疫苗異源接種對SARS-CoV-2變異株體液免疫反應之研究

Abstract

COVID-19在全球造成大流行，其病原體SARS-CoV-2不斷地變異，陸續出現傳染力更高，對抗體中和能力具抗性的變異株，進而影響疫苗的保護力。目前，最新的Omicron變異株在世界各地迅速傳播，造成很多突破性感染。此外，某些疫苗注射的安全性隱憂，使得各國開始提出不同疫苗混合接種 (異源接種) 的策略，目前已有研究表明混合接種載體/mRNA疫苗能產生更強的免疫反應，但混合接種第三劑mRNA疫苗加強劑是否能增強對變異株的中和能力仍需更多研究來證明。本篇論文的研究首先分析了疫苗異源接種所誘導的體液免疫反應，結果發現anti- Spike RBD IgG抗體都有顯著的上升；對比施打兩劑AZ組來說，其它組別的抗體效價都增加了13倍以上，而混打的組別與施打兩劑Moderna組的結果相當。針對SARS-CoV-2 Alpha和Delta變異株，異源接種相較於單純接種AZ可誘導更高的中和抗體效價，證實AZ混打Moderna疫苗確實可誘導出較好的體液免疫反應，而延長疫苗接種間隔時間不會影響抗體效價。我們接下來探討對於前兩劑施打AZ疫苗的個體，如果第三劑接種mRNA疫苗加強劑，能否誘導出更強及更廣效的抗體。依第三劑疫苗種類分為三組，分別為Moderna全劑、半劑或BNT加強劑疫苗。結果發現全劑的Moderna疫苗產生最高的抗體效價。第三劑混打比第二劑混打對於病毒變異株產生更強的中和抗體反應，但針對Omicron和Delta株的中和抗體效價，相較於Alpha株有明顯地降低。三種SARS-CoV-2抗體檢測方法中，ELISA、NT和PRNT針對原始病毒株都具有良好的相關性，但在RBD上有突變的變異株則會降低結合抗體和中和抗體之間的相關性，影響ELISA評估抗體保護力的能力。總體來說，本篇論文的研究證實了疫苗異源接種的安全性和可行性，接種第三劑mRNA疫苗能夠顯著提高對於不同變異株的中和抗體效價。

Since the beginning of the COVID-19 pandemic, evolving mutations in the SARS-CoV-2 spike protein have led to the generation of divergent variants of concern (VoCs) of SARS-CoV-2, which have been reported to increase transmissibility, and reduce the capability of neutralizing antibodies obtained through natural infection, therapeutic monoclonal antibodies, or vaccination. Currently, Omicron variant (B.1.1.529) becomes the most prevalent variant, and dominates infection events around the world. Heterologous prime-boost vaccination is currently recommended in several countries, as the vector vaccine was halted due to an increased risk of thrombotic events. Several studies have shown that heterologous vaccination could induce robust immune responses. Nonetheless, whether heterologous vaccination with a third dose of mRNA vaccine booster can enhance the neutralization antibody responses against VOCs were not available. In this prospective study, we first analyzed the immunogenicity of heterologous vaccine, and found that heterologous vector/mRNA prime–booster regimens induced higher titers of neutralizing antibodies against SARS-CoV-2 Alpha and Delta variants than the homologous vector vaccine group, and comparable to the homologous mRNA vaccine group. Then we examined whether the mRNA booster could increase the immunogenicity in individuals which had previously received two doses of ChAdOx1 vaccines. The participants were randomized into three groups for the third dose booster vaccination, including full-dosed mRNA-1273 vaccine, half-dosed mRNA-1273 vaccine and full-dosed BNT-162b2 vaccine. Our results show that the three-dose regimens induced stronger neutralizing antibody responses against SARS-CoV-2 VOCs than the two-dose regimens. Nevertheless, the neutralizing antibody titers against the Delta and Omicron variants were significantly lower than those against the Alpha variant. The three SARS-CoV-2 antibody detection methods, ELISA, NT and PRNT, all have good correlation with each other when the Alpha strain was used. When the variant strains with mutations on the RBD were used, the correlation between binding antibodies and neutralizing antibodies reduced, which might influence the application of ELISA as a tool in interpreting neutralizing antibody titers. Overall, the study results demonstrated that heterologous vaccination is safe and could induce a strong humoral response in healthy individuals. Boosting a third dose of mRNA vaccine can significantly increase the neutralizing antibody titer against VOCs.