Department Integrative Biology, University of Texas, Austin, Texas, United States of America.
Department of Biological Sciences, University of Idaho, Moscow, Idaho, United States of America.
PLoS Comput Biol. 2019 Jul 19;15(7):e1006857. doi: 10.1371/journal.pcbi.1006857. eCollection 2019 Jul.
Replicating recombinant vector vaccines consist of a fully competent viral vector backbone engineered to express an antigen from a foreign transgene. From the perspective of viral replication, the transgene is not only dispensable but may even be detrimental. Thus vaccine revertants that delete or inactivate the transgene may evolve to dominate the vaccine virus population both during the process of manufacture of the vaccine as well as during the course of host infection. A particular concern is that this vaccine evolution could reduce its antigenicity-the immunity elicited to the transgene. We use mathematical and computational models to study vaccine evolution and immunity. These models include evolution arising during the process of manufacture, the dynamics of vaccine and revertant growth, plus innate and adaptive immunity elicited during the course of infection. Although the selective basis of vaccine evolution is easy to comprehend, the immunological consequences are not. One complication is that the opportunity for vaccine evolution is limited by the short period of within-host growth before the viral population is cleared. Even less obvious, revertant growth may only weakly interfere with vaccine growth in the host and thus have a limited effect on immunity to vaccine. Overall, we find that within-host vaccine evolution can sometimes compromise vaccine immunity, but only when the extent of evolution during vaccine manufacture is severe, and this evolution can be easily avoided or mitigated.
复制型重组载体疫苗由经过工程改造的完全有效的病毒载体骨架组成，该骨架用于表达来自外源转基因的抗原。从病毒复制的角度来看，转基因不仅是可有可无的，甚至可能是有害的。因此，在疫苗制造过程中和宿主感染过程中，可能会出现删除或失活转基因的疫苗回复突变体，从而主导疫苗病毒群体。一个特别令人关注的问题是，这种疫苗进化可能会降低其抗原性，即对转基因的免疫反应。我们使用数学和计算模型来研究疫苗进化和免疫。这些模型包括制造过程中产生的进化、疫苗和回复突变体生长的动力学，以及感染过程中先天和适应性免疫的诱导。尽管疫苗进化的选择基础很容易理解，但免疫后果却并非如此。一个复杂因素是，疫苗进化的机会受到宿主内病毒种群清除前的短暂生长周期的限制。更不明显的是，回复突变体的生长可能仅在宿主中对疫苗生长产生微弱干扰，从而对疫苗免疫的影响有限。总的来说，我们发现，宿主内疫苗进化有时会损害疫苗免疫，但只有在疫苗制造过程中进化的程度严重时才会发生，而且这种进化很容易避免或减轻。
