Yang Song

The COVID-19 pandemic highlighted both the transformative potential of mRNA vaccines and the structural challenges associated with their supply chains. Unlike traditional vaccine platforms, mRNA vaccines depend on highly specialized raw materials, including plasmid DNA (pDNA), nucleotides, enzymes, and lipid nanoparticles (LNP), that are produced by a limited number of global suppliers. These dependencies, combined with platform-specific manufacturing processes and stringent cold chain requirements, introduce vulnerabilities across production, distribution, and regulatory oversight. This narrative review examines the distinctive features of mRNA vaccine supply chains and identifies key challenges and opportunities across three interconnected domains: manufacturing systems, logistics and distribution, and regulatory governance. Drawing on literature published between January 2021 and March 2026, the review synthesizes evidence on supply chain bottlenecks revealed during the COVID-19 pandemic, including upstream raw-material dependencies, limitations in manufacturing scale-up, cold chain constraints, and regulatory fragmentation. Particular attention is given to the implications of these challenges for low- and middle-income countries, where infrastructure, technical capacity, and regulatory resources may limit participation in mRNA vaccine production and deployment. The review also highlights emerging strategies to strengthen supply chain resilience, including diversification of input suppliers, development of regional manufacturing hubs, improvements in vaccine thermostability, regulatory harmonization initiatives, and the use of digital technologies for supply chain management. By integrating insights from manufacturing, logistics, and regulatory perspectives, this study contributes to a better understanding of the structural characteristics shaping mRNA vaccine supply chains and identifies priority areas for strengthening global preparedness for future health emergencies.

The authors would like to make the following corrections to this published paper

Enterovirus C116 (EV‐C116) is a new member of the enterovirus C group which is closely associated with several infectious diseases. Although sporadic studies have detected EV‐C116 in clinical samples worldwide, there is currently limited information available. In this study, two EV‐C‐positive fecal specimens were detected in apparently healthy children, which harbored low abundance, through meta‐transcriptome sequencing. Based on the prototypes of several EV‐Cs, two lineages were observed. Lineage 1 included many types that could not cause EV‐like cytopathic effect in cell culture. Three genogroups of EV‐C116 were divided in the maximum likelihood tree, and the two strains in this study (XZ2 and XZ113) formed two different lineages, suggesting that EV‐C116 still diffuses worldwide. Obvious inter‐type recombination events were observed in the XZ2 strain, with CVA22 identified as a minor donor. However, another strain (XZ113) underwent different recombination situations, highlighting the importance of recombination in the formation of EV‐Cs biodiversity. The EV‐C116 strains could propagate in rhabdomyosarcoma cell cultures at low titer; however, EV‐like cytopathic effects were not observed. HEp‐2, L20B, VERO, and 293T cell lines did not provide an appropriate environment for EV‐C116 growth. These results challenge the traditional recognition of the uncultured nature of EV‐C116 strains and explain the difficulty of clinical detection.

Human respiratory syncytial virus (HRSV) poses a significant disease burden on global health. To date, two vaccines that primarily induce humoral immunity to prevent HRSV infection have been approved, whereas vaccines that primarily induce T-cell immunity have not yet been well-represented. To address this gap, 25 predicted T-cell epitope peptides derived from the HRSV fusion protein with high human leukocyte antigen (HLA) binding potential were synthesized, and their ability to be recognized by PBMC from previously infected HRSV cases was assessed using an ELISpot assay. Finally, nine T-cell epitope peptides were selected, each of which was recognized by at least 20% of different donors’ PBMC as potential vaccine candidates to prevent HRSV infection. The protective efficacy of F-9PV, a combination of nine peptides along with CpG-ODN and aluminum phosphate (Al) adjuvants, was validated in both HLA-humanized mice (DR1-TCR transgenic mice, Tg mice) and wild-type (WT) mice. The results show that F-9PV significantly enhanced protection against viral challenge as evidenced by reductions in viral load and pathological lesions in mice lungs. In addition, F-9PV elicits robust Th1-biased response, thereby mitigating the potential safety risk of Th2-induced respiratory disease during HRSV infection. Compared to WT mice, the F-9PV mice exhibited superior protection and immunogenicity in Tg mice, underscoring the specificity for human HLA. Overall, our results demonstrate that T-cell epitope peptides provide protection against HRSV infection in animal models even in the absence of neutralizing antibodies, indicating the feasibility of developing an HRSV T-cell epitope peptide-based vaccine.

Coxsackievirus A16 (CVA16) is a major pathogen that causes hand, foot, and mouth disease (HFMD). The recombination form (RF) shifts and global transmission dynamics of CVA16 remain unknown. In this retrospective study, global sequences of CVA16 were retrieved from the GenBank database and analyzed using comprehensive phylogenetic inference, RF surveys, and population structure. A total of 1,663 sequences were collected, forming a 442-sequences dataset for VP1 coding region analysis and a 345-sequences dataset for RF identification. Based on the VP1 coding region used for serotyping, three genotypes (A, B, and D), two subgenotypes of genotype B (B1 and B2), and three clusters of subgenotype B1 (B1a, B1b, and B1c) were identified. Cluster B1b has dominated the global epidemics, B2 disappeared in 2000, and D is an emerging genotype dating back to August 2002. Globally, four oscillation phases of CVA16 evolution, with a peak in 2013, and three migration pathways were identified. Europe, China, and Japan have served as the seeds for the global transmission of CVA16. Based on the 3D coding region of the RFs, five clusters of RFs (RF-A to -E) were identified. The shift in RFs from RF-B and RF-C to RF-D was accompanied by a change in genotype from B2 to B1a and B1c and then to B1b. In conclusion, the evolution and population dynamics of CVA16, especially the coevolution of 3D and VP1 genes, revealed that genotype evolution and RF replacement were synergistic rather than stochastic.

Current vaccines based on production of neutralizing antibodies fail to prevent the infection and transmission of SARS-CoV-2 Omicron and its subvariants. Understanding the critical factors and avoiding the disadvantages of vaccine strategies are essential for developing a safe and effective COVID-19 vaccine, which would include a more effective and durable cellular response, minimal effects of viral mutations, rapid production against emerging variants, and good safety.

The aim of this study was to determine the global genetic diversity and transmission dynamics of coxsackievirus B4 (CVB4) and to propose future directions for disease surveillance. Next-generation sequencing was performed to obtain the complete genome sequence of CVB4, and the genetic diversity and transmission dynamics of CVB4 worldwide were analyzed using bioinformatics methods such as phylogenetic analysis, evolutionary dynamics, and phylogeographic analysis. Forty complete genomes of CVB4 were identified from asymptomatic infected individuals and hand, foot, and mouth disease (HFMD) patients. Frequent recombination between CVB4 and EV-B multiple serotypes in the 3D^pol region was found and formed 12 recombinant patterns (A-L). Among these, the CVB4 isolated from asymptomatic infected persons and HFMD patients belonged to lineages H and I, respectively. Transmission dynamics analysis based on the VP1 region revealed that CVB4 epidemics in countries outside China were dominated by the D genotype, whereas the E genotype was dominant in China, and both genotypes evolved at a rate of > 6.50 × 10⁻³ substitutions/site/year. CVB4 spreads through the population unseen, with the risk of disease outbreaks persisting as susceptible individuals accumulate. Our findings add to publicly available CVB4 genomic sequence data and deepen our understanding of CVB4 molecular epidemiology.

Coxsackievirus A6 (CVA6), a member of species A enterovirus, is associated with outbreaks of hand-foot-and-mouth disease and causes a large nationwide burden of disease. However, the molecular pathogenesis of CVA6 remains unclear. In the present study, we established a suckling Institute of Cancer Research (ICR) mouse infection model to explore the neural pathogenicity of CVA6. Five-day-old mice infected with CVA6 strain F219 showed lethargy and paralysis, and died 5 or 6 days after infection via IM injection. Cerebral edema and neuronal cell swelling were observed in the infected brain tissue, and we found that the CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in infected mouse brain using an immunofluorescence assay. CVA6 strain F219 can also infect human glioma (U251) cells. Transcriptome analysis of brain tissues from infected mice and infected U251 cells showed that significantly differentially expressed genes were enriched in antiviral and immune response and neurological system processes. These results indicate that CVA6 could cause neural pathogenesis and provide basic data for exploring the mechanism of how host–cell interactions affect viral replication and pathogenesis. Importance: Coxsackievirus A6 (CVA6) surpasses the two main pathogens, enterovirus 71 (EV-A71) and coxsackievirus A16 (CVA16), which are the leading pathogens causing HFMD in many provinces of China. In our study, CVA6 infection caused neurogenic pathogenesis in a neonatal murine model, manifesting as cerebral edema and neuronal cell swelling, CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in the infected mouse brain. Based on CVA6-infected brain tissue and U251 cell transcriptome analysis, we found upregulated antiviral and immune response-related genes such as Zbp1, Usp18, Oas2, Irf7, Ddx60, Ifit3, Ddx58, and Isg15, while the neurological system process-related genes were downregulated, including Fcrls, Ebnrb, Cdk1, and Anxa5.

A 2.5‐year‐old pediatric patient with acute flaccid paralysis was diagnosed with primary immunodeficiency (PID) in Ningxia Province, China, in 2011. Twelve consecutive stool specimens were collected from the patient over a period of 10 months (18 February 2011 to 20 November 2011), and 12 immunodeficiency vaccine‐derived poliovirus (iVDPV) strains (CHN15017‐1 to CHN15017‐12) were subsequently isolated. Nucleotide sequencing analysis of the plaque‐purified iVDPVs revealed 2%–3.5% VP1 ‐region differences from their parental Sabin 3 strain. Full‐length genome sequencing showed they were all Sabin 3/Sabin 1 recombinants, sharing a common 2C‐region crossover site, and the two key determinants of attenuation (U472C in the 5′ untranslated region and T2493C in the VP1 region) had reverted. Temperature‐sensitive experiments demonstrated that the first two iVDPV strains partially retained the temperature‐sensitive phenotype's nature, while the subsequent ten iVDPV strains distinctly lost it, possibly associated with increased neurovirulence. Nineteen amino‐acid substitutions were detected between 12 iVDPVs and the parental Sabin strain, of which only one (K1419R) was found on the subsequent 10 iVDPV isolates, suggesting this site's potential as a temperature‐sensitive determination site. A Bayesian Monte Carlo Markov Chain phylogenetic analysis based on the P1 coding region yielded a mean iVDPV evolutionary rate of 1.02 × 10 ⁻² total substitutions/site/year, and the initial oral‐polio‐vaccine dose was presumably administered around June 2009. Our findings provide valuable information regarding the genetic structure, high‐temperature growth sensitivity, and antigenic properties of iVDPVs following long‐term evolution in a single PID patient, thus augmenting the currently limited knowledge regarding the dynamic changes and evolutionary pathway of iVDPV populations with PID during long‐term global replication.

Nineteen CVA9 isolates were obtained between 2010 and 2019 from six provinces of mainland China, using the HFMD surveillance network established in China. Nucleotide sequencing revealed that the full-length VP1 of 19 CVA9 isolates was 906 bases encoding 302 amino acids. The combination of the thresholds of the phylogenetic tree and nucleotide divergence of different genotypes within the same serotype led to a value of 15–25%, and enabled CVA9 worldwide to be categorized into ten genotypes: A–J. The phylogenetic tree showed that the prototype strain was included in genotype A, and that the B, C, D, E, H, and J genotypes disappeared during virus evolution, whereas the F, I, and G genotypes showed co-circulation. Lineage G was the dominant genotype of CVA9 and included most of the strains from nine countries in Asia, North America, Oceania, and Europe. Most Chinese strains belonged to the G genotype, suggesting that the molecular epidemiology of China is consistent with that observed worldwide. The 165 partial VP1 strains (723 nt) showed a mean substitution rate of 3.27 × 10⁻³ substitution/site/year (95% HPD range 2.93–3.6 × 10⁻³), dating the tMRCA of CVA9 back to approximately 1922 (1911–1932). The spatiotemporal dynamics of CVA9 showed the spread of CVA9 obviously increased in recent years. Most CVA9 isolates originated in USA, but the epidemic areas of CVA9 are now concentrated in the Asia–Pacific region, European countries, and North America. Recombination analysis within the enterovirus B specie (59 serotypes) revealed eight recombination patterns in China at present, CVB4, CVB5, E30, CVB2, E11, HEV106, HEV85, and HEV75. E14, and E6 may act as recombinant donors in multiple regions. Comparison of temperature sensitivity revealed that temperature-insensitive strains have more amino acid substitutions in the RGD motif of the VP1 region, and the sites T283S, V284M, and R288K in the VP1 region may be related to the temperature tolerance of CVA9.