Dendritic Cell-targeted Virus-Like Particles as mRNA Vaccine Vectors

Researchers from Shanghai Jiao Tong University in China recently published a research paper titled "Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers" online in Nature Biomedical Engineering. This study reports the design and performance of a virus-like particle targeting dendritic cells (DCs). The particles feature the Sindbis viral glycoprotein engineered to recognize surface proteins on DCs and package mRNA encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein or herpes simplex virus 1 glycoproteins B and D.

Compared to non-targeted virus-like particles and lipid nanoparticle formulations, injection of a SARS-CoV-2 mRNA vaccine targeting DCs into mouse footpads resulted in higher and sustained antigen-specific immunoglobulin-G titers and cellular immune responses. The vaccine also protected mice against infection with SARS-CoV-2 or herpes simplex virus 1. Virus-like particles preferentially taken up by dendritic cells may aid in the development of effective preventive and therapeutic vaccines.

The success of vaccines against coronavirus disease 2019 (COVID-19) has given a huge impetus to the development of messenger RNA vaccines. Since mRNA is easily degraded by nucleases and cannot enter cells on its own, a variety of mRNA carriers have been developed for transfer, including lipid nanoparticles (LNPs), polymers, peptides, virus-like particles, and dendritic cells (DCs). LNPs are now the most popular carriers. However, currently approved LNP-mRNA vaccines are not cell-specific and can be taken up by almost any cell type near or distant from the injection site, including liver cells. Although mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are effective in preventing severe consequences of COVID-19, they do not completely control the spread of the virus. In addition, the potential of mRNA vaccines beyond SARS-CoV-2 infection needs to be further explored.

DCs are the primary antigen-presenting cells (APCs) and are critical to vaccine function. It stimulates T cell immune responses by processing and presenting antigens to T cells and inducing antibody responses by processing and presenting antigens to B cells. The DCs-based Provenge vaccine has been approved by the US Food and Drug Administration for the treatment of prostate cancer. However, it is produced in vitro by activating APCs isolated from patients, and its production is labor-intensive, which limits its availability to the wider population. In addition, nonprofessional APCs translating antigen mRNA may become targets for cytotoxic T lymphocyte (CD8+ T cell)-mediated killing, which is associated with the "COVID arm". This is a condition that occurs in some patients after receiving the mRNA1273 SARS-CoV-2 vaccine. Furthermore, antibody-dependent cytotoxicity may destroy cells that insert or secrete antigenic proteins associated with the plasma membrane.

Therefore, targeting DCs in situ is the development direction of the next generation of mRNA vaccines. This will simplify the production process, reduce costs and improve the safety of the vaccine. DCs-specific intercellular adhesion molecule 3-grab non-integrin (DC-SIGN) is the pattern recognition receptor and adhesion receptor of DCs. It plays an important role in DC migration and adhesion, inflammatory response, T cell activation and initiation of immune response. Compared with non-specific lentiviral vectors, pseudotyped recombinant lentiviral vectors using Sindbis viral glycoprotein as DC-SIGN ligand showed potentially improved performance. However, the risk of insertional mutations is a factor limiting its clinical application. Although LNPs have been conjugated with specific antibodies or ligands to obtain DC specificity, evidence of the effectiveness of DC-targeted mRNA vaccines based on LNPs is still scarce.

The research team first engineered the Sindbis virus glycoprotein SV-G and replaced the broad-spectrum affinity glycoprotein VSV-G to achieve specific targeting of DCs by virus-like particles by recognizing the DC surface protein DC-SIGN. By tracking the infection of DC cell lines in vitro and the infection of DC cells in vivo, the research team verified that the SV-G modified virus-like particle indeed obtained the targeting ability of DC cells. The research team named this virus-like particle vaccine technology with DC cell targeting DVLP. By detecting the distribution of mRNA in the body, the research team found that compared with LNP, DVLP can efficiently deliver antigen mRNA into DCs, and DCs can migrate to lymph nodes more effectively. DVLP also activated cellular immunity more effectively than LNP mRNA vaccine.

Figure 1. HSV vaccine production schematic and prevention effect display based on DVLP platform. (Yin, Di, et al. 2024)

Finally, the research team used two viral infections, SARS-CoV-2 and HSV-1, as disease models to evaluate the protective effect of the DVLP vaccine on mice. In the SARS-CoV-2 true virus infection experiment, the research team found that mice immunized with DVLP Spike had significantly reduced viral loads in the lungs and trachea, and at the same time attenuated the pulmonary inflammatory response. In the HSV-1 skin infection model, the research team found that mice immunized with DVLP gB1-gD1 produced neutralizing antibodies that were cross-protective against HSV-1 and HSV-2. After immunization, the viral load in the skin and ganglia of mice was significantly reduced, effectively preventing HSV infection from damaging the mouse skin.

In summary, this study developed a new vaccine technology, DVLP, which can target DCs in vivo, deliver mRNA and display antigenic proteins at the same time, and stimulate strong humoral and cellular immune responses. Therefore, DVLP is expected to become a new generation vaccine technology to combat viral infections, prevent and treat tumors and aging. At present, preparatory work has also been launched for anti-tumor clinical research based on this vaccine technology.

Reference

Yin, Di, et al. "Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers." Nature Biomedical Engineering (2024): 1-16.