Ribonucleic acid (RNA) is a crucial molecule for human existence. It collects life’s instructions from DNA and helps produce the proteins that enable essential functions like breathing, eating, and movement. Despite being fragile and short-lived, it serves various purposes, and was used to develop the Covid-19 vaccines using messenger RNA (mRNA) technology. By leveraging the body’s own cells, these vaccines have saved countless lives. The scientists behind this breakthrough, Katalin Karikó and Drew Weissman, recently received the Nobel Prize in Medicine for their pioneering work. Beyond Covid-19, mRNA holds immense potential in combating other diseases like cancer, the flu, HIV and autoimmune conditions.
Messenger RNA technology involves designing RNA in a lab that contains instructions for making proteins or pieces of viruses. When this synthetic molecule is introduced into a cell, the cell’s machinery reads it and starts producing the desired proteins. In the case of Covid-19, mRNA vaccines work by transporting the external RNA instructions into cells. This prompts cells to produce the coronavirus spike protein, which is then recognized by the immune system.
Developing the technique into an effective therapy was not an easy journey. Karikó's initial research faced rejection and even cost her a university position. However, the successful global Covid-19 vaccination program gave a significant boost to the technique. “The impressive flexibility and speed with which mRNA vaccines can be developed pave the way for using the new platform also for vaccines against other infectious diseases. In the future, the technology may also be used to deliver therapeutic proteins and treat some cancer types,” said the press release announcing the 2023 Nobel Prize in Physiology or Medicine.
The scientific community is actively researching a universal flu vaccine using mRNA technology. About a year ago, studies in mice showed promising results, demonstrating protection against all known subtypes of the influenza virus, around 20 in all. While it doesn’t prevent infection, this vaccine offers protection against the most severe stages of the disease, much like the Covid-19 vaccine.
In a recent interview with EL PAÍS, Karikó noted that Moderna — one of the pharmaceutical companies that developed a Covid-19 vaccine — is working on a vaccine for respiratory syncytial virus (RSV), which is the leading causes of bronchiolitis in very young children every year. “This company also has two ongoing trials of a vaccine against HIV and also against the Epstein-Barr virus, which could be the cause of multiple sclerosis,” said Karikó. “There is also a new experimental vaccine against nipah [an emerging virus in Asia that has a mortality of between 40% and 75%]. Both Moderna and BioNTech have announced that they are developing RNA vaccines against shingles. One already exists, but costs about €800 ($852). The advantage of mRNA vaccines is that they are cheap and can be developed very quickly.”
No mRNA target in HIV identified yet
Regarding use of mRNA technology for HIV, Drew Weissman told EL PAÍS in 2022 that he was optimistic about its potential after numerous unsuccessful attempts to develop a vaccine. “We have extensively researched HIV vaccines for a number of years, and we are currently conducting clinical trials using RNA vaccines. We are optimistic that within the next six or seven years, we will develop a highly effective vaccine for HIV.”
Julià Blanco, a researcher with Spain’s IrsiCaixa AIDS Research Institute, agrees that RNA technology has a place in the development of an HIV vaccine, but warns about a significant obstacle. “The crucial step is identifying the specific antigen to include in the vaccine. The vaccine’s RNA will induce the production of an HIV protein in our body, aiming to generate neutralizing antibodies. However, this task is exceedingly challenging due to the nature of HIV. The difficulty lies in identifying the desired protein, as it is essential for the RNA to effectively combat the virus.” Blanxco also stresses that implementing an HIV vaccination program will be very complex. “HIV poses a significant challenge in Africa, particularly in Sub-Saharan Africa. However, RNA technology may not be the most suitable solution due to its temperature sensitivity and the difficulties in transferring the necessary infrastructure and logistics to Africa.”
According to Blanco, mRNA technology has a significant advantage in that it enables “quick production of vaccines.” This was evident during the pandemic, when it took Moderna only 42 days to develop a candidate mRNA vaccine after the genetic sequence of SARS-CoV-2 was published by China. Blanco says this technology has proven its value in terms of speed, as building RNA is simpler than building proteins, the previous approach to developing vaccines. “In mRNA vaccines, the RNA is built and injected, and our own cells create the proteins.”
In addition to viruses, mRNA research is also being conducted to create vaccines for malaria, borreliosis (transmitted by tick bites), and tick-borne encephalitis.
Promising signs for cancer
Messenger RNA technology has a significant role in cancer treatment. Even before the pandemic, Dr. Ugur Sahin, an immunologist and co-founder of BioNTech (one of the developers of the Pfizer Covid-19 vaccine), conducted human trials for personalized cancer vaccines. The approach analyzes the tumor’s DNA, identifies surface proteins, and creates mRNA instructions for protein production. This activates the body’s defenses against cancer, showing great promise.
Last year, pharmaceutical companies Moderna and Merck reported positive results from their early trials (phase 2b) of a mRNA therapy for melanoma. Their combined vaccine and immunotherapy treatment, along with pembrolizumab, showed a 44% decrease in the risk of death and relapse. These are “promising” results, says Laura Angelats, an oncologist at the Hospital Clínic of Barcelona, but says caution is warranted due to the limited number of patients and specific tumor type. “Gathering more data across multiple tumor types is needed for a comprehensive understanding.” According to Angelats, research is also underway in lung cancer and hepatocellular carcinoma, although it is still in its early stages. “We are talking about complementary treatments to surgery for cancer that has not metastasized.”
Eight patients with pancreatic cancer — the deadliest type of tumor — responded positively to a combination of messenger RNA vaccine and conventional drugs. The therapy activated the immune system in half of the patients during the 18-month trial, and none of them experienced a relapse. “This is an advance, because it was thought that in this tumor it was impossible. But the treatment only worked in half the patients,” said Karikó. “It should be noted that the 16 patients in this clinical trial had undergone several courses of treatment with various drugs. It was their last hope because their immune systems were very weak. What we needed was to generate immunity mediated by killer T-lymphocytes [a type of white blood cell]. Eight responded, and 18 months later their cancer had not come back. Eight others did not respond and relapsed. One of the patients who responded had metastases, and yet his tumors disappeared. We don’t know why. We did see that the non-responders had slightly larger tumors. This is an initial trial with few patients, so we cannot generalize. Now we have to keep accumulating information and understand why some people react and others don’t. Such is science.”
Angelats again emphasizes the need for caution when interpreting the data and highlights the high cost and technical requirements associated with developing such technology. It is crucial to implement this technology in institutions with a high level of technical expertise. “To administer the vaccine, a biopsy of the patient’s tumor and a blood test are performed. The antigens present in the tumor but not in the blood are sequenced and analyzed. Once identified, a specific number of antigens are selected to design the personalized vaccine for each patient and their respective tumor.”
The full potential of this technology has yet to be revealed. “RNA is going to be used in more and more therapies,” Weissman predicted a little over a year ago, after receiving the Frontiers of Knowledge Award from the BBVA Foundation. “Using RNA, we have successfully modified two immune cell types in mice and utilized CAR-T to treat cardiac fibrosis. Excitingly, we are now progressing towards translating this approach to humans. Our goal is to cure sickle cell anemia with a single RNA injection.” The scientist confirmed that research is underway to use this technology for treating autoimmune conditions like lupus or rheumatoid arthritis.
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