Possible strategies for mRNA nanovaccines targeting virus-infected diseases

Xiaoping Li¹, Jianshe Yang^2*

1. Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China

2. Tongji University School of Medicine, Shanghai 200072, China

Xiaoping Li, professor of Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China. E-mail: lixiaoping@uestc.edu.cn.

*Correspondence should be addressed to Professor Jianshe Yang, Academician of European Academy of Sciences and Arts, Tongji University School of Medicine, Shanghai 200072, China. Tel/Fax: +86-21-66302721. E-mail: 2305499@tongji.edu.cn

Though during the past arduous four years we have battled against COVID-19, caused by the family coronavirus with high-frequency and nonconservative RNA mutation, we still encounter the significant challenge of emerging infectious viral diseases.

During the march of the struggle, the US FDA fully approved two new coronavirus vaccines, on August 23, 2021 and January 31, 2022, both of which were mRNA vaccines, namely Comirnaty (BNT162b2) developed by Pfizer/BioNTech and Spikevax (mRNA-1273) by Moderna, respectively (1), as a main measure at the middle stage of disease fast spreading, which have threw the light on pandemic control (2–5). This research hotspot positioned RNA vaccines as potential and hopeful solutions for terminating the pandemic.

Certain important clinical trials or experiments have demonstrated that these mRNA vaccines achieved promising outcomes compared to traditional solutions, such as pathogen-originated vaccines and drugs (2–4). However, besides a home truth of its side effects, new problems made mRNA vaccines controversial and difficult to sustain. For example, the new spike S2 subunit inhibits p53 activation of p21 (WAF 1), TRAIL death receptor DR5, and MDM 2 in cancer cells, suggesting that the novel coronavirus spike protein might interfere with anticancer activity and could potentially promote cancer development (6).

In general, both adaptive and active immunities are not the best systems to address highly mutant coronaviruses. Therefore, changing our perspective and conducting research that focuses on other coronavirus characteristics is inevitable and necessary.

Due to the complexity of pandemic control through routine countermeasures, it is time to look back and acknowledge the precious experience we have gathered since mankind first recognized viruses and find a simple method from the primary natures of viruses, such as chemical and physical characteristics, rather than its senior biological features.

We therefore advocate to develop a non-traditional adaptive nano-vaccine research project (7) due to the following reasons.

Coronavirus is a non-conservative high-frequency mutant RNA virus type with irregular mutant virulence strength. Therefore, the pathogen spectrum characteristics of different populations are highly heterogeneous, hence personalized and adaptive virus inhibitor development is an urgent need.

Due to the high frequency of irregular mutations and the potentially complex adaptive response to immune system, the virus could easily achieve immune adaptation and escape the immune check. A certain lag of epitope update can not evoke the effective innate immune response from T cell epitope recognition on time, this will make the line of defense against high virulence of infection collapse.

At present, more advanced RNA vaccines are also designed according to the genetic sequence of the newly discovered mutant virus strain, which is time-consuming. From the classical immune theory perspective, the true effect of the newly developed RNA vaccine cannot meet the theoretical expectations, or would even be ineffective.

The coronaviridae has common physicochemical characteristics, that is, sensitivity to heat, acids, and bases. Temperature increase or pH change reportedly inhibits coronavirus replication and proliferation effectively. Therefore, designing a system that could modify these physicochemical parameters appears to propose an ideal virus prevention and control approach which would not be affected by the genetic sequence variation of the virus.

Functionalized nanostructured substances have the potential to target the virus and the viral infection machinery. After directional modifications, the nanomaterials could possess the possibility and feasibility to change the physical and chemical properties of the viral environment.

However, most of the existing nanoadjuvant or delivery system types for mRNA vaccine design are inorganic metals or liposomes. Research has confirmed the relatively obvious side effects of these substances with signal interference. Therefore, efficient and directional signaling and the immune effect of vaccine cannot be fully achieved, and their use could even cause immune storm-related uncontrollable signal disturbance. The development of an immunogenic-free nano-delivery system would thus be highly demanded, eventually, a research of a novel nanovaccine based on this immunogenic-free nano-delivery system would be highly recommended.

References

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6. S. Zhang, W.S. El-Deiry, Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure. Oncotarget15, 275–284 (2024). doi: 10.18632/oncotarget.28582.

7. J. Chen, Q. Wang, F. Zhang, J. Yang, The immune response of nano carbon-based photic-driving vaccines tosevere acute respiratory syndrome coronavirus 2. Explor Immunol 4, 325–332 (2024). doi: 10.37349/ei.2024.00143.

 Acknowledgments

Funding:

There is no funding support this research.

Authors contributions:

Y.-J.S. and L.-X.P. conceptualized, wrote and revised the article.

Competing interests:

Authors declared no competing interests.

Data and materials availability:

Not applicable as this is a commentary piece and does not include data.