How does the mRNA/lipid nanoparticle platform promote protective adaptive immunity against SARS-CoV-2?

By Jocelyn Solis-MoreiraAug 5 2021

Modified mRNA combined with lipid nanoparticles may be beneficial in boosting adaptive immunity against the severe acute respiratory coronavirus 2 (SARS-CoV-2). Research led by Botond Z. Igyártó from Thomas Jefferson University’s Department of Microbiology and Immunology in Pennsylvania recently found that the lipid nanoparticles induce protective adaptive immune responses with antibody titers against lethal doses of the virus.

Tissue-resident macrophages, Langerhans cells, do not appear to disrupt the mRNA and lipid nanoparticle platform from inducing a protective immune response. Instead, the combination platform seems to operate through an IL-6 dependent and neutrophil independent mechanism.

The researchers write:

Here we show that the mRNA-LNP platform widely used in pre-clinical animal vaccine studies promotes protective adaptive immune responses against influenza and SARS-CoV-2 infections in the absence of LCs and cDC1s. We further identified IL-6 as a crucial inflammatory cytokine in supporting the induction of adaptive immune responses by this platform and showed that neutrophils were dispensable for these responses.”

The study “Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective antiinfluenza and anti-SARS-CoV-2 responses” was published on the preprint bioRxiv* server.

Study: Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 responses. Image Credit: Love Employee / Shutterstock

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Study details

The researchers sought to find how modified mRNA and lipid nanoparticles supported a protective immune response. They narrowed down their predictions to several mechanisms related to the inflammatory cytokine IL-6, neutrophils, and dendritic cells. Dendritic cells are essential in initiating different types of immune responses.

The researchers used mice deficient in either dendritic cells, IL-6, or neutrophils and exposed them to different doses of the flu virus and SARS-CoV-2. The mice were then administered the mRNA and lipid nanoparticle platform.

Dendritic cells are unlikely to be involved in the platform’s mechanism

Despite the absence of Langerhan cells and cDC1s, mice still expressed a protective adaptive immune response towards flu and SARS-CoV-2 infections. Specifically, there was no noticeable change in the generation of T follicular helper cell and B cell responses.

There was a significant decrease in adaptive immune responses in the absence of both cell types, indicating an essential role in driving T follicular help cell and antibody responses.

In the absence of both cell types, the platform was still successful in protecting against SARS-CoV-2.

The necessity of IL-6 n stimulating an adaptive immune response against SARS-CoV-2

IL-6 was essential for the modified mRNA and lipid nanoparticle platform to work and produce an immune response. Previous studies suggested the platform triggers high IL-6 levels.

Mice lacking in IL-6 were administered 10 micrograms of the mRNA-lipid nanoparticle platform. They found that not having IL-6 affected the induction of T follicular helper cells and B cells, which in turn negatively impacted the immune response. Additionally, there were lower levels of anti-HA serum IgG antibody levels in mice deficient with IL-6 compared to mice with IL-6.

While the results indicate IL-6 is likely to be involved in the platform’s mechanism of action, the researchers point that more studies are needed to pinpoint the cellular source of IL-6 and other cells not evaluated in this current study.

“The absence of IL-6 did not lead to a complete lack of Tfh cells and antibody responses. Therefore, other cytokines and co-stimulatory molecules previously described to play essential roles in regulating humoral immune responses, such as IL-1β and IFNα, are expected to contribute,” wrote the authors.

Neutrophils are not necessary for the mRNA-LNP platform

The researchers investigated the role of neutrophils in the platform’s ability to trigger immunity. Two days before immunization, the team depleted all the neutrophils in mice.

The results showed that neutrophils did not affect the production of T follicular helper cells and B cell responses.

There was a small decrease in anti-HA serum IgG antibody levels, but this did not reach significance.

Based on the findings, the researchers suggest neutrophils are likely not needed in producing an mRNA and lipid nanoparticle-induced adaptive immune response.

The mRNA and lipid nanoparticle platform has shown evidence of immune responses against influenza and the coronavirus in animal models. But how this platform performs in humans remains poorly understood. Therefore, the researchers conclude that more clinical research is required before approving the platform for humans.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources