Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost.
Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost.
复制标题
DOI：
10.3389/fimmu.2021.776933
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Dixit NM
中科院分区：
文献类型：
--
作者：
Garg AK;Mittal S;Padmanabhan P;Desikan R;Dixit NM
新冠肺炎疫苗的效力似乎在很大程度上取决于疫苗剂量以及主要剂量和加强剂量之间的间隔。出乎意料的是，在临床试验中，较低剂量的Prime和较长的Prime-Boost间隔产生了更高的疗效。为了阐明这些影响的来源，我们建立了生发中心(GC)反应的随机模拟模型，并预测了不同接种方案引起的抗体反应。模拟预测，由于抗原可用性降低，较低剂量的PRIME可能会增加GC的选择严格性，导致选择与靶抗原具有更高亲和力的GC B细胞。Boost可以放松这种选择的严格程度，并允许所选择的高亲和力GC B细胞的扩张，从而改善整体反应。随着给药间隔的延长，抗原随时间的衰减可以进一步提高选择的严格性，从而放大这一效应。这一效应在我们的模拟中仍然存在，即使在增强后的新GC必须由质数之后形成的记忆B细胞播种。这些预测为观察到的剂量和剂量间隔对疫苗效力的矛盾影响提供了一个可信的解释。在GC中调整选择的严格性，使用优质增强剂量和剂量间隔作为处理，可能有助于提高疫苗效率。
The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.
登录
查看更多内容
定义和操纵B细胞免疫优势层次结构，以广泛中和针对流感病毒的抗体反应。
影响因子：
9.3
作者：
Amitai A;Sangesland M;Barnes RM;Rohrer D;Lonberg N;Lingwood D;Chakraborty AK
通讯作者：
Chakraborty AK
DOI：
10.1002/psp4.12700
发表时间：
2021-10
期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
--
作者：
Giorgi M;Desikan R;van der Graaf PH;Kierzek AM
通讯作者：
Kierzek AM
DOI：
10.1056/nejmoa2035389
发表时间：
2021-02-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Baden LR;El Sahly HM;Essink B;Kotloff K;Frey S;Novak R;Diemert D;Spector SA;Rouphael N;Creech CB;McGettigan J;Khetan S;Segall N;Solis J;Brosz A;Fierro C;Schwartz H;Neuzil K;Corey L;Gilbert P;Janes H;Follmann D;Marovich M;Mascola J;Polakowski L;Ledgerwood J;Graham BS;Bennett H;Pajon R;Knightly C;Leav B;Deng W;Zhou H;Han S;Ivarsson M;Miller J;Zaks T;COVE Study Group
通讯作者：
COVE Study Group
影响因子：
64.5
作者：
Bonsignori M;Zhou T;Sheng Z;Chen L;Gao F;Joyce MG;Ozorowski G;Chuang GY;Schramm CA;Wiehe K;Alam SM;Bradley T;Gladden MA;Hwang KK;Iyengar S;Kumar A;Lu X;Luo K;Mangiapani MC;Parks RJ;Song H;Acharya P;Bailer RT;Cao A;Druz A;Georgiev IS;Kwon YD;Louder MK;Zhang B;Zheng A;Hill BJ;Kong R;Soto C;NISC Comparative Sequencing Program;Mullikin JC;Douek DC;Montefiori DC;Moody MA;Shaw GM;Hahn BH;Kelsoe G;Hraber PT;Korber BT;Boyd SD;Fire AZ;Kepler TB;Shapiro L;Ward AB;Mascola JR;Liao HX;Kwong PD;Haynes BF
通讯作者：
Haynes BF
影响因子：
5.4
作者：
de Boer, Rob J.;Perelson, Alan S.
通讯作者：
Perelson, Alan S.