- 學位論文
接種COVID-19疫苗後的抗體反應評估
Evaluation of Antibody Responses to SARS-CoV-2 among Taiwanese Population with COVID-19 Vaccination
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摘要
嚴重特殊傳染性肺炎(COVID-19)於2019年底在中國出現並且迅速造成全球大流行，對全人類健康和生命都造成嚴重影響。世界各國隨即投入檢驗試劑、治療藥物以及疫苗的研發，希望建立群體免疫進而讓疫情儘快受到控制外。目前主要的COVID-19疫苗分做三大類，分別是載體疫苗、mRNA疫苗和蛋白質次單元疫苗，這三類疫苗各有其優缺點。 台灣政府陸續購入數種通過緊急使用授權(Emergency Use Authorization, EUA)的COVID-19疫苗，追加劑施打政策則自2022年1月7日起兩劑基礎疫苗接種滿3個月可以進行追加劑接種，疫苗追加劑於國人身上的功效倍受關注，由於疫苗的種類不同，誘發的免疫反應也不相同，免疫保護力的持續性可能會有所差異，加上不同機轉的疫苗廠牌混合施打後對於免疫反應可能會有交互作用，因此本研究之目的，在對於受試者接種同廠牌以及不同廠牌COVID-19疫苗追加劑，使用四種不同的抗體檢測方法，進行追加劑接種前後體內抗體生成反應與持續性的監測評估，作為疫苗後續追加接種組合與時機的參考。 研究收集完成二劑基礎疫苗滿3個月共669例受試者，受試者年齡平均為52.4歲，其中基礎疫苗施打的廠牌為阿斯特捷利康AZ疫苗（ChAdOx1, AstraZeneca）160例（23.9 %）、莫德納Moderna疫苗(mRNA127, Moderna）121例（18.1 %）、輝瑞BNT疫苗（BNT162b2, BioNTech/ Pfizer）57例 (8.5 %)、AZ/Moderna 232例（34.7 %）、高端MVC疫苗（MVC-COV1901, Medigen Vaccine Biologics Corp.）99例，BNT與MVC兩族群的平均年齡較低，基礎劑疫苗族群在年齡上的差異與台灣各廠牌疫苗取得與施打的時間以及接種政策的年長者順位優先相關。而在追加劑廠牌的選擇則為Moderna 435例（65 %）、BNT 136例（20.3 %）、MVC 98例（14.6 %），顯示受試者在疫苗種類的選擇mRNA疫苗多於選擇蛋白質疫苗。 分析接種後抗體變化，顯示基礎接種後3個月以上的反應抗體和中和抗體效價，以施打一劑或二劑mRNA疫苗最高、MVC次之、AZ效價最低，除了Moderna與BNT組別無顯著差異外，其餘各組別相比皆有顯著差異（p < 0.05）。此外，各組抗體效價平均值女性皆高於男性，並且除了AZ組別在60歲以上抗體效價為最高外，其他二劑Moderna、AZ/Mordena和二劑MVC組別中60歲以上年長者的抗體效價平均值皆為最低。 追加劑接種1個月後，反應抗體效價在各族群皆大幅提升，尤其是基礎劑為AZ的組群，增幅可達16.2-49.8倍。而各族群的棘蛋白 IgG抗體效價平均值，最高為基礎劑與追加劑皆為Modern的族群（47797 ± 46581 AU/mL），而AZ/AZ/MVC族群（5286 ± 3947 AU/mL）則為最低。比較各組別抗體效價，AZ/AZ/Moderna與AZ/AZ/MVC組別有顯著差異，基礎劑與追加劑皆為MVC蛋白疫苗的組別，其抗體效價與其他組別相比皆有顯著差異（ p < 0.05 ）。 追加劑接種6個月後(V3)，各族群的反應抗體比起追加劑接種1個月(V2)的抗體效價皆為下降趨勢，棘蛋白總抗體效價平均值降低為V2的17-39%，而棘蛋白IgG抗體效價平均值降低為V2的15-27 %。統計族群棘蛋白IgG抗體效價平均值，以基礎劑與追加劑皆為Moderna族群的效價為最高（12881 ± 14501 AU/mL），其次則為AZ/Modern/Moderna（4591 ± 4156 AU/mL），而AZ/AZ/MVC族群（1338 ± 945.8 AU/mL）則為最低。而三劑皆為MVC蛋白疫苗的抗體效價除了與AZ/AZ/MVC族群比較無差異外，與其他組別相比皆有顯著差異（ p < 0.05 ）。 至於在抗體的中和能力部分，統計族群中和抗體效價平均值由追加劑施打前38.8-88.3 % 到施打後1個月提升為95.9 %-97.2 %，而在施打後6個月則中和抗體平均效價會些微下降至78.1%-95.9%，以基礎劑與追加劑皆為Moderna族群的效價為最高（95.9 ± 7.2%），而基礎劑與追加劑皆為MVC族群為最低（78.1 ± 20.1%）。基礎劑與追加劑皆為MVC蛋白疫苗的組別，其抗體效價除AZ/AZ/MVC與AZ/Moderna/BNT組別外，與其他組別相比皆有顯著差異（p < 0.05）。 藉由檢測抗體效價是間接評估疫苗保護力較快速的方式之一，研究顯示不論是反應抗體或是中和抗體的效價在施打疫苗追加劑後短時間內都會快速大幅上升，但是隨著時間推移皆有下降的趨勢，並且選擇mRNA疫苗的抗體效價都高於選擇蛋白質疫苗。COVID-19 疫苗接種後可以持續提供多久的保護能力，還需要更長時間的追蹤監測。
並列摘要
Since the Coronavirus disease 2019 (COVID-19) emerged at the end of 2019 in China, it has rapidly evolved as a pandemic and resulted in serious repercussions to human health and life. Many countries in the world immediately devoted resources to the development of testing reagents, therapeutic drugs and even vaccines for herd immunity to control and overcome the harm of the new coronavirus epidemic. Currently, there are three major categories of COVID-19 vaccines: adenovirus vector vaccines, mRNA vaccines and genetic recombinant protein vaccines. Each of these three types of vaccines has its own advantages and disadvantages. Taiwan government has also successively purchased several COVID-19 vaccines that have passed Emergency Use Authorization (EUA). In Taiwan, the policy for booster vaccination started on January 7, 2022, and people can receive the boost vaccination 3 months after completion of the two doses of primary vaccines. Therefore, the purpose of this study is to monitor and evaluate the antibody response and persistence in subjects who have COVID-19 booster vaccination (including homologous and heterologous prime-booster immunization), hoping to provide references for vaccination administration. The study enrolled 669 subjects who completed two doses of primary vaccines for 3 months, with an averaged age of 52.4 years old. The brand of primary vaccine administered was AZ (ChAdOx1-1nCov-19, AstraZeneca) for 160 subjects (23.9%), Moderna (mRNA-1273, Moderna) for 121 subjects (18.1%), BNT (BNT162b2, BioNTech/ Pfizer) for 57 subjects (8.5%), AZ/Moderna for 232 subjects (34.7%), and MVC （MVC-COV1901, Medigen Vaccine Biologics Corp.） for 99 subjects. The averaged age of participants in the BNT and MVC groups was younger, which may be related to the priority of AZ vaccine administration for older people under the vaccine policy. For the booster vaccine, 435 subjects (65%) received Moderna, BNT for 136 subjects (20.3%), and MVC for 98 subjects (14.6%). Antibody analysis following the primary vaccination revealed that reactive and neutralizing antibody titers remained high for more than 3 months after initial vaccination. The highest titers were observed in individuals who received mRNA vaccines (1 or 2 doses), followed by MVC, and the lowest titers were observed in those who received AZ. Except for the Moderna and BNT groups which show no significant difference, there are significant differences among all other groups (p < 0.05). In addition, the averaged antibody levels were higher in females than in males. Among the Moderna, AZ/Moderna, and MVC groups, individuals over 60 years old had the lowest antibody titers, except in the AZ group, where those over 60 years old had the highest titers. After one month of the booster vaccination, there was a significant increase in antibody titers, particularly in the primary vaccination group of the AZ, with an 16.2-49.8 fold of increase. The highest averaged spike IgG antibody titers were observed in the group that received both primary and boost vaccination of Moderna (47797 ± 46581 AU/mL), while the lowest titer was observed in the AZ/AZ/MVC group (5286 ± 3947 AU/mL). In the group that received both primary and boost vaccination of MVC protein vaccine, the antibody titers are significantly different from the other groups (p < 0.05). Six months after the booster vaccination (V3), the titers of reactive antibodies were lower than those detected at one month after the booster vaccination (V2), with Roche S decreasing by 17-39% of V2, and Abbott S IgG decreasing by 15-27% of V2. The highest averages spike IgG antibody titers were observed in the group that received both primary and boost vaccination of Moderna (12881 ± 14501 AU/mL), followed by the AZ/Modern/Moderna (4591 ± 4156 AU/mL), while the lowest titer was observed in the group of AZ/AZ/MVC (1338 ± 945.8 AU/mL). The antibody titers in the group that received both primary and boost vaccination of MVC, show significant differences when compared to other groups except for the AZ/AZ/MVC group, showing no significant difference (p < 0.05). The averaged neutralization ability of antibodies increased from 38.8-88.3% before the booster vaccination to 95.9%-97.2% one month after the vaccination. However, after six months post-vaccination, the averaged neutralizing antibody titers may slightly decline to 78.1%-95.9%. The highest titers were observed in in the group that received both the primary and boost vaccination of the Moderna (95.9 ± 7.2%), while the lowest titers were found in the group that received both the primary and boost vaccination of the MVC (78.1 ± 20.1%). The group that received the primary and boost vaccination of the MVC protein vaccine, except for the AZ/AZ/MVC and AZ/Moderna/BNT groups, show significant differences in antibody titers when compared to other groups (p < 0.05). Antibody detection can be one of the indirect and rapid methods for evaluating the protective efficacy of vaccines. Studies have shown that both response antibodies and neutralizing antibody titers increase significantly shortly after vaccination, but they tend to decrease over time. Moreover, the antibody titers for mRNA vaccines are higher compared to protein-based vaccines. The duration of protection provided by COVID-19 vaccines requires further prolonged monitoring.
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