Potential of RNA Vaccines for Covid-19 - BiopharmaDirect

Potential of RNA Vaccines for Covid-19

RNA vaccine technology can completely change immunization methods against AIDS, malaria, influenza and other diseases. Last month, two RNA vaccine candidates received the first emergency use authorization (EUA) from multiple national regulatory agencies to fight COVID-19—one is from the US pharmaceutical giant Pfizer and BioNTech, and the other is from Moderna located in Massachusetts. This marks the arrival of the era of RNA vaccines.

Figure 1. RNA vaccines. (Cuiling Zhang, et. Al. 2019)

The idea of using RNA in vaccines emerged nearly thirty years ago. Compared with traditional methods, genetic technology is more simplified, allowing researchers to quickly track multiple stages of vaccine development. Now, the strong public interest in RNA vaccine may promote the use of RNA technology to treat diseases that are hard to conquer in the past, such as tuberculosis, AIDS and malaria. Moreover, the rapid production of RNA vaccines can improve the effectiveness of seasonal influenza vaccines. Previously, the production speed of traditional vaccines cannot keep up with the speed of seasonal influenza virus mutation.

However, there are still some challenges regarding the further application of this technology. For instance, the raw materials are expensive and the side effects can be disturbing. RNA technology has proven to be useful in the treatment of COVID-19. Let's see how RNA vaccines have been evolved in the past decades and what potentials they have for treating other diseases.

Lipid nanoparticles (LNP) technology

Vaccines allow the body to recognize and eliminate pathogenic factors. Usually, weakened pathogens or proteins or sugars on their surfaces (these are antigens) are injected to train the immune system to recognize invaders. But RNA vaccines only need to guide the production of these antigen proteins. The goal is to make them enter human cells and make them produce antigens, thereby turning the human body into its own vaccination factory.

The idea of an RNA-based vaccine dates back to the 1990s, when French researchers first used RNA encoding influenza antigens in mice. The mice responded, but the lipid delivery system used by the team proved too toxic to be used in humans. More than 10 years later, companies focusing on RNA interference technology (using RNA to block the synthesis of specific proteins) developed Lipid nanoparticles (LNP) technology, which laid the foundation for the success of the RNA vaccine development. LNP technology enables messenger RNA to be applied to a variety of different disease indications. In the past ten months alone, at least six RNA-based COVID-19 vaccines have entered human testing. Several more will be available soon.

Figure 2. Characterization of saRNA lipid nanoparticle formulations. (Anna K. Blakney, et. Al. 2019)

RNA vaccine development is quick and can respond to urgent needs.

Researchers can quickly extract potential antigen-coding fragments from the genetic sequence of pathogens, insert the sequence into a DNA template, synthesize the corresponding RNA, and then package the vaccine for delivery to the body. In contrast, the classic vaccine production method requires an expensive and time-consuming process of de novo development. However, with RNA, vaccine manufacturers can switch to effective antigens more quickly. They only need to change the RNA sequence wrapped in it.

In addition, RNA vaccines can assist basic research. Justin Richner, a vaccinologist at the University of Illinois College of Medicine in Chicago, is developing an RNA-based dengue vaccine in his own laboratory. Richner et al. routinely adjusted the gene sequence encoding the envelope protein used by the dengue virus to attack human cells. By iterating their design, the researchers tested about 15 vaccine candidates in mice. Richner also pointed out that it is very easy to manipulate the RNA sequence of a vaccine to try new hypotheses and strategies.

RNA vaccines may contain instructions for multiple antigens, which are either strung together in a chain or encapsulated in a single nanoparticle together with multiple RNAs. Norbert Pardi, a vaccine scientist at Perelman School of Medicine at the University of Pennsylvania, used the latter method to make an experimental flu vaccine. The multiple vaccine consists of four RNA strands, each of which encodes a different influenza protein, successfully protecting mice from infection with a specific influenza virus subtype.

Now, Pardi and his collaborators at the Icahn School of Medicine at Mount Sinai in New York City hope to repeat the above test for the other two major viral subtypes, and then put all the sequences into a 12-RNA chain In the flu vaccine, to replace the annual vaccination requirement (because the influenza virus strains are not the same every year, so it must be vaccinated every year). Pardi reminded that if multiple components of the virus are targeted, a broad protective immune response can be induced.

Stability and Security

Despite many potential advantages, the current RNA vaccine technology still has room for improvement. Robin Shattock, an immunologist at Imperial College London, pointed out that this technology is still in its early stages, and he suspects that we will see continuous improvements in RNA vaccine technology in the next few years.

First, low temperatures are required for the storage of RNA vaccine. Second, the RNA vaccines used in humans to test against COVID-19 or other diseases usually need to double the dose to be effective. However, many people who received the first dose of the vaccine will not go for the second dose. Third, the RNA vaccine may have serious side effects. In clinical trials, more than 80% of individuals receiving Moderna vaccination have systemic effects on the vaccine. Reactions, accompanied by fatigue, muscle pain, and other symptoms that are often shown to make people weak. In addition, for any vaccine for infants, researchers will definitely want to reduce reactogenicity. Contaminants in vaccine synthesis and LNP delivery systems are considered to be the two main sources of reactogenicity. The current purification system has a limited ability to remove pollutants, so the purity of LNP is also limited. For these reasons, vaccine manufacturers usually reduce the dosage to limit the amount of pollutants and LNP that enter the body. For conventional RNA vaccines, lower doses mean lower efficacy. However, companies such as Arcturus Therapeutics of San Diego, California and VaxEquity of London have devised workarounds to create self-amplifying RNA constructs for their COVID-19 vaccine.

Figure 3. How does RNA vaccines work? (Joshua Peters. 2020)

Different from the previous RNA-based vaccines, the new RNA vaccine not only contains the coding sequence of the coronavirus spike protein and the regulatory sequences at both ends, but also includes RNA replicase.

Although such vaccine constructs are slightly larger, require more sequence optimization and higher production equipment, they allow lower dosages. Replicating RNA vaccines are closer to natural viral infections, which can trigger a stronger and broader immune response. In this case, a single-dose vaccination can be made possible.