JP6585624B2 - 肺炎連鎖球菌(Streptococcus pneumoniae)莢膜多糖体およびそれらのコンジュゲート - Google Patents
肺炎連鎖球菌(Streptococcus pneumoniae)莢膜多糖体およびそれらのコンジュゲート Download PDFInfo
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- JP6585624B2 JP6585624B2 JP2016564448A JP2016564448A JP6585624B2 JP 6585624 B2 JP6585624 B2 JP 6585624B2 JP 2016564448 A JP2016564448 A JP 2016564448A JP 2016564448 A JP2016564448 A JP 2016564448A JP 6585624 B2 JP6585624 B2 JP 6585624B2
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- serotype
- capsular polysaccharide
- polysaccharide
- streptococcus pneumoniae
- immunogenic
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Description
(a)肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B細菌細胞の発酵培養物を調製するステップと、
(b)前記発酵培養物中の細菌細胞を溶解するステップと、
(c)発酵培養物から肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を精製するステップと、
(d)精製した肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を高圧ホモジナイゼーションによりサイズ調節するステップと
を含むプロセスを提供する。
(a)本明細書に開示する活性型多糖体を担体タンパク質と混ぜ合わせるステップと、
(b)混ぜ合わせた活性型多糖体および担体タンパク質を還元剤と反応させて、血清型15B莢膜多糖体−担体タンパク質のコンジュゲートを形成するステップと
を含むプロセスを提供する。一態様では、本開示は、上記のプロセスにより得られるまたは得ることができる免疫原性コンジュゲートを提供する。
本明細書で使用する場合、多糖体または多糖体−担体タンパク質のコンジュゲートの「分子量」は、多角レーザー光散乱検出器(MALLS)と組み合わせたサイズ排除クロマトグラフィー(SEC)により計算する分子量を指す。
図1に示すように、血清型15Bの多糖体の反復単位は、分枝三糖骨格(1つのN−アセチルグルコサミン(GlcpNAc)、1つのガラクトピラノース(Galp)および1つのグルコピラノース(Glcp))と、GlcpNAcのC4ヒドロキシル基に連結するαGalp−βGalpの二糖分枝とからなる。ホスホグリセロールは、二糖分枝中のβGalp残基のC3ヒドロキシル基に連結する。血清型15B莢膜多糖体はO−アセチル化されており、O−アセチル化の総量は、多糖体の反復単位1つ当たりおよそ0.8〜0.9個のO−アセチル基である(例えば、C.Jonesら、Carbohydrate Research、340(2005)403〜409を参照されたい)。血清型15C血清型の莢膜多糖体は、血清型15Bと同一の骨格構造を有するが、O−アセチル化を欠く。
(a)血清型15B肺炎連鎖球菌(Streptococcus pneumoniae)細菌細胞の発酵培養物を調製するステップと、
(b)前記発酵培養物中の細菌細胞を溶解するステップと、
(c)発酵培養物から血清型15B多糖体を精製するステップと、
(d)精製した血清型15B多糖体を高圧ホモジナイゼーションによりサイズ調節するステップと
を含むプロセスにより得ることができる。
単離血清型15B莢膜多糖体を担体タンパク質にコンジュゲートさせて、免疫原性コンジュゲートを得ることができる。単離多糖体を、当業者に公知の方法により担体タンパク質にコンジュゲートさせることができる(例えば、米国特許出願公開第20060228380号、第20070184071号、第20070184072号、第20070231340号、またはWO2011/100151を参照されたい)。
活性型の血清型15B莢膜多糖体を、単離血清型15B莢膜多糖体を酸化剤と反応させることによって得る。例えば、前記活性型の血清型15B莢膜多糖体を、
(a)血清型15B肺炎連鎖球菌(Streptococcus pneumoniae)細菌細胞の発酵培養物を調製するステップと、
(b)前記発酵培養物中の細菌細胞を溶解するステップと、
(c)発酵培養物から血清型15B多糖体を精製するステップと、
(d)精製した血清型15B多糖体を高圧ホモジナイゼーションによりサイズ調節するステップと、
(e)サイズ調節した血清型15B多糖体を酸化剤と反応させるステップと
を含むプロセスにより得ることができる。
活性型の血清型15B莢膜多糖体を、
(a)活性型の血清型15B莢膜多糖体を担体タンパク質と混ぜ合わせるステップと、
(b)混ぜ合わせた活性型の血清型15B莢膜多糖体および担体タンパク質を還元剤と反応させて、血清型15B莢膜多糖体−担体タンパク質のコンジュゲートを形成するステップと
を含むプロセスにより、担体タンパク質にコンジュゲートさせることができる。
(a)血清型15B肺炎連鎖球菌(Streptococcus pneumoniae)細菌細胞の発酵培養物を調製するステップと、
(b)前記発酵培養物中の細菌細胞を溶解するステップと、
(c)発酵培養物から血清型15B多糖体を精製するステップと、
(d)精製した血清型15B多糖体を高圧ホモジナイゼーションによりサイズ調節するステップと、
(e)サイズ調節した血清型15B多糖体を酸化剤と反応させるステップと、
(f)活性型の血清型15B多糖体を担体タンパク質と混ぜ合わせるステップと、
(g)混ぜ合わせた活性型の血清型15B多糖体および担体タンパク質を還元剤と反応させて、血清型15B多糖体−担体タンパク質のコンジュゲートを形成するステップと、
(h)未反応のアルデヒドをNaBH4の添加によりキャップ(クエンチング)するステップと
を含む。
用語「免疫原性組成物」は、抗原、例えば、微生物またはその構成成分を含有する任意の医薬組成物に関し、この組成物を使用して、対象の免疫応答を惹起することができる。
(1)アルミニウム塩(ミョウバン)、例として、水酸化アルミニウム、リン酸アルミニウム、硫酸アルミニウム等;
(2)水中油型乳剤の製剤(ムラミルペプチド(下記に定義)または細菌細胞壁の構成成分等のその他の特異的な免疫賦活剤がある場合またはない場合の)、例えば、
(a)5%スクアレン、0.5%5Tween80および0.5%Span85を含有し((必ずしも必要ではないが)種々の量のMTP−PE(下記を参照されたい)を含有していてもよい)、顕微溶液化装置、例として、モデル11OY顕微溶液化装置(Microfluidics、Newton、MA)を使用してサブミクロン粒子に製剤化されたMF59(PCT公開第WO90/14837号)
(b)10%スクアレン、0.4%Tween80、5%プルロニックブロックポリマーL121およびthr−MDP(下記を参照されたい)を含有し、顕微溶液化したサブミクロン乳剤またはボルテックスして作製したより大きな粒子サイズの乳剤のいずれかのSAF、さらに、
(c)2%スクアレン、0.2%Tween80、ならびに米国特許第4,912,094号(Corixa)に記載されている3−O−デスアシルモノホスホリルリピドA(MPL(商標))、トレハロースジミコール酸(TDM)および細胞壁骨格(CWS)からなる群から得られる1つまたは複数の細菌細胞壁構成成分、好ましくは、MPL+CWS(Detox(商標))を含有するRibi(商標)アジュバント系(RAS)(Corixa、Hamilton、MT)
等;
(3)サポニンのアジュバント、例として、Quil AもしくはSTIMULON(商標)QS−21(Antigenics、Framingham、MA)(米国特許第5,057,540号)を使用することができ、またはそれらから作製した粒子、例として、ISCOM(免疫賦活複合体);
(4)細菌のリポ多糖;合成リピドA類似体、例として、Corixaから入手可能であり、米国特許第6,113,918号に記載されているアミノアルキルグルコサミンホスフェート化合物(AGP)またはそれらの誘導体もしくは類似体;1つのそのようなAGPが、水性形態または安定な乳剤として製剤化された2−[(R)−3−テトラデカノイルオキシテトラデカノイルアミノ]エチル2−デオキシ−4−O−ホスホノ−3−O−[(R)−3−テトラデカノイルオキシテトラデカノイル]−2−[(R)−3−テトラデカノイルオキシテトラデカノイルアミノ]−b−D−グルコピラノシドであり、これは、529としてもまた公知である(以前は、RC529として公知であった);合成ポリヌクレオチド、例として、CpGモチーフを含有するオリゴヌクレオチド(米国特許第6,207,646号);
(5)サイトカイン、例として、インターロイキン(例えば、IL−1、IL−2、IL−4、IL−5、IL−6、IL−7、IL−12、IL−15、IL−18等)、インターフェロン(例えば、ガンマインターフェロン)、顆粒球マクロファージコロニー刺激因子(GM−CSF)、マクロファージコロニー刺激因子(M−CSF)、腫瘍壊死因子(TNF)、共刺激分子87−1および87−2等;
(6)細菌のADPリボシル化毒素の解毒突然変異体、例として、コレラ毒素(CT)の野生型もしくは突然変異体形態のいずれか、例えば、公開されている国際特許出願公開第WO00/18434号(また、WO02/098368およびWO02/098369も参照されたい)に従う29位のアミノ酸のグルタミン酸が別のアミノ酸、好ましくは、ヒスチジンで置き換えられているもの、百日咳毒素(PT)、または大腸菌(E.coli)の熱不安定性毒素(LT)、特に、LT−K63、LT−R72、CT−S109、PT−K9/G129(例えば、WO93/13302およびWO92/19265を参照されたい);さらに、
(7)免疫賦活剤として作用して組成物の有効性を増強する、その他の物質
が挙げられる。
5’TCGTCGTTTTTCGGTGCTTTT3’(配列番号3)、または
5’TCGTCGTTTTTCGGTCGTTTT3’(配列番号4)、または
5’TCGTCGTTTTGTCGTTTTGTCGTT3’(配列番号5)、または
5’TCGTCGTTTCGTCGTTTTGTCGTT3’(配列番号6)、または
5’TCGTCGTTTTGTCGTTTTTTTCGA3’(配列番号7)
を有する。
5’T*C*G*T*C*G*T*T*T*T*T*C*G*G*T*G*C*T*T*T*T3’(配列番号8)、または
5’T*C*G*T*C*G*T*T*T*T*T*C*G*G*T*C*G*T*T*T*T3’(配列番号9)、または
5’T*C*G*T*C*G*T*T*T*T*G*T*C*G*T*T*T*T*G*T*C*G*T*T3’(配列番号10)、または
5’T*C*G*T*C*G*T*T*T*C*G*T*C*G*T*T*T*T*G*T*C*G*T*T3’(配列番号11)、または
5’T*C*G*T*C*G*T*T*T*T*G*T*C*G*T*T*T*T*T*T*T*C*G*A3’(配列番号12)
が挙げられ、
ここで、*は、ホスホロチオエート結合を指す。
5’TCGCGTCGTTCGGCGCGCGCCG3’(配列番号13)、または
5’TCGTCGACGTTCGGCGCGCGCCG3’(配列番号14)、または
5’TCGGACGTTCGGCGCGCGCCG3’(配列番号15)、または
5’TCGGACGTTCGGCGCGCCG3’(配列番号16)、または
5’TCGCGTCGTTCGGCGCGCCG3’(配列番号17)、または
5’TCGACGTTCGGCGCGCGCCG3’(配列番号18)、または
5’TCGACGTTCGGCGCGCCG3’(配列番号19)、または
5’TCGCGTCGTTCGGCGCCG3’(配列番号20)、または
5’TCGCGACGTTCGGCGCGCGCCG3’(配列番号21)、または
5’TCGTCGTTTTCGGCGCGCGCCG3’(配列番号22)、または
5’TCGTCGTTTTCGGCGGCCGCCG3’(配列番号23)、または
5’TCGTCGTTTTACGGCGCCGTGCCG3’(配列番号24)、または
5’TCGTCGTTTTCGGCGCGCGCCGT3’(配列番号25)
を有する。
5’T*C_G*C_G*T*C_G*T*T*C_G*G*C*G*C_G*C*G*C*C*G3’(配列番号26)、または
5’T*C_G*T*C_G*A*C_G*T*T*C_G*G*C*G*C_G*C*G*C*C*G3’(配列番号27)、または
5’T*C_G*G*A*C_G*T*T*C_G*G*C*G*C_G*C*G*C*C*G3’(配列番号28)、または
5’T*C_G*G*A*C_G*T*T*C_G*G*C*G*C*G*C*C*G3’(配列番号29)、または
5’T*C_G*C_G*T*C_G*T*T*C_G*G*C*G*C*G*C*C*G3’(配列番号30)、または
5’T*C_G*A*C_G*T*T*C_G*G*C*G*C_G*C*G*C*C*G3’(配列番号31)、または
5’T*C_G*A*C_G*T*T*C_G*G*C*G*C*G*C*C*G3’(配列番号32)、または
5’T*C_G*C_G*T*C_G*T*T*C_G*G*C*G*C*C*G3’(配列番号33)、または
5’T*C_G*C_G*A*C_G*T*T*C_G*G*C*G*C_G*C*G*C*C*G3’(配列番号34)、または
5’T*C*G*T*C*G*T*T*T*T*C*G*G*C*G*C*G*C*G*C*C*G3’(配列番号35)、または
5’T*C*G*T*C*G*T*T*T*T*C*G*G*C*G*G*C*C*G*C*C*G3’(配列番号36)、または
5’T*C*G*T*C_G*T*T*T*T*A*C_G*G*C*G*C*C_G*T*G*C*C*G3’(配列番号37)、または
5’T*C_G*T*C*G*T*T*T*T*C*G*G*C*G*C*G*C*G*C*C*G*T3’(配列番号38)
が挙げられ、
ここで、*は、ホスホロチオエート結合を指し、_は、リン酸ジエステル結合を指す。
5’T*C_G*T*C_G*A*C_G*A*T*C_G*G*C*G*C_G*C*G*C*C*G3’(配列番号:40)
が挙げられ、
ここで、*は、ホスホロチオエート結合を指し、_は、リン酸ジエステル結合を指す。
本開示はまた、本明細書に記載する免疫原性組成物についての使用方法も含む。例えば、本開示の一実施形態は、肺炎連鎖球菌(Streptococcus pneumoniae)に対する免疫応答を誘発する方法であって、免疫原性量の、本明細書に記載する免疫原性組成物のいずれかを対象に投与するステップを含む方法を提供する。
単離肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体の調製
1.1 発酵および精製
血清型15B莢膜多糖体は、当業者に公知の単離の手順を使用して細菌から直接得ることができる(例えば、米国特許出願公開第20060228380号、第20060228381号、第20070184071号、第20070184072号、第20070231340号および第20080102498号、またはWO2008118752に開示されている方法を参照されたい)。血清型15Bの肺炎連鎖球菌(Streptococcus pneumoniae)を、培養ボトル中で増殖し、次いで、培養発酵槽に移した。細胞が標的とする光学密度に達したら、細胞を生産用発酵槽に移した。発酵ブロスを、N−ラウロイルサルコシンを添加することによって不活性化し、限外ろ過および透析ろ過により精製した。
多糖体の酸化を、100mMのリン酸カリウム緩衝液(pH6.0±0.2)中で、2.0g/Lの多糖体の最終濃度を得るように計算された量の500mMのリン酸カリウム緩衝液(pH6.0)およびWFIを逐次添加することによって実施した。必要であれば、反応pHを、およそpH6.0に調整した。pH調整の後に、反応温度を、23±2℃に調整した。酸化を、およそ0.25モル当量の過ヨウ素酸ナトリウムを添加することによって開始した。酸化反応を、23±2℃でおよそ16時間の間実施した。
コンジュゲーションのプロセスは、
a)スクロース賦形剤と混ぜ合わせ、凍結乾燥を行うステップと、
b)凍結乾燥した活性型多糖体およびCRM197を復元するステップと、
c)活性型多糖体をCRM197にコンジュゲートさせ、キャップするステップと、
d)コンジュゲートを精製するステップと
からなる。
活性型多糖体をスクロースと混ぜ合わせて、活性型多糖体1グラム当たり25グラムのスクロースの比とした。次いで、混ぜ合わせた混合物のボトルを凍結乾燥した。凍結乾燥に続き、凍結乾燥した活性型多糖体を含有するボトルを、−20±5℃で保存した。計算量のCRM197タンパク質を別途、シェルフリーズおよび凍結乾燥した。凍結乾燥したCRM197を、−20±5℃で保存した。
凍結乾燥した活性型多糖体を、無水ジメチルスルホキシド(DMSO)中で復元した。多糖体が完全に溶解したら、等しい量の無水DMSOを凍結乾燥したCRM197に添加して、復元を行った。
反応槽中で、復元した活性型多糖体を復元したCRM197と組み合わせ(投入量の比:0.8:1)、続いて、徹底的に混合して、透明溶液を得てから、シアノ水素化ホウ素ナトリウムを用いてコンジュゲーションを開始した。反応溶液中の多糖体の最終濃度は、およそ1g/Lである。コンジュゲーションを、反応混合物に1.0〜1.5MEqのシアノ水素化ホウ素ナトリウムを添加することによって開始し、インキュベーションを23±2℃で40〜48時間行った。2MEqの水素化ホウ素ナトリウム(NaBH4)を添加して、未反応のアルデヒドをキャップすることによって、コンジュゲーション反応を止めた。このキャッピング反応を、23±2℃で3±1時間継続した。
コンジュゲート溶液を、100〜300KのMWCOメンブランを使用するタンジェンシャルフローろ過による精製に備えて、冷やした5mMコハク酸−0.9%生理食塩水(pH6.0)を用いて1:10に希釈した。希釈したコンジュゲート溶液を5μmのフィルターに通し、透析ろ過を、媒体として5mMコハク酸−0.9%生理食塩水(pH6.0)を使用して実施した。透析ろ過の完了の後に、コンジュゲート保持液を0.22μmのフィルターに通した。
CRM197に共有結合的に連結された肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を含む免疫原性コンジュゲートの特徴付け
コンジュゲート1は、実施例1に開示したプロセスにより調製した。コンジュゲート2および3は、異なる量の酸化剤を使用する類似のプロセスにより調製した。コンジュゲート4は、類似のプロセスにより調製したが、ただし、精製した血清型15B莢膜多糖体は、サイズ調節せずに、活性化させて、より低いDO(より高い酸化のレベル)を得、コンジュゲーションは、水性媒体中で実施した。コンジュゲート5は、類似のプロセスにより調製したが、ただし、精製した血清型15B莢膜多糖体は、化学的加水分解によりサイズ調節し、コンジュゲーションは、水性媒体中で実施した。コンジュゲート6および7は、類似のプロセスにより調製したが、ただし、精製した血清型15B莢膜多糖体は、サイズ調節しなかった。
オプソニン化貪食活性(OPA)アッセイ
本発明のコンジュゲートの免疫原性は、下記に記載するオプソニン化貪食作用アッセイ(OPA)を使用して評価することができる。
血清型15Bと血清型15Cとの間の交差機能性OPA応答
肺炎球菌血清群15には、4つの、構造的に関連のある血清型:15A、15B、15Cおよび5Fが含まれる。血清型15Bおよび15Cは、遺伝子タイピングの技法によっては区別できず、15B−PSは15C−PSのO−アセチル化バリアントであることを除いて、類似の莢膜多糖体(PS)組成を有する。血清型15Bについての抗莢膜PS抗体が血清型15Cに対して機能的な交差反応性を示すかどうかを理解するために、10匹のウサギを、本明細書に開示するCRM197に共有結合的に連結された肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を含む免疫原性コンジュゲートをいずれもその製剤の一部として含有するPCV16vワクチンおよびPCV20vワクチンを用いて免疫した。ワクチン接種の前および後に得られた血清を、OPAアッセイ中で、血清型15Bおよび15Cの標的の肺炎球菌の菌株に対して試験した。
Claims (19)
- 担体タンパク質に共有結合的に連結された単離肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を含む免疫原性コンジュゲートであって、前記血清型15B莢膜多糖体中に存在するO−アセチルの数が、前記血清型15B莢膜多糖体1μmol当たり少なくとも0.6、0.7または0.8μmolであり、前記血清型15B莢膜多糖体が100kDa〜350kDaの間の分子量を有する、免疫原性コンジュゲート。
- 前記血清型15B莢膜多糖体中に存在するグリセロールの数が、前記血清型15B莢膜多糖体1μmol当たり少なくとも0.1、0.2、0.3、0.4、0.5、0.6、0.7または0.8μmolである、請求項1に記載の免疫原性コンジュゲート。
- 前記血清型15B莢膜多糖体中に存在するグリセロールの数が、前記血清型15B莢膜多糖体1μmol当たり少なくとも0.6μmolである、請求項1または2に記載の免疫原性コンジュゲート。
- 担体タンパク質がCRM197である、請求項1から3のいずれか一項に記載の免疫原性コンジュゲート。
- 血清型15B莢膜多糖体の総量と比較して、遊離の血清型15B莢膜多糖体を約50、45、40、35、30、25、20または15%未満を含む、および/または
3000〜20000kDa;8000〜20000kDa;8000〜16000kDa;または10000〜16000kDaの間の分子量を有する、および/または
コンジュゲート中の担体タンパク質に対する血清型15B莢膜多糖体の比が、0.4〜2の間である、および/または
少なくとも40%の免疫原性コンジュゲートが、CL−4Bカラム中で0.3以下のKdを有する、および/または
コンジュゲーションの程度が、2〜15;2〜13;2〜10;2〜8;2〜6;2〜5;2〜4;3〜15;3〜13;3〜10;3〜8;3〜6;3〜5;3〜4;5〜15;5〜10;8〜15;8〜12;10〜15;または10〜12の間である、
請求項1から4のいずれか一項に記載の免疫原性コンジュゲート。 - 請求項1から5のいずれか一項に記載の免疫原性コンジュゲート、および生理学的に許容できるビヒクルを含む免疫原性組成物。
- 少なくとも1つの追加の抗原および/またはアジュバントをさらに含む、請求項6に記載の免疫原性組成物。
- 請求項6または7に記載の免疫原性組成物を含むワクチン。
- 担体タンパク質に共有結合的に連結された肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を含む免疫原性コンジュゲートを調製するためのプロセスであって、
(a)血清型15B莢膜多糖体中に存在するO−アセチルの数が、前記血清型15B莢膜多糖体1μmol当たり少なくとも0.6、0.7または0.8μmolであり、かつ、100kDa〜350kDaの間の分子量を有する、血清型15B莢膜多糖体を酸化剤と反応させることによって得られる活性型の血清型15B莢膜多糖体を担体タンパク質と混ぜ合わせるステップと、
(b)混ぜ合わせた活性型多糖体および担体タンパク質を還元剤と反応させて、血清型15B莢膜多糖体−担体タンパク質のコンジュゲートを形成するステップと
を含むプロセス。 - 活性型の血清型15B莢膜多糖体が100kDa〜300kDaの間の分子量を有する、および/または
活性型の血清型15B莢膜多糖体中に存在するグリセロールの数が、前記血清型15B莢膜多糖体1μmol当たり少なくとも0.1、0.2、0.3、0.4、0.5、0.6、0.7または0.8μmolである、および/または
活性型の血清型15B莢膜多糖体が2〜20、2〜15、2〜10、2〜5、5〜20、5〜15、5〜10、10〜20、10〜15または15〜20の間の酸化の程度により特徴付けられる、
請求項9に記載のプロセス。 - 血清型15B莢膜多糖体が、
(a)血清型15Bの肺炎連鎖球菌(Streptococcus pneumoniae)細菌細胞の発酵培養物を調製するステップと、
(b)前記発酵培養物中の細菌細胞を溶解するステップと、
(c)発酵培養物から肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を精製するステップと、
(d)精製した肺炎連鎖球菌(Streptococcus pneumoniae)血清型15B莢膜多糖体を高圧ホモジナイゼーションによりサイズ調節するステップと
を含むプロセスによって得られる、請求項9または10に記載のプロセス。 - 担体タンパク質がCRM197である、請求項9から11のいずれか一項に記載のプロセス。
- 請求項9のステップ(a)およびステップ(b)が、DMSO中で実施される、または水溶液中で実施される、請求項9から12のいずれか一項に記載のプロセス。
- ステップ(b)の活性型の血清型15B莢膜多糖体の濃度が、0.1〜10mg/mL、0.5〜5mg/mLまたは0.5〜2mg/mLの間である、および/または
活性型の血清型15B莢膜多糖体対担体タンパク質の初期投入量の比が、5:1〜0.1:1、2:1〜0.1:1、2:1〜1:1、1.5:1〜1:1、0.1:1〜1:1、0.3:1〜1:1、0.6:1〜1:1または0.6:1〜1.5:1の間である、および/または
ステップ(b)において、活性型多糖体を、約1〜2の間のモル当量のシアノ水素化ホウ素ナトリウムと約20〜26℃の間の温度で約40〜50時間の間反応させる、
請求項9から13のいずれか一項に記載のプロセス。 - 追加の、
(c)未反応のアルデヒドをNaBH4の添加によりキャップするステップを含む、請求項9から14のいずれか一項に記載のプロセス。 - コンジュゲートを多価ワクチンとして製剤化するステップをさらに含む、請求項9から15のいずれか一項に記載のプロセス。
- 請求項9のコンジュゲーションのステップ(b)の収率が50%超である、請求項9から16のいずれか一項に記載のプロセス。
- 免疫原性量の請求項6もしくは7に記載の免疫原性組成物または請求項8に記載のワクチンを含む、血清型15Bの肺炎連鎖球菌(Streptococcus pneumoniae)による感染の防御剤。
- 治療有効量または予防有効量の請求項6もしくは7に記載の免疫原性組成物または請求項8に記載のワクチンを含む、血清型15Bおよび/または15Cの肺炎連鎖球菌(Streptococcus pneumoniae)と関連がある肺炎連鎖球菌(Streptococcus pneumoniae)による感染、疾患または状態の治療剤または予防剤。
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