mRNA Vaccine Development in the Fight Against Zoonotic Viral Diseases

Abstract

Zoonotic diseases are transmitted from animals to humans, and they impose a significant global burden by impacting both animal and human health. It can lead to substantial economic losses and cause millions of human deaths. The emergence and re-emergence of zoonotic diseases are heavily influenced by both anthropogenic and natural drivers such as climate change, rapid urbanization, and widespread travel. Over time, the unprecedented rise of new and re-emerging zoonotic diseases has prompted the need for rapid and effective vaccine development. Following the success of the COVID-19 mRNA vaccines, mRNA-based platforms hold great promise due to their rapid design, swift development and ability to elicit robust immune responses, thereby highlighting their potential in combating emerging and pre-pandemic zoonotic viruses. In recent years, several mRNA vaccines targeting emerging and re-emerging zoonotic viral diseases, such as rabies, Nipah, Zika, and influenza, have advanced to clinical trials, demonstrating promising immunogenicity. This review explores recent advances, challenges, and future directions in developing mRNA vaccines against emerging and re-emerging zoonotic viral diseases.

Keywords: emerging zoonotic diseases; mRNA vaccine; re-emerging zoonotic diseases; vaccine development; viruses; zoonotic diseases.

Figure 1

Different types of mRNA vaccines. (A) Non-replicating mRNA (nrRNA) contains a 5′ cap, 5′ and 3′ UTRs, antigen coding region (ORF), 3′ UTR, and a 3′ poly(A)tail. (B) The self-amplifying mRNA (saRNA) features all mRNA components of nrRNA and an additional RNA replication machinery. (C) The trans-amplifying mRNA (taRNA) is composed of two individual mRNAs: one encoding the antigen coding region, whilst the other contains the RNA replication machinery. (D) The circular mRNA (circRNA) contains an internal ribosome entry site (IRES) element, ORF, and the internal homology region. The figure was created in https://BioRender.com.

Figure 2

Structural features of in vitro transcribed (IVT) mRNA for optimized stability and translation efficiency. The figure was created in https://BioRender.com.

Figure 3

Schematic diagram of the SARS-CoV-2 genome structure. The SARS-CoV-2 genome contains two large genes, ORF1a (yellow) and ORF1b (blue), which encode 11 (nsp1–nsp11) and 5 (nsp12–nsp16) non-structural proteins, respectively. The structural genes (orange) encode the structural proteins, spike (S), envelope (E), membrane (M), and nucleocapsid (N). The spike glycoprotein consists of receptor-binding S1 (green) and membrane-fusion S2 (red) subunits. SARS-CoV-2 spike is proteolytically activated at the S1/S2 boundary (black), where S1 dissociates and S2 undergoes a distinct structural change. S1 constitutes the signal peptide (SP), N-terminal domain (NTD), and the receptor-binding domain (RBD). S2 constitutes the fusion peptide (FP), two heptad-repeat domains (HR1 and HR2), a transmembrane domain (TM), and a C-terminal intracellular tail (IC). The figure was created in https://BioRender.com.

Figure 4

Schematic diagram of the Ebolavirus (EBOV) genome structure. The single-stranded negative-sense RNA EBOV genome encodes seven proteins (NP, VP35, VP40, GP, VP30, VP24, L) flanked by 3′ and 5′ untranslated regions. The surface glycoprotein (GP) forms trimers and is composed of GP1 and GP2 subunits linked by a disulfide bond. The figure was created in https://BioRender.com.

Figure 5

Schematic diagram of the Nipah virus (NiV) genome structure. NiV genome is a single-stranded, negative-sense RNA encoding six structural proteins (N, P, M, F, G, L), which are arranged accordingly from 3′ to 5′. The figure was created in https://BioRender.com.

Figure 6

Schematic diagram of the Influenza A virus (IAV) genome structure. The IAV genome comprises eight negative-sense RNA segments encoding PB2, PB1, PA, HA, NP, NA, M, and NS (indicated in white boxes). The 3′ and 5′ untranslated regions (UTRs) (dark green) flank each segment, whilst the adjacent packing signals (light green) ensure proper virion assembly. The figure was created in https://BioRender.com.

Figure 7

Schematic diagram of the rabies virus (RABV) genome structure. The RABV genome is a non-segmented negative-sense RNA genome encoding five structural proteins (N, P, M, G, L), flanked by 3′ and 5′ untranslated regions (UTRs). The figure was created in https://BioRender.com.

Figure 8

Schematic diagram of Zika virus (ZIKV) genome structure. ZIKV possesses a positive-sense RNA genome encoding a single polyprotein, which is cleaved into structural proteins (C, prM, E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The figure was created in https://BioRender.com.

Figure 9

Schematic diagram of dengue virus (DENV) genome structure. DENV possesses a positive-sense single-stranded RNA genome encoding a single polyprotein which is cleaved into structural proteins (C, prM, E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The figure was created in https://BioRender.com.

Figure 10

Schematic diagram of the Rift Valley fever virus (RVFV) genome structure. RVFV possesses a single-stranded, tripartite RNA genome consisting of three negative-sense segments. S-segment is ambisense, which encodes the nucleocapsid protein (N), is in the negative-sense orientation whilst the non-structural protein NSs, is in the positive-sense orientation. M segment encodes the NSm and the envelope glycoproteins, Gn and Gc. L-segment encodes the L-protein (RNA-dependent RNA polymerase). The figure was created in https://BioRender.com.

Figure 11

Schematic diagram of the Powassan virus (POWV) genome structure. POWV possesses a single-stranded positive-sense RNA genome encoding a single polyprotein, which is cleaved into structural proteins (C, prM, E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5), flanked by 5′ and 3′ untranslated regions (UTRs). The figure was created in https://BioRender.com.

Figure 12

Schematic diagram of the Crimean-Congo Hemorrhagic Fever (CCHF) virus genome structure. CCHF virus possesses a tripartite negative-sense genome consisting of the S-segment, M-segment, and L-segment. The S-segment encodes the N protein. The M-segment encodes a precursor to the viral glycoproteins (GPC), which is further processed into surface glycoproteins Gn and Gc. L-segment encodes the L-protein (RNA-dependent RNA polymerase). The figure was created in https://BioRender.com.

Figure 13

Schematic diagram of the Severe Fever with Thrombocytopenia Syndrome (SFTS) virus genome structure. SFTS virus possesses a tripartite negative sense genome consisting of the S-segment, M-segment, and L-segment. The S-segment is ambisense, which encodes the nucleocapsid protein (Np) in the negative-sense orientation, and the non-structural protein NSs is in the positive-sense orientation. M-segment encodes a precursor to the viral glycoprotein GP, which is further processed into surface glycoproteins Gn and Gc. L-segment encodes the L-protein (RNA-dependent RNA polymerase). The figure was created in https://BioRender.com.

Figure 14

Schematic diagram of the Lassa virus (LASV) genome structure. LASV genome comprises two ambisense RNA segments. The S-segment contains the glycoprotein precursor (GPC) in positive-sense orientation, whilst the nucleoprotein (NP) is in the negative-sense orientation. The L-segment contains the Z matrix protein, which is in the positive-sense orientation, whilst the L-protein (RNA-dependent RNA polymerase) is in the negative-sense orientation. The figure was created in https://BioRender.com.