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Longevity Briefs: The Road To Better mRNA Vaccines

Posted on 17 August 2022

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: mRNA vaccines for COVID-19 are a form of gene therapy that work by delivering genetic material called messenger RNA (mRNA) to your cells. mRNA acts as a template that cells can use to build a protein, in this case the coronavirus spike protein, which trains the immune system to recognise and fight the real virus. While we typically think of vaccines as a way of protecting people against infectious diseases, it may be possible to vaccinate against some non-communicable diseases as well. Cancer cells can mutate to produce proteins that are not found anywhere else in the body, so we might be able to teach the immune system to attack these proteins and thereby help it to remove cancer cells.

Lipid nanoparticles, the microscopic ‘bubbles’ used to deliver mRNA, are primarily absorbed by the liver, which hinders their application for many diseases. One of the top priorities for gene therapy in the coming decades will be developing new lipid nanoparticles that can deliver their contents to wherever they are needed.

What did the researchers do: In this study, researchers tweaked the composition of lipid nanoparticles in an attempt to improve their uptake by the lymph nodes, the sites at which immune cells multiply in response to intruders. They did this by changing some of the specific lipids used to formulate the nanoparticles, as well as by altering the ratio of different lipids making up the nanoparticles. They then used this new nanoparticle to deliver mRNA coding for cancer specific proteins in two mouse models of melanoma, the most serious type of skin cancer.

Key takeaway(s) from this research: The lipid nanoparticle modifications were successful in increasing the delivery of mRNA to the lymph nodes, with about 75% of the nanoparticles reaching the desired target. The mRNA was effectively taken up by a group of cells called antigen presenting cells (APCs), which are important for initiating an immune response. When combined with anti PD-1 therapy, a cancer treatment that works by stopping cancer cells from suppressing the immune system, the nanoparticle treatment was associated with slower tumour growth in all mice and with remission in 2 of 5 mice (compared 1 of 5 mice treated with a different nanoparticle, and no remissions in mice treated with anti PD-1 therapy alone). Furthermore, these mice were protected against recurrence even when injected with tumour cells.

Above: Experiment outline
Below: Counts of macrophage and dendritic cell (two types of APC) found at the tumour site 7 days after the second vaccination in untreated mice (blue), mice treated using the nanoparticle used in the Pfizer-BioNTech Covid vaccine (red), mice treated with the new nanoparticle (green) and with the new nanoparticle + anti-PD-1 therapy (purple).
Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response

The mouse model of cancer used here is quite unlike human melanoma. The mice didn’t develop cancer ‘naturally’, but were implanted with a pre-existing lines of cancer cells, which means the researchers already knew of proteins that would make effective targets. Finding effective targets in human cancers is not always straightforward because mutated cancer proteins often look similar to normal proteins, and because these mutations are inherently random, meaning they will vary between individuals. Also, there were only 5 mice per group, which means that different remission rates could quite easily have been due to chance. In a way, the more exciting aspect of this study is how the researchers were able to modify the lipid nanoparticles to target the lymph nodes, as this could open the door for more effective mRNA vaccines targeting many diseases.

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    Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response:

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