This is the third article in a series on next-generation mRNA vaccines. The first two installments can be read here and here, respectively.
Messenger RNA (mRNA) generation has been at the center of the global reaction to Covid-19, allowing for the immediate manufacture of effective vaccines. But the virus continues to evolve, learning to thwart past immunity, through infection or vaccination. To keep pace, researchers and brands have developed the next generation of mRNA vaccines. Here, we take a look at one such example: the first mRNA vaccine manufactured in India, Gemcovac-19, manufactured through Gennova Biopharmaceuticals. The Office of the Comptroller General of Medicines of India (DCGI) has granted the Emergency Use Authorization of the Vaccine (EUA), and an express booster injection is already being prepared for Omicron.
Self-powered RNA technology
The first next-generation feature of Gennova’s vaccine is the generation of self-powered RNA. While classic Covid-19 mRNA vaccines are based only on the genetic series encoding the SARS-CoV-2 spike protein, Gemcovac-19 includes a series of alphavirus RNA encoding 4 non-structural proteins. Once inside a host cell, those nonstructural proteins combine to form a molecule called RNA replicase, a portable “photocopier” that prints copies of the mRNA series (Figure 1). This means that each series of mRNAs included in the vaccine is able to make copies of itself, which increases the amount of antigen produced. It also increases the duration of mRNA translation over a longer period of time; Vaccine-derived mRNA typically degrades after a day or two, restricting protein expression to a maximum of two to three days. one month.
Self-powered RNA generation has many advantages. For one, because each series of mRNA will produce multiple copies of itself, brands can use a much smaller amount according to the dose of the vaccine. The lower dose allows several other strands of mRNA, each encoding its own antigen, to be included in an individual vaccine. The dose-saving technique also particularly reduces the cost of production; the value of the vaccine falls accordingly, making it more available to low- and middle-income countries that traditional Pfizer/BioNTech or Moderna counterparts may not be able to.
The main merit of the moment is on the immunogenicity front: since self-powered mRNA can produce more target antigen, over a longer period of time, it gives our immune formula a greater chance of learning what it wants to expand a highly specific reaction. . Longer exposure to an antigen allows the antibody reaction to mature, resulting in neutralizing antibodies of higher affinity, as well as antibodies that can cause cellular cytotoxicity. In addition, longer exposure to the antigen is necessary to generate reminiscent T cells for lasting reminiscence. the inclusion of alphavirus RNA, which mimics viral replication, can act as an herbal adjuvant through stimulation of trending popularity receptors.
Freeze-drying: facilitating garage and transport
One disadvantage of first-generation mRNA vaccines is that they will need to be stored at incredibly low temperatures. The Pfizer/BioNTech Covid-19 vaccine, for example, must be kept at minus 103 degrees Fahrenheit (about -75 degrees Celsius); In a traditional refrigerator, the vaccine degrades in five days, and at room temperature, this is reduced to just six hours. This poses demanding logistical situations for the transport and storage of vaccines, especially in spaces where the mandatory infrastructure of the “bloodless ultrachain” is missing: the lack of a network of refrigerators, freezers, coolers and bloodless rooms used to keep vaccines in the correct position at the correct temperature.
Gennova’s vaccine alleviates this challenge through freeze-drying or freeze-drying. This is a procedure through which the solvent is gradually removed from the vaccine solution (Figure 2). Once the solution is frozen, which is the first component of the procedure, it is then placed in a low-pressure chamber to “jump” directly from a forged state to a gaseous state. This jump removes approximately 95% of the solvent, leaving a calcareous powder. The remaining liquid is removed in a moment drying cycle.
FIGURE 2. A schematic diagram of the three-part freeze-drying process.
The vaccine powder that remains after freeze-drying has a particularly more solid temperature than the liquid solution. Compared to the sub-zero temperatures required for first-generation mRNA vaccines, the Gemcovac-19 vaccine can be stored between 35 and 46 degrees Fahrenheit (35 and 46 degrees Fahrenheit). two and 8 degrees Celsius) any problem. Instead of special freezers, it can be stored in a general refrigerator. Even in any refrigeration, the freeze-dried vaccine can retain its effectiveness for an extended period of time.
This provides countries that might not have the infrastructure to meet the ultracold storage needs of traditional mRNA vaccines with a more robust and similarly effective counterpart. Freeze-drying also reduces weight and volume, reduces shipping costs, and makes it more available to low- and middle-income countries.
Intradermal management stimulates immunogenicity and improves absorption
Another feature that distinguishes the Gennova vaccine from older first-generation Covid-19 mRNA vaccines is the fact that it is administered intradermally (Figure 3).
Our skin is made up of 3 layers: the outermost protective layer called the epiepidermis, an intermediate layer called the epidermis, and a layer of fat on the back called the hypoepidermis or subcutaneous tissue. Most Covid-19 vaccines are injected into muscle tissue, which is deep under the skin. This has been the technique for a long time. But intradermal management has some distinct advantages.
FIGURE 3. Comparison of other injection angles.
The epidermis layer of the skin is densely filled with immune mobiles, adding mobile antigen providers (APCs). These play an important role in activating and modulating our immune system, adding our adaptive immune response. In particular, other types of dendritic mobiles attach to antigens and provide them to naïve T mobiles, helping to form and mature a specific mobile immune response. Since intradermal injection allows antigen to be produced very close to antigen-providing mobiles, it can lead to a faster and more subtle adaptive response. immune response. A recent study comparing intradermal and intramuscular management of the receptor-binding domain (RBD) of SARS-CoV-2 showed this, describing stepped T-mobile responses after injection into the epidermis.
Intradermal injection also holds promise for prices and increased production, as a lower dose triggers the same immunogenicity as a higher dose administered through classical intramuscular injection.
Finally, intradermal treatment comes with the added advantages of needle-free delivery options, such as jet injectors (Figure 4). These use springs or compressed fuel to produce a tight flow of high-pressure fluid that penetrates the skin and delivers the vaccine. . The absence of needles is aiding absorption, especially in younger needle-refractory populations. The World Health Organization (WHO) has sponsored the advent of needle-free delivery systems for use with inactivated polio vaccines in Somalia and Pakistan. The share of the needle-free vaccination campaign in Pakistan increased to 18. 4% over the past year. Health workers and vaccinators overwhelmingly liked the delivery without needles instead of needles and syringes, and one hundred percent consistently of caregivers surveyed admitted that they would be more likely to take their children back for a long-term vaccination crusade using needle-free injectors.
Needle-free delivery also denies the option of needle reuse and upcoming cross-contamination, which remains a common challenge in many parts of the world, with up to 1. 3 million deaths per year attributed to such practices. Needle-free delivery also prevents accidental puncture injuries, which can lead to cross-contamination and infection. Puncture injuries are also prevented by overlooking the need to remove sharp objects, which is a complex and expensive procedure prone to errors and mishandling.
FIGURE 4. Diagram of a PharmaJet Tropis needleless injector.
consequences
Gennova Biopharmaceuticals’ new Covid-19 vaccine, Gemcovac-19, represents a step towards next-generation mRNA vaccines. The use of self-powered RNA generation allows effective dosing of vaccines and provides our immune formula with more time to expand high-affinity antibodies. and mature T cells. The fact that it is freeze-dried makes shipping and storage easier, adding spaces that would possibly not have simple access to the bloodless chain infrastructure. And needle-free intradermal handling allows for fast and safe delivery, which can aid absorption, cellular immunity and reduce the risk of cross-contamination.