The Application of Single-Cell Technologies for Vaccine Development Against Viral Infections

Abstract

The development of vaccines against viral infections has advanced rapidly over the past century, propelled by innovations in laboratory and molecular technologies. These advances have expanded the range of vaccine platforms beyond live-attenuated and inactivated vaccines to include recombinant platforms, such as subunit proteins and virus-like particles (VLPs), and more recently, mRNA-based vaccines, while also enhancing methods for evaluating vaccine performance. Despite these innovations, a persistent challenge remains: the inherent complexity and heterogeneity of immune responses continue to impede efforts to achieve consistently effective and durable protection across diverse populations. Single-cell technologies have emerged as transformative tools for dissecting this immune heterogeneity, providing comprehensive and granular insights into cellular phenotypes, functional states, and dynamic host-pathogen interactions. In this review, we examine how single-cell epigenomic, transcriptomic, proteomic, and multi-omics approaches are being integrated across all stages of vaccine development-from infection-informed discovery to guide vaccine design, to high-resolution evaluation of efficacy, and refinement of cell lines for manufacturing. Through representative studies, we highlight how insights from these technologies contribute to the rational design of more effective vaccines and support the development of personalized vaccination strategies.

Keywords: COVID-19; infectious diseases; influenza; mRNA; multi-omics; recombinant protein; single-cell technology; vaccine development; viral diseases; virus-like particles (VLPs).

Figure 1

Timeline of the development of novel vaccine platforms and key laboratory techniques [3,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45].

Figure 2

Options and applications of single-cell technologies for vaccine development. Created in BioRender. Vanderzee, I. O. (2025) https://BioRender.com/c679z0b (accessed on 14 April 2025).

Figure 3

Stages of vaccine development. Green arrows indicate standard sequential progression. Red arrows indicate failure-driven return to earlier stages. Orange arrows indicate information flow that refines prior stages.