Moderna, a biotechnology company, has announced positive preliminary results from a phase 3 trial of their messenger RNA (mRNA) vaccine for respiratory syncytial virus (RSV) in the elderly population.

RSV is a virus responsible for bronchiolitis, a viral respiratory infection that affects the small bronchi in infants. This news comes as a promising development in the fight against infectious diseases, as the potential of mRNA vaccines has been highlighted during the ongoing COVID-19 pandemic. These vaccines can be developed quickly, as was seen with the COVID-19 vaccines, and have the ability to effectively contain the spread of the virus and limit its impact.

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The recent success of mRNA vaccines, such as Moderna’s for COVID-19, can be attributed to the mRNA molecule at its core. However, other important players also contribute to the effectiveness of these vaccines. Lipid nanoparticles play a crucial role by encapsulating and protecting the mRNA while transporting it into cells. This not only ensures the mRNA remains intact, but also amplifies the immune response. Despite these advantages, there are also some drawbacks to be aware of with this technology.

RNA is not everything

Conventional vaccines consist of fragments of a virus that are used to educate the immune system. In contrast, mRNA vaccines only contain a single “assembly plan” in the form of the mRNA molecule.

After injection, the mRNA enters cells and is used to create a fragment of the virus that stimulates the immune defenses. This process “educates” the immune system, preparing it to react to the actual virus if encountered later.

mRNA molecules are fragile and can quickly degrade, especially in the presence of enzymes found in the body. To protect the mRNA and ensure it reaches cells safely, the mRNA is packaged in tiny lipid “nanocapsules.” These lipid nanoparticles, also known as “nanovaccines”, consist of ionizable lipids, phospholipids, cholesterol, and lipids conjugated to polyethylene glycol chains.

In vivo, these ionizable lipids allow the nanoparticles to enter cells and release the mRNA, which is then read and translated into proteins. These proteins trigger the vaccine response and are recognized as foreign by the body. The lipid nanoparticles also protect the mRNA from degradation and enhance its uptake by cells at the injection site. However, they can also be linked to some adverse effects.

Adjuvant Boosts Immune Responses in Vaccines

RNA vaccines, like any other vaccine, must activate immune cells called “antigen-presenting cells” in order to create an effective immune response. In traditional vaccines that use antigenic proteins, an adjuvant is added to the vaccine to achieve this.

RNA vaccines do not contain any adjuvants because the positively charged lipids in the lipid nanoparticles that encapsulate the mRNA serve this purpose. This adjuvant effect of the lipid nanoparticles leads to a stronger stimulation of antigen-specific lymphocytes in the lymph nodes near the injection site.

The immune responses generated are more potent than those from traditional adjuvants and specifically target “follicular T lymphocytes,” which play a key role in producing antibodies that neutralize the virus. Studies have also shown that these follicular T lymphocytes specific to the vaccine antigen can persist in the lymph nodes of vaccinated individuals for several months.

The precise mechanisms of the adjuvant activity of lipid nanoparticles are not fully understood, but it is known that they involve the stimulation of different populations of white blood cells, such as dendritic cells, and the production of hormones necessary for activating immune responses, such as cytokines and chemokines. These chemical messengers also cause an inflammatory reaction that can lead to adverse effects, known as reactogenicity, which are usually benign and short-lived.

Adverse Effects of RNA Vaccines: Known and Suspected

RNA vaccines can cause symptoms of reactogenicity, such as pain at the injection site, fever, headache, and fatigue. These symptoms occur frequently but typically disappear within a few days. Recent research suggests that polyethylene glycol may cause higher levels of reactogenicity in individuals who have been previously exposed to this component through certain pharmaceutical or cosmetic products. However, the role of polyethylene glycol in rare but serious allergic reactions remains debated.

The inflammatory reaction to the vaccine can cause swelling in the lymph nodes of the armpits and neck near the injection site. This phenomenon, likely caused by the lipid nanoparticles, is most commonly observed after the second dose of the Moderna vaccine. In most cases, the swelling subsides within a few days. However, if it persists for more than two weeks, further examination is necessary to rule out pre-existing malignancy.

Myocarditis and post-vaccination hepatitis are very rare complications of anti-COVID-19 RNA vaccines, which have been recognized by regulatory authorities. Fortunately, the prognosis for these cases is favorable with rapid healing in the majority of cases.

The involvement of lipid nanoparticles in these cases has not been proven, but it is plausible as both of these complications involve significant inflammatory reactions and infiltration of the heart by T lymphocytes.

Exploring RNA Vaccines at the Intersection of Nanomedicine and Immunology

RNA vaccines have several advantages that make them a promising solution for fighting viral infections. They can be developed quickly and mass-produced once the genetic sequence of the antigen is identified. This is how new anti-COVID-19 vaccines targeting sub-variants of the Omicron variant were made available in just a few months.

A single RNA vaccine can protect against multiple viruses or variants. For example, an American team has created a vaccine containing RNAs for 20 variants of the influenza virus’s hemagglutinin, paving the way for a universal flu vaccine.

Another advantage of RNA vaccines is their ability to induce strong immune responses, making them a potential solution for viruses that traditional vaccines can’t control, such as HIV and cytomegalovirus.

Scientists also hope that RNA vaccines will lead to significant advances in cancer research. Positive results have already been reported for melanoma, a type of skin cancer.

The use of RNA vaccines in the COVID-19 pandemic has marked the beginning of a new era in vaccinology, known as “nanovaccines.” Further research is needed to optimize these vaccines, particularly at the intersection of nanomedicine and immunology.

While the vaccines used during the pandemic have had a favorable benefit-risk balance, future RNA vaccines will continue to be closely monitored to identify patients at risk of developing adverse reactions.