新型冠狀肺炎 ( COVID-19 )，由 SARS-CoV-2 所引發的全球性大流行傳染病，於2019年底對於人類的健康帶來嚴重的傷害，隨後在2020年初迅速擴散至全球多國，逐漸變成一場全球性大瘟疫。在懷孕期間感染COVID-19的孕婦其死亡率及產期併發症都會比未懷孕的婦女來得高，也會大幅提升胎兒死在子宮內的機率。雖然以目前來說依舊沒有疫苗適合給新生兒接種，但是在之前與疫苗相關的研究中指出孕婦在施打疫苗後所產生的抗體可以通過胎盤及母乳傳遞，可以透過這種方式來保護新生兒。本研究以評估孕婦施打不同種類的新冠肺炎疫苗與新生兒之間的抗體傳遞效率為主軸，本實驗收集超過200位施打過新冠肺炎疫苗之20歲以上孕婦，主要以酵素結合免疫吸附分析法 (ELISA) 去進行SARS-CoV-2 Spike RBD的中和抗體檢測，以打兩劑或是三劑的孕婦為主，採集在生產時的孕婦血液以及新生兒臍帶血，測量其中和抗體濃度以及IgG濃度，整理病人的臨床資料(如打多少劑、疫苗種類、施打疫苗與生產相差週數、施打時妊娠週數、是否有特殊疾病等)，另外再對檢體做MicroRNA Array來探討mRNA疫苗對於免疫系統microRNA調控是否有影響來進行結果分析。最後加上前面ELISA套組檢測、患者之臨床數據結果綜合起來，以評估孕婦施打新冠肺炎疫苗的劑數、種類及施打時間對於不同SARS-CoV-2變異株中和抗體傳遞效率，以及有無施打百日咳或流感疫苗是否會對新冠肺炎疫苗接種後抗體濃度生成及胎盤傳遞造成影響。本研究最終目標是希望能藉由了解孕婦施打新冠肺炎疫苗後之免疫反應及不同疫苗之間是否會有相互影響，去強調開發有效的疫苗策略的重要性，提高預測適當的疫苗接種時間之準確性以利於給予孕婦更有效的疫苗接種建議，更加保障孕婦及小孩的未來。

COVID-19, caused by SARS-CoV-2 in the end of 2019. It quickly spread to many countries around the world and gradually turned into a global pandemic. Pregnant women who contract COVID-19 during pregnancy have higher rates of mortality and perinatal complications than non-pregnant women, as well as a significantly higher chance of stillbirth. Although there is still no vaccine suitable for neonatal vaccination, previous vaccine-related studies have pointed out that the antibodies produced by pregnant women after vaccination can be transmitted through the placenta and breast milk and can provide effective neonatal protection. This study focuses on evaluating the efficiency of antibody transmission between pregnant women who are administered different types of COVID-19 vaccines and their newborns. The experiment mainly uses ELISA to conduct the SARS-CoV-2 neutralizing antibody test of SRBD collects more than 200 pregnant women over 20 years old who have been vaccinated against the new coronary pneumonia, mainly pregnant women who have received two or three doses, and collect the blood of pregnant women and newborns during delivery. Measure the concentration of different variants neutralizing antibody and IgG and organize the clinical data of the patient, and then do MicroRNA Array to explore whether the mRNA vaccine has an effect on the immune system to analyze the results. Finally, all of the results were combined to evaluate the delivery efficiency of neutralizing antibodies to different SARS-CoV-2 variant. And whether the presence or absence of pertussis or influenza vaccine affects the production of antibody concentrations and placental transmission after COVID-19 vaccination. The goal of this study is to underscore the importance of developing effective vaccine strategies and improve the prediction of appropriate vaccination by understanding the immune response of pregnant women following COVID-19 vaccine and whether there is an interaction between different vaccines. Accuracy of time to give pregnant women more effective vaccines followed by advice to protect the future of pregnant women and their children.

摘要-----------------------------------------------------------------I
Abstract------------------------------------------------------------II
謝誌---------------------------------------------------------------III
目錄----------------------------------------------------------------IV
圖目錄--------------------------------------------------------------VI
表目錄--------------------------------------------------------------IX
第一章 緒論-----------------------------------------------------------1
1-1嚴重特殊傳染性肺炎（COVID-19）--------------------------------------1
1-1-1嚴重急性呼吸道症候群冠狀病毒2型（SARS-CoV-2）----------------------2
1-1-2冠狀病毒棘蛋白 ( Spike Protein )---------------------------------3
1-1-3 SARS-CoV-2不同變異株--------------------------------------------5
1-2 SARS-CoV-2以及COVID-19疫苗產生的免疫反應---------------------------8
1-2-1病毒感染之免疫反應-----------------------------------------------8
1-2-2疫苗引起之免疫反應----------------------------------------------10
1-2-3 COVID-19不同種類之疫苗-----------------------------------------11
1-3 懷孕婦女施打疫苗的效益及對新生兒的影響-----------------------------13
1-3-1懷孕期間感染COVID-19的風險--------------------------------------14
1-3-2對孕婦懷孕期間施打COVID-19疫苗之建議-----------------------------14
1-4 研究動機--------------------------------------------------------16
第二章 實驗材料與方法------------------------------------------------17
2-1 研究對象--------------------------------------------------------17
2-2 實驗設計--------------------------------------------------------18
2-3 酵素結合免疫吸附分析法 (Enzyme-linked immunosorbent assay)--------19
2-3-1 IgG抗體檢測套組------------------------------------------------21
2-3-2 SARS-CoV-2中和抗體檢測套組(SARS-CoV-2 Surrogate Virus Neutraliz
ation Test Kit )----------------------------------------------------22
2-4 micorRNA qPCR分析-----------------------------------------------25
2-5 統計分析--------------------------------------------------------27
第三章 SARS-CoV-2中和抗體實驗結果與討論-------------------------------28
3-1 對孕婦及新生兒之間SARS-CoV-2中和抗體傳遞之初步評估-----------------28
3-2 比較SARS-CoV-2 Alpha, Beta, Gamma變異株中和抗體傳遞效率差異-------36
3-3 比較季節性流感和百日咳疫苗在孕婦中對新冠疫苗的免疫影響---------------45
3-4 使用側向流體免疫分析法結合基於光譜分析器檢測接種疫苗的孕婦和新生兒的SARS-CoV-2中和抗體--------------------------------------------------55
第四章 MicroRNA Array實驗結果與討論----------------------------------60
4-1 以打三劑mRNA疫苗和未施打任何疫苗的孕婦做初步評估--------------------60
4-2 mRNA疫苗接種後與炎症細胞因子相關的血漿microRNAs--------------------64
第五章 結論與未來展望------------------------------------------------87
參考文獻 ------------------------------------------------------------93
著作目錄 -----------------------------------------------------------102

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