December 8, 2021

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Non-viral COVID-19 vaccine delivery system

The third mRNA COVID-19 vaccine: Final clinical trial results are released!

Non-viral COVID-19 vaccine delivery system


Non-viral COVID-19 vaccine delivery system.  In less than a year reported in December 2019, SARS-CoV-2 spread globally at an alarming rate, causing tens of millions of cases and more than 1 million deaths.

Since then, companies and research institutions have competed to develop SARS-CoV-2 vaccines, ranging from traditional virus and protein vaccines to more advanced vaccines, including vaccines based on DNA and mRNA.

Each vaccine exhibits different potency and effectiveness, depending on the antigen design, adjuvant molecule, vaccine delivery platform and immunization method.

In this review, we will introduce some of the major non-viral vaccines that are in clinical development.

As of November 2020, according to World Health Organization, there are more than 170 SARS-CoV-2 vaccines under development, of which 13 are undergoing Phase III human clinical trials. These candidate vaccines can be divided into four vaccine platforms: viral vector vaccines, RNA vaccines, DNA vaccines and protein vaccines (Figure 1, Table 1).

Non-viral COVID-19 vaccine delivery system

Figure 1 Various vaccine platforms used to vaccinate SARS-CoV-2 vaccine


Table 1 A new coronavirus vaccine is currently being developed
Non-viral COVID-19 vaccine delivery system


The mRNA vaccine is the most advanced COVID-19 vaccine in the phase III clinical trial. In the phase I clinical trial of mRNA-1273, 47 participants found a significant NAb reaction after being vaccinated with the two vaccines. The same level of neutralizing activity observed in the serum of 19 patients during the recovery period. According to Figure 2, the humoral immune response (ab) and cellular immune response (cd) of mRNA-1273 to SARS-CoV-2; the humoral immune response (ef) and cellular immune response (gh) of mRNA-1273 to SARS-CoV-2 ), early clinical results show that the mRNA vaccine is well tolerated and induces humoral and cellular immune responses against COVID-19.

Non-viral COVID-19 vaccine delivery system

Figure 2 Humoral and cellular immune responses of mRNA-1273 and BTN-162b1

As shown in Table 1, all COVID-19 mRNA vaccines under clinical development are delivered via lipid nanoparticles (LNP). LNPs encapsulate mRNA in a solid lipid structure, which consists of four parts (Figure 3): cationic or dissociable lipids are used for the complexation of mRNA, cholesterol stabilizes nanoparticles, helps the formation and intracellular release of phospholipids, and polymerizes Glycolated lipids reduce non-specific interactions. In addition to LNPs, cationic liposomes can also be used for mRNA vaccine applications. Another important type of mRNA delivery system is based on polymers and polymer/lipid hybrid particles.

Non-viral COVID-19 vaccine delivery system

Figure 3 An mRNA vaccine delivery system suitable for COVID-19 vaccine development

In general, mRNA vaccines are a powerful technology against pandemics such as COVID-19. Although mRNA vaccines against COVID-19 are generally optimistic, more research is needed to effectively deal with other emerging pathogens, as well as potential cases of SARS-CoV-2 mutations or seasonal recurrences.

DNA vaccines are based on bacterial plasmids and encode vaccine antigens driven by eukaryotic promoters. Unlike protein antigens, plasmids (DNA vaccines) must enter the nucleus of locally transfected cells, including APCs.

The advantages of DNA vaccines are that they are easy to manufacture, store, and are safe. The disadvantage is that DNA vaccines can activate oncogenes and potentially cause autoimmune reactions. In addition, because the vaccines continuously stimulate humoral immune responses or induce immune tolerance to the protein antigens produced , Chronic inflammation may also occur.

Inovio Pharmaceuticals has developed a vaccine and delivery device for the SARS-CoV-2S protein (INO-4800) (Figure 4). Preclinical studies on INO-4800-immunized mice and guinea pigs have shown that anti-SARS-CoV-2 binding antibodies block ACE2 binding, which is the main receptor for SARS-CoV-2 cells to enter.

In the phase I clinical trial of INO-4800, 40 healthy adults aged 18-50 received a dose of 1 mg or 2 mg, respectively, with an interval of 4 weeks. The INO-4800 vaccine induced a balance of body fluids and cells. In response, 94% of participants showed an immune response based on humoral (binding and neutralization) and T cell immune responses.

Based on these positive data and no serious adverse events, the phase I trial has been expanded to include older participants, and the phase II/III efficacy trial is planned to start after FDA regulatory approval.

Figure 4 Inovio Pharmaceutical’s INO-4800 DNA vaccine caused an immune response in BALB/c mice.

DNA vaccine is a promising vaccine strategy against SARS-CoV-2. Compared with other vaccine platforms, the main disadvantage of DNA vaccines is relatively weak immunogenicity, but more research is currently being carried out to improve this aspect through various delivery strategies.

DNA and RNA-based vaccines only require the genetic sequence of the virus, compared to protein vaccines that require other techniques and purification steps. The in vitro cellular protein expression system for SARS-CoV-2 is currently in phase I, II and III clinical trials.

Preclinical studies and Phase I/II human clinical trials conducted with NVX-CoV2373 in mice and baboons showed that the titer of anti-S protein IgG (anti-S IgG) was increased and it had strong neutralizing activity (Figure 5a) It is worth noting that co-injection with adjuvants significantly improves the effectiveness of the vaccine, allowing potential dose savings, which is a key advantage for future mass vaccination.

Serum antibodies blocked the binding of hACE2 to S protein and also neutralized the virus (Figure 5b). In addition to humoral reactions, strong cellular responses were also observed, as shown by ELISPOT and mouse intracellular staining (Figure 5c).

Figure 5 Humoral and cellular immune responses were observed in mice and baboons after vaccination of NVX-CoV2373 + Matrix-M vaccine


Virus-like particles (VLPs) are designed to express the surface proteins or nucleic acid sequences of natural viruses without the risk of replication or infection. Peptide-chain vaccines refer to the use of peptides as immunogens. Generally, the amino acid sequence of the antigen is divided into multiple short sequences, and the immunogenicity of each short sequence is studied. This technology has been used to study the reactivity of antibodies produced against SARS-CoVS fragments and nucleocapsid proteins, providing important information on the regional immune advantage of each protein.

Each vaccine exhibits different efficacy and duration of efficacy, which is determined by the antigen design, adjuvant molecule, vaccine delivery platform and injection method.

Adjuvants trigger PRR on adaptive immune cells. Depending on which type of PRR the adjuvant is designed to activate, different immune response pathways will be triggered. Therefore, the use of strong and well-matched adjuvants can greatly improve the effectiveness of the vaccine.

At present, many COVID-19 vaccine developers use adjuvants in vaccines, which have been shown to greatly improve the efficacy of vaccines in preclinical and clinical studies.

Although the COVID-19 vaccination route mainly uses intramuscular injection (Table 1), other vaccination routes should also be considered, including intradermal, subcutaneous, intranasal and intravenous injections.


Past experience in similar diseases caused by SARS-CoV and MERS-CoV has laid the foundation for accelerating the development of SARS-CoV-2 vaccines. The current global situation urgently requires strict compliance with SARS-CoV-2 vaccine safety guidelines. Develop vaccines quickly and be prepared to deal with the potential mutations of SARS-CoV-2 and its seasonal recurrence.

In addition, we should also formulate effective countermeasures for other emerging pathogens; due to the delivery of vaccines mediated by nanoparticles in the past 20 years Progress has been made in this regard, and future research should focus on simplifying the nanoparticle vaccine delivery system so that the final vaccine product can be easily produced and formulated.





Non-viral COVID-19 vaccine delivery system

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