New technology improves SARS-CoV-2 mRNA vaccine-induced immune response

○March 11^th In 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. In the fight against COVID-19, two FDA-approved mRNA vaccines have been developed by Pfizer/Biontech (BNT162b2) and Moderna (mRNA-1273). They generate SARS-CoV-2 spike proteins that activate potent B- and T-cell responses.^1,2 B cells produce antibodies that bind to the spike protein on the surface of the SARS-CoV-2 virus.² Some of these antibodies, called neutralizing antibodies, block the virus from attaching to cells, thereby effectively preventing infection.³ In addition to mRNA vaccines, protein-based vaccines, such as the Novavax NVX-CoV2373 vaccine, which presents the SARS-CoV-2 spike protein on the surface of virus-like nanoparticles, can also induce strong antibody responses. increase.

Magnus Hoffmann, a former Caltech graduate student and now an independent scientist at Caltech’s Merkin Institute, wanted to combat two major problems with current vaccination approaches. The first is that the SARS-CoV-2 virus evolves over time, making available vaccines less effective, as observed with the Omicron mutant.^Four A second problem is that antibody titers generated by vaccinated individuals decline over time, increasing susceptibility to future infections and requiring frequent boosters to maintain strong immunity. was to become^Five

In recent publications, cellHoffman describes a new technique he developed that combines features of mRNA and protein nanoparticle-based vaccines to generate potent antibody and T-cell responses. This approach is based on a novel technique that induces the generation of self-assembled enveloped virus-like particles (eVLPs) that contain a dense array of spike proteins on their surface.⁶

Hoffman et al. strategically engineered the SARS-CoV-2 spike mRNA sequence to recruit the cellular endosomal sorting complex (ESCRT) required for trafficking to the cytoplasmic tail of the spike protein during translation and protein folding. Designed to add a short area to This complex promotes the formation of eVLPs containing spike proteins that bud from the plasma membrane. The researchers hoped that if the modified mRNAs were used as vaccines, they would produce spike proteins on the surface of cells and released eVLPs, stimulating antibody production beyond existing options.

“MRNA vaccines mimic infected cells, whereas protein nanoparticle-based vaccines mimic viruses. During natural infection, the immune system is exposed to both,” Hoffman said. “What we’re doing is mimicking natural infection more accurately, where you see infected cells, but you also see viral particles.”

Fifty-six days after injecting eVLP-forming mRNA into immunized mice, the researchers found a 5-fold increase in antibody titers against the SARS-CoV-2 strain WA.1 and a 10-fold increase against the Omicron BA.1 mutant. observed to increase. Spike mRNA used in conventional vaccines.⁶ “Traditional mRNA vaccines require at least three immunizations to get a strong neutralizing response to those variants, but we did it with two immunizations,” Hoffman said. says Mr.

“I think it’s a very smart study, and one that has important real-world applications,” said Wes Sundquist, an ESCRT expert at the University of Utah who was not involved in the study. “The advantage is that he only needs one gene to create these. [eVLPs] And we can purify them from the cells. More importantly, they can be delivered as a single mRNA. ”

Hoffman believes this approach could provide a strong neutralizing response to virus variants and reduce the total number of vaccine doses needed. Professor Hoffmann plans to test the eVLP-producing mRNA in non-human primates before entering the clinical trial stage to develop similar vaccines against other viruses, such as influenza virus and human immunodeficiency virus (HIV). making plans.

References

1. C. Zheng et al., “Real-world efficacy of COVID-19 vaccines: a literature review and meta-analysis.” Int J infected disk114:252–260, 2022.
2. SJ Kent et al., “Unraveling the Relative Importance of T-cell Responses in COVID-19: Leading Role or Supporting Role?” Nat Rev Immunol22(6):387–397, 2022.
3. KL Rock et al., “Present Yourself! With MHC Class I and MHC Class II Molecules.” Trend Immunol37(11):724–737, 2016.
4. NP Hachmann et al., Neutralization Evasion by SARS-CoV-2 Micron Subvariants BA.2.12.1, BA.4, and BA.5. N English J Medicine387(1):86–88, 2022.
5. Z. Zhang et al., “Humoral and Cellular Immune Memory for Four COVID-19 Vaccines.” cell185(14):2434-2451.e17, 2022.
6. MAG Hoffmann et al., “ESCRT Recruitment to SARS-CoV-2 Spike Induces Virus-Like Particles That Improve mRNA Vaccines” cell, 186(11):2380-2391.e9, 2023.