TW201442724A - 免疫原之睪丸內注射 - Google Patents
免疫原之睪丸內注射 Download PDFInfo
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- TW201442724A TW201442724A TW103109597A TW103109597A TW201442724A TW 201442724 A TW201442724 A TW 201442724A TW 103109597 A TW103109597 A TW 103109597A TW 103109597 A TW103109597 A TW 103109597A TW 201442724 A TW201442724 A TW 201442724A
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- rabies
- vaccine
- chemical sterilization
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- zinc gluconate
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Abstract
本發明係關於一種藉由將免疫原注射至個體之睾丸中來誘導免疫反應之方法。一種睾丸內注射用組成物包括諸如狂犬病疫苗之免疫原，及經中和至pH 6.0至7.5之由能夠形成水溶液之葡萄糖酸鋅及胺基酸形成的化學絕育劑。當睾丸內注射時，該免疫原得到緩慢釋放，從而減少或消除對「加強」劑量之需要，同時該化學絕育劑有效地減少了狗群體數量。
Description
本發明係關於能夠誘導免疫反應之免疫原之睾丸內注射。該注射經由將該免疫原緩慢釋放至個體之血管系統中來使該個體之免疫系統受到持續刺激。諸如化學絕育劑之其他醫學產品可與該免疫原組合用於睾丸內注射。
舉例而言，疫苗當經注射至個體之身體中時會誘導免疫反應。已知皮下注射疫苗會導致局部反應，諸如刺激、發炎、肉芽腫形成及壞死。由於該原因，大多數疫苗係經由肌肉內途徑投予至大腿之三角肌或前外側面。因為肌肉血液供給豐富而使疫苗快速分散至個體之血管系統中，所以肌肉可免受注射於其中之物質的有害作用。疫苗刺激個體之免疫系統以產生對抗感染所需之微生物對抗工具，其中一些係在已觸發免疫反應之後保持於迴圈中。但遲早地，由疫苗提供之免疫性會逐漸減弱且可能需要「加強(booster)」劑量來使免疫性程度恢復。這便需要第二次肌肉內注射。
儘管有效狂犬病疫苗可用於肌肉內注射，但在一些國家，狂犬病仍是一個嚴重問題。例如在泰國，流浪狗及社區狗為狂犬病之主要載體且一直未得到處理，大多數被狂犬病狗咬到之受害者會死亡，且許多為兒童。存在昂貴之暴露後處理，但在許多地區，暴露後處理仍不可利用。為了控制狂犬病，已發現必須對60%至80%之狗進行狂犬病疫苗接種。為了在可承受之預算內在流浪狗及社區狗群體中達成該目標，可能有必要減少狗之數目。但文化障礙會阻止大規模挑選狗以便對狗群體中足夠量之狗進行疫苗接種以消除狂犬病。當不足量的狗經接種疫苗以自狗群體消除狂犬病時，有必要以三年或三年以下之間隔向經免疫之狗投予「加強」劑量，此會極大地增加控制狂犬病之成本。
根據本發明，揭示了睾丸內注射之免疫原的藥物動力學釋放會比肌肉內注射時持續更長之時段，因此使個體之免疫系統得到持續刺激。一種睾丸內注射用組成物包含化學絕育劑及能夠誘導免疫反應之免疫原，其中該化學絕育劑為能夠形成水溶液之葡萄糖酸鋅及胺基酸，該葡萄糖酸鋅與胺基酸係以實質上等莫耳之量及在約0.05M至2.0M之範圍內之濃度下存在且經中和至約6.0至約7.5之pH值。當該免疫原為狂犬病疫苗且與化學絕育劑組合時，可能需要注射較少狂犬病疫苗以實現針對狂犬病之接種。所揭示之方法中包括當免疫原為乾燥之不活化狂犬病疫苗時形成上述組成物之方法。在該情況下，組成物必須在形成之後立即注射或冷藏儲存。
上文概括之本發明包含下述組成物及方法，本發明之範疇係由隨附申請專利範圍指示。
圖1為顯示在肌肉內注射乙酸鋅之後定期收集之血液中之鋅含量的圖；圖2為顯示在睾丸內注射乙酸鋅之後定期收集之血液中之鋅含量的圖；以及圖3為顯示在睾丸內注射Esterilsoltm及安慰劑、狂犬病疫苗及安慰劑以及Esterilsol及狂犬病疫苗之後四周之時間內的狂犬病抗體效價之圖。
免疫原為當注射至宿主身體中時能夠誘導免疫反應之物質。舉例而言，疫苗免疫原典型地含有類似於致病性微生物之藥劑，且經常由弱化或殺滅形式之微生物、其毒素或一種其表面蛋白製成。該藥劑刺激身體之免疫系統以將該藥劑識別成外來的、破壞其且記得其，以使免疫系統可更容易地識別及破壞其稍後遇到之任何微生物。疫苗注射並不保證完全保護以避免該疾病，而是通常，當一經接種疫苗之個體確實顯現接種疫苗所針對之疾病時，疾病可能比未接種疫苗時溫和。
可用疫苗免疫原治療之疾病中包括炭疽、白喉、b型流感嗜血
桿菌(Hib)、A型肝炎、B型肝炎、人類乳頭狀瘤病毒(HPV)、流感、日本腦炎、萊姆病(Lyme Disease)、麻疹(Measles)、腦膜炎球菌、腮腺炎、百日咳(Pertussis；Whooping Cough)、肺炎球菌疾病、脊髓灰質炎(Polio)、狂犬病、輪狀病毒、風疹(Rubella)、帶狀皰疹(Shingles；Herpes Zoster)、天花、破傷風、結核、傷寒、水痘(Varicella；Chickenpox)及黃熱病。
組合疫苗將預防不同疾病之免疫原或防禦導致同一疾病之多種傳染物病毒株的免疫原合併至單一產品中。因此，其會減少預防一些疾病所需之注射的數目。代表性組合疫苗包括白喉及破傷風毒素及全細胞百日咳疫苗(DDTwP)；麻疹-腮腺炎-風疹疫苗(MMR)；及三價不活化脊髓灰質炎疫苗(IPV)。在美國得到許可之其他組合包括白喉及破傷風類毒素及非細胞百日咳疫苗(DTaP)、DTwP-b型流感嗜血桿菌(Hib)疫苗(DTwP-Hib)、DTaP-Hib及Hib-B型肝炎(HepB)疫苗(Hib-HepB)。如單個病毒株疫苗之組合疫苗可為睾丸內注射之候選物。
申請者之工作集中于向狗睾丸內注射與化學絕育劑組合之狂犬病疫苗，但本發明可應用於具有陰囊睾丸之其他物種(包括人類)及無化學絕育劑之免疫原注射。
適用於睾丸內注射之用於對狗進行預防接種之狂犬病疫苗可含有不活化狂犬病病毒或活的減弱病毒。大多數當今使用之狂犬病疫苗含有不活化狂犬病病毒。若干製造商提供組合疫苗，其包括多種不同抗原(例如瘟熱(distemper)、腺病毒、鉤端螺旋體、副流行性感冒、小病毒(parvovius)等)以及狂犬病免疫原。過去已使用了活的減弱病毒疫苗，諸如LEP(低卵胚繼代(low egg passage))、HEP(高卵胚繼代)及ERA(Evelyn Rokitniki Abelseth)，且亦可使用重組型疫苗及其他基因工程產品。
許多市售狂犬病疫苗係以乾燥形式提供且在復原之後需要冷藏或應棄置。舉例而言，由Sanofi Pasteur SA製造之Imovaxtm狂犬病疫苗為無菌、穩定、經冷凍乾燥之狂犬病病毒懸浮液且在不含防腐劑之單劑量小瓶中提供用於肌肉內注射。在復原之後，公司說明書規定應立即肌肉內注射完整1.0ml量之疫苗且若不立即投予，則棄置。對於睾丸內注射，注射至睾丸中之狂犬病疫苗之量可與推薦用於肌肉內注射之量相當，但如實施例3中
所示，可能必需較小量。
Fahim之美國專利第5,070,080號中揭示與免疫原組合之用於本發明的化學絕育劑，且Wang之美國專利第7,276,535號中揭示注射化學絕育劑之較佳方法。'080專利中所述之化學絕育劑為能夠形成水溶液之葡萄糖酸鋅鹽及胺基酸，其以酸中和至在範圍6.0至8.0、較佳約6.0至約7.5且最佳為約7.0之pH值。適用于中和葡萄糖酸鋅之胺基酸包括丙胺酸、纈胺酸、異白胺酸、脯胺酸、甘胺酸、絲胺酸、酥胺酸、天冬醯胺、麩醯胺酸、離胺酸、精胺酸、組胺酸及其混合物。
在中和葡萄糖酸鋅時，較佳的是，葡萄糖酸鋅與胺基酸係以實質上等莫耳之量存在且需要最小可能之有效量之化學絕育劑注射至睾丸中。在'080專利中，自側部或底部將化學絕育劑注射至睾丸之中線。但如'535專利中所揭示，可藉由將化學絕育劑注射至附睾旁之睾丸的背側前方部分(dorsal cranial portion)中來將劑量減到最小。Wang之國際公開案第WO 2009/045337 A1號中描述化學絕育劑用於控制狗群體之用途。如所揭示，化學絕育劑在狗群體中實現絕育而不影響絕育狗之狀態。絕育狗與接受性雌性「交配」，但不會產生小狗且遲早會使狗群體減少。
化學絕育劑與狂犬病疫苗之組合及上述方法藉由降低經處理之雄性之交配效力來減少社區中之狗群體數量。其亦使狂犬病疫苗持續釋放以便持續刺激狗對狂犬病之免疫反應，從而減少(或消除)對「加強」劑量之需要。此作用組合可甚至在開發中國家之預算內對狂犬病加以控制。
以下資料說明本發明，其中睾丸內注射免疫原。
對六隻40日齡且平均重量為15kg之混合杜洛克豬(Duroc pig)(三隻雄性及三隻雌性)于左肩肌肉內注射30mg/kg乙酸鋅。自頸靜脈定期收集血液直至血液中之鋅含量達至如表1中所示之基線為止，表1之資料經繪於圖1中。
對六隻25日齡且平均重量為12kg之雄性約克夏豬(Yorkshire pig)睾丸內注射0.5ml(74mg/ml乙酸鋅)至各睾丸中。自頸靜脈定期收集血液直至血液中之鋅含量達至如表2中所示之基線為止，表2之資料經繪圖於圖2中。
無論肌肉內或睾丸內注射，在注射後，鋅均被快速吸收且在30分鐘與60分鐘之間達峰值。在經肌肉內注射之豬中，血漿中之鋅濃度返回至在36小時與48小時之間的生理基線。對於經睾丸內注射之豬，注射後24小時存在第二吸收階段，產生接近60小時之平均滯留時間。注射後，鋅濃度返回至在48小時與72小時之間的基線。
兩種研究係在兩個不同實驗室中進行且採取不同的表述在零時刻的血液中鋅量之方式。在睾丸內研究中，血液中之鋅在零時刻取為零。在肌肉內研究中，血液中之鋅在零時刻為生理含量。
在2010年7月期間，由納瓦霍國家動物管理計畫(Navajo Nation Animal Control Program)引導，自經集合之狗獲得十八隻混合品種之雄性狗。按照納瓦霍國家動物管理法(納瓦霍部落法典；標題13，章節1711，關著之動物)，集合後3天對由動物管理處聚集之無人認領之狗進行安樂死。選擇超過3個月齡之雄性狗用於此研究而非進行安樂死。用識別標籤個別地標記各狗且所有狗均得到鎮靜且收集血液作為基礎日。所有注射均根據產品包裝插頁上之程式來完成且將蒸餾水用作A組及B組中之安慰劑。將狗圈養在具有足夠尺寸以允許自由活動之標準商業化養犬場(canine
run)處。保留所有狗以便在研究機構進行觀察。水係可隨意獲取的且標準商業乾燥狗食亦為可得的。在該研究中不使用其他藥物或程式。獸醫工作人員會在整個研究階段監測狗。每週一次且在研究結束時收集血樣，檢查所有狗之性器官。
將狗分成以下組：
A組：六隻動物。所有均經睾丸內注射Esterilsoltm且將肌肉內投予之安慰劑注射至右上後腿。
B組：六隻動物。所有均藉由經肌肉內注射向右上後腿投予單次1ml DEFENSOR-3狂犬病接種疫苗而經接種疫苗，且經睾丸內注射安慰劑。
C組：六隻動物。所有均經睾丸內注射Esterilsol且經肌肉內注射向右上後腿投予單次1ml DEFENSOR-3狂犬病接種疫苗。
Esterilsoltm(Ark Sciences,Inc.,Baltimore,MD,USA)由經1-精胺酸中和之葡萄糖酸鋅組成。各2-ml小瓶含有儲存在室溫下之13.1mg/ml葡萄糖酸鋅及34.1mg/ml精胺酸。
狂犬病病毒疫苗為市售不活化狂犬病病毒(DEFENSOR 3,Pfizer,Inc.,New York,NY,USA)。將各1ml容器儲存在冷藏條件下於4℃下直至準備使用為止。
測定EsterilsolTM功效
在第33日，自所有動物均取得睾丸及附睾且固定在中性緩衝之10%福馬林中，包埋於石蠟中，切片成4μm大小，用蘇木精及伊紅染色以便進行組織病理學評價。將器官送至密蘇裡大學獸醫學院(University of Missouri College of Veterinary Medicin)進行完整評價。
測定狂犬病VNA效價
每週一次使用配備有20號針之12ml注射器自各狗之頸靜脈抽血。將血樣儲存在冰櫃中之藍冰上，接著離心。將血樣送至佐治亞州亞特蘭大疾病控制中心(Centers for Disease Control in Atlanta,GA)進行分析。將編碼之血清快速解凍且在56℃水浴中進行熱滅活1小時。使用快速螢光焦點抑制試驗(Rapid Fluorescent Focus Inhibition Test)測定狂犬病VNA效價。
結果
所有狗均健康；在注射後追蹤階段期間未注意到重大的一般併發症。睾丸及附睾組織病理學報告顯示接受狂犬病疫苗之B組僅具有生精管上皮之所有階段，而且識別出所有精細胞發育之階段。精子存在於附睾內。接受EsterilsolTM之A組及C組在大部分細精管中具有嚴重的雙側退化，間質之部分受到淋巴細胞性浸潤及破壞。所檢查之睾丸網及輸出小管之區段似乎已經歷一些退化。在附睾之任何切片中均未觀察到精子。
經33日之階段測定各組之狂犬病VNA效價。圖3中展示效價。B組及C組中接受狂犬病疫苗接種之所有狗均對狂犬病疫苗有反應，表明狂犬病疫苗接種與Esterilsoltm之效力無交叉干擾。
將四十只SD性成熟之雄性大鼠分成四組，每組10只大鼠：
第1組：將0.05ml狂犬病疫苗(1)注射至各睾丸中。
第2組：將0.1ml ZEUTERINtm加0.1ml狂犬病疫苗注射至各睾丸中。
第3組：經肌肉內注射0.1ml狂犬病疫苗。
第4組：將0.1ml ZEUTERINtm加0.05狂犬病疫苗注射至各睾丸中。
ZEUTERINtm(Ark Sciences,Inc.,Baltimore,MD,USA)為含有13.1mg/ml呈葡萄糖酸鋅形式之鋅、用34.8mg/ml 1-精胺酸中和、pH值用鹽酸調節至7.0之水溶液。狂犬病病毒疫苗為市售不活化狂犬病病毒(DEFENSOR 3,Pfizer,Inc.,New York,NY,USA)，其係冷藏儲存直至準備使用為止。
下表給出結果。
因為在不偏離本發明之範疇的情況下可對上述組成物及方法進行各種改變，因此可預期上述說明書及隨附實施例中所含之所有內容均應解釋為說明性而不以限制性含義解釋。
Claims (12)
- 一種誘導免疫反應之方法，其包括形成當經肌肉內注射至個體之身體中時能夠誘導免疫反應之免疫原的溶液，該溶液之pH值在約6.0與7.5之間；及將該溶液注射至一個體之各睾丸中。
- 如申請專利範圍第1項之方法，其中該注射係注入附睾旁之該睾丸的背側前方部分。
- 如申請專利範圍第1項之方法，其中所注射之溶液之量為當肌肉內注射時有效誘導免疫反應之免疫原的量。
- 如申請專利範圍第3項之方法，其中該免疫原為疫苗。
- 一種睾丸內注射用組成物，其包含化學絕育劑及能夠誘導免疫反應之免疫原，該化學絕育劑包含能夠形成水溶液之葡萄糖酸鋅及胺基酸，該葡萄糖酸鋅與胺基酸係以實質上等莫耳之量及在約0.05M至2.0M之範圍內之濃度下存在且經中和至約6.0至約7.5之pH值。
- 如申請專利範圍第5項之組成物，其用於狗群體及狂犬病控制，其中該免疫原為狂犬病疫苗。
- 如申請專利範圍第6項之組成物，其中該狂犬病疫苗含有不活化狂犬病病毒。
- 如申請專利範圍第7項之組成物，其中該化學絕育劑水溶液經調節至約pH 7.0且含有13.1mg/ml葡萄糖酸鋅及34.8mg/ml 1-精胺酸。
- 一種形成用於狗群體及狂犬病控制之睾丸內注射用組成物之方法，其包括製備化學絕育劑，其包含能夠形成水溶液之葡萄糖酸鋅及胺基酸，該葡萄糖酸鋅與胺基酸係以實質上等莫耳之量及在約0.05M至2.0M之範圍內之濃度下存在且經中和至約6.0與約7.5之間的pH值；復原乾燥之不活化狂犬病疫苗；組合該化學絕育劑與復原之不活化狂犬病疫苗以便在該不活化狂犬病疫苗已復原之後立即進行睾丸內注射，或冷藏化學絕育劑與復原之不活化狂犬病疫苗之該組合以便後面注射。
- 一種向雄性狗投予化學絕育劑及狂犬病疫苗以進行群體及狂犬病控制 之方法，該方法包括製備化學絕育劑，其包含能夠形成水溶液之葡萄糖酸鋅及胺基酸，該葡萄糖酸鋅與胺基酸係以實質上等莫耳之量及在約0.05M至1.0M之範圍內之濃度下存在且經中和至約6.0與約7.5之間的pH值；復原乾燥之不活化狂犬病疫苗；組合該化學絕育劑與復原之不活化狂犬病疫苗；將化學絕育劑與不活化狂犬病疫苗之該組合注射至該狗之睾丸中，該化學絕育劑之存在量足以使得該狗絕育且該不活化狂犬病疫苗之存在量足以針對狂犬病對該狗接種。
- 如申請專利範圍第10項之方法，其中該化學絕育劑水溶液經調節至約pH 7.0且含有13.1mg/ml葡萄糖酸鋅及34.8mg/ml 1-精胺酸。
- 如申請專利範圍第11項之方法，其中該睾丸內注射係注入附睾旁之該等睾丸的背側前方部分。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/837,755 US20140271716A1 (en) | 2013-03-15 | 2013-03-15 | Intra-testicular Injection of Immunogens |
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| TW201442724A true TW201442724A (zh) | 2014-11-16 |
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| US (1) | US20140271716A1 (zh) |
| AR (1) | AR095503A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4191746A (en) * | 1979-03-08 | 1980-03-04 | All India Institute Of Medical Sciences | Sterilization process for mammals |
| US5070080A (en) | 1988-08-10 | 1991-12-03 | Fahim Mostafa S | Method of inhibiting generation, maturation, motility and viability of sperm with minerals in bioavailable form |
| US7276535B1 (en) | 2003-04-14 | 2007-10-02 | Technology Transfer, Inc. | Intratesticular injection of chemical sterilant |
| WO2008130399A1 (en) * | 2007-04-18 | 2008-10-30 | Fahim Technology, Inc. | Method for improving the quality of meat by reducing boar taint |
| US20090088471A1 (en) | 2007-09-28 | 2009-04-02 | Min Wang | Chemical sterilant for adult male dog population control with concomitant reduction in human dog-bite acquired rabies |
| BRPI0919174B1 (pt) * | 2008-09-17 | 2020-11-17 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, Centers For Disease Control And Prevention | vírus da raiva recombinante, composição imunogênica e seu uso |
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| US20140271716A1 (en) | 2014-09-18 |
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