Knife's edge: Balancing immunogenicity and reactogenicity in mRNA vaccines

Abstract

Since the discovery of messenger RNA (mRNA), there have been tremendous efforts to wield them in the development of therapeutics and vaccines. During the COVID-19 pandemic, two mRNA vaccines were developed and approved in record-breaking time, revolutionizing the vaccine development landscape. Although first-generation COVID-19 mRNA vaccines have demonstrated over 90% efficacy, alongside strong immunogenicity in humoral and cell-mediated immune responses, their durability has lagged compared to long-lived vaccines, such as the yellow fever vaccine. Although worldwide vaccination campaigns have saved lives estimated in the tens of millions, side effects, ranging from mild reactogenicity to rare severe diseases, have been reported. This review provides an overview and mechanistic insights into immune responses and adverse effects documented primarily for COVID-19 mRNA vaccines. Furthermore, we discuss the perspectives of this promising vaccine platform and the challenges in balancing immunogenicity and adverse effects.

Fig. 1. COVID-19 mRNA vaccine-induced immune responses.

After mRNA vaccination, secreted spike antigens are identified by cognate B-cells and induce potent neutralizing antibody responses with a strong germinal center reaction. Dendritic cells (DCs) uptake soluble spike antigens and stimulate antigen-specific CD4 and CD8 T-cells via the MHC II and cross-presentation pathways, respectively. In addition, endogenously expressed spike proteins in DCs can activate antigen-specific CD8 T-cells through the MHC I pathway. LNP, lipid nanoparticle; FDC, follicular dendritic cell; TFH, T follicular helper cell; TH1, type 1 T helper cell; CTL, cytotoxic T lymphocyte; PFN, perforin; GZB, granzyme B; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor-alpha.

Fig. 2. Adverse events following mRNA vaccination against COVID-19.

Adverse events following mRNA vaccination against COVID-19 were sorted and summarized by organs from the head to the feet of a human body.

Fig. 3. Risk factors and the cytotoxic mechanisms of mRNA vaccines.

A LNP-induced immune activation. Schematic structure of mRNA encapsulated into LNP formulations composed of an ionizable cationic lipid, helper lipid, cholesterol, and PEG. LNPs can induce immune activation by stimulating Toll-like receptor (TLR) 2 and TLR4 and leading to NF-kB activation and cytokine secretion. Preexisting anti-PEG antibodies can lead to complement activation and subsequently complement-mediated phenomena, such as ABC or CARPA. B LNP-encapsulated mRNA is taken up by immune cells through endocytosis. In endosomes, TLR7/8 and TLR3 recognize ssRNA and dsRNA, respectively, and the receptors activate MyD88 and TLR3 in Toll-interleukin-1 domain-containing adapter-inducing interferon (TRIF). Eventually, the related signaling cascades transduce to the nucleus where type I IFN and pro-inflammatory cytokine production is promoted by transcription factors (NF-kB, IRF3, and IRF7). Endosomal escape is used to transport small amounts of mRNA and IVT reaction byproducts to the cytoplasm. The RNAs are recognized by RIG-I and MDA5 and then both signaling pathways activate the transcription factors for inflammatory gene expression.