Stoddard Madison, Yuan Lin, Sarkar Sharanya, Mangalaganesh Shruthi, Nolan Ryan P, Bottino Dean, Hather Greg, Hochberg Natasha S, White Laura F, Chakravarty Arijit
Fractal Therapeutics, Lexington, MA 02420, USA.
Department of Microbiology and Immunology, Dartmouth College, Hanover, NH 03755, USA.
Vaccines (Basel). 2023 Apr 6;11(4):806. doi: 10.3390/vaccines11040806.
SARS-CoV-2 vaccinations were initially shown to substantially reduce risk of severe disease and death. However, pharmacokinetic (PK) waning and rapid viral evolution degrade neutralizing antibody (nAb) binding titers, causing loss of vaccinal protection. Additionally, there is inter-individual heterogeneity in the strength and durability of the vaccinal nAb response. Here, we propose a personalized booster strategy as a potential solution to this problem. Our model-based approach incorporates inter-individual heterogeneity in nAb response to primary SARS-CoV-2 vaccination into a pharmacokinetic/pharmacodynamic (PK/PD) model to project population-level heterogeneity in vaccinal protection. We further examine the impact of evolutionary immune evasion on vaccinal protection over time based on variant fold reduction in nAb potency. Our findings suggest viral evolution will decrease the effectiveness of vaccinal protection against severe disease, especially for individuals with a less durable immune response. More frequent boosting may restore vaccinal protection for individuals with a weaker immune response. Our analysis shows that the ECLIA RBD binding assay strongly predicts neutralization of sequence-matched pseudoviruses. This may be a useful tool for rapidly assessing individual immune protection. Our work suggests vaccinal protection against severe disease is not assured and identifies a potential path forward for reducing risk to immunologically vulnerable individuals.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）疫苗最初被证明可大幅降低重症和死亡风险。然而，药代动力学（PK）衰减和病毒快速进化会降低中和抗体（nAb）结合滴度，导致疫苗保护作用丧失。此外，疫苗诱导的nAb反应的强度和持久性存在个体间异质性。在此，我们提出一种个性化加强免疫策略作为解决这一问题的潜在方案。我们基于模型的方法将个体对SARS-CoV-2初次疫苗接种的nAb反应异质性纳入药代动力学/药效学（PK/PD）模型，以预测疫苗保护的群体水平异质性。我们还根据nAb效力的变异倍数降低情况，进一步研究了进化性免疫逃逸随时间对疫苗保护的影响。我们的研究结果表明，病毒进化将降低疫苗对重症的保护效力，尤其是对免疫反应持久性较差的个体。更频繁的加强免疫可能会恢复免疫反应较弱个体的疫苗保护作用。我们的分析表明，电化学发光免疫分析（ECLIA）的受体结合域（RBD）结合试验能有力预测对序列匹配假病毒的中和作用。这可能是快速评估个体免疫保护的有用工具。我们的研究表明，疫苗对重症的保护作用并非有保障，并确定了一条降低免疫脆弱个体风险的潜在前进道路。
