155305A1 (en) | 2009-06-18 |
EP1948233A2 (en) | 2008-07-30 |
US20120107345A1 (en) | 2012-05-03 |
CA2628860A1 (en) | 2007-05-18 |
RU2444374C2 (ru) | 2012-03-10 |
JP2009514942A (ja) | 2009-04-09 |
US20140302087A1 (en) | 2014-10-09 |
JP2013056940A (ja) | 2013-03-28 |
RU2008123006A (ru) | 2009-12-20 |
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