The world changed in January 2020. What was once a flu-like virus spreading among citizens in one Chinese city soon became a global pandemic seemingly no one in the entire world had an answer for. While a viable medical treatment was still months away, there were groups of scientists who immediately knew where to turn—messenger RNA, or mRNA.
“We've known about [mRNA] for a long time, well before COVID-19,” said Van Morris, M.D., professor, Department of Gastrointestinal Medical Oncology, at The University of Texas MD Anderson Cancer Center.
Of course that’s true, with some researchers working on mRNA technology for decades; but, the technology was most often considered far-fetched, a moonshot or even “before it’s time.” The emergence of COVID-19 changed that, and Pfizer and BioNTech's BNT162b2 vaccine became the first mRNA-based vaccine to be approved for use in December 2020. Moderna’s mRNA-1273 vaccine was approved for emergency use authorization just a week later. Consequently, the world went from zero mRNA vaccines to two effective, safe options in less than 12 months.
And while mRNA vaccines can add “ending a global pandemic” to the accomplishments section of their resumes, the initial and continued success of these vaccines is so much more than that.
“This is a tremendous achievement for vaccine science as a whole,” said Dennis Burton, professor and chair of the Department of Immunology and Microbiology at Scripps Research. “We believe this type of vaccine engineering can be applied more broadly, bringing about a new day in vaccinology."
HIV
Traditional vaccines contain small or inactivated doses of the disease-causing organism, which are introduced into the body to provoke the immune system into mounting a response. In contrast, mRNA vaccines contain a synthetic version of the mRNA that a virus uses to build its infectious proteins. This mRNA is delivered into the human body, whose cells read it as instructions to build that viral protein, creating some of the virus’s molecules themselves. The immune system then detects these viral proteins and starts to produce a defensive response to them.
In the case of COVID-19 vaccines, the mRNA causes the recipient’s cells to produce the spike protein from the SARS-CoV-2 virus. The immune system recognizes the spike protein as foreign and produces antibodies to defend itself.
A collaborative team at IAVI and the Scripps Research Institute are leveraging this approach to beneficial antibodies in the quest to significantly accelerate the pace of HIV vaccine development—something that has been traditionally difficult with the constantly mutating HIV virus (not unlike new COVID-19 mutations).
HIV researchers have long looked to exploit the power of broadly neutralizing antibodies, or bnAbs, to neutralize diverse strains of HIV. These specialized blood proteins could attach to HIV spikes and disable them via difficult-to-access regions that don’t vary much from strain-to-strain.
The IAVI and Scripps Research team recently tested a vaccine to prevent HIV in a Phase 1 clinical trial. The vaccine demonstrated great success, actively stimulating production of the immune cells needed to generate antibodies in 97 percent of the participants who received it.
“We and others postulated many years ago that in order to induce bnAbs, you must start the process by triggering the right B cells—cells that have special properties giving them potential to develop into bnAb-secreting cells,” said William Schief, professor and immunologist at Scripps Research and executive director of vaccine design at IAVI's Neutralizing Antibody Center. “In this trial, the targeted cells were only about one in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells. The data from this trial affirms the ability of the vaccine immunogen to do this.”
Now, the researchers are partnering with Moderna to develop and test an mRNA-based vaccine that harnesses this approach to prevent HIV infection.
If successful, the team says they believe this vaccination method could also be applied to other challenging pathogens, such as influenza, dengue, Zika, hepatitis C viruses and malaria.
Cancer
MD Anderson’s Morris is leading a clinical trial to test whether mRNA technology could prevent colorectal cancer from recurring.
The standard treatment for many colorectal cancer patients is surgery, but cancer cells can remain in the body after the tumor is removed. These remaining cancer cells shed DNA into the bloodstream as circulating tumor DNA (ctDNA). After surgery, doctors check for the presence of ctDNA via a blood test. If there is ctDNA present in the patient’s blood stream, there is a higher risk of cancer reoccurrence.
The Phase 2 clinical trial is following high-risk patients with stage II or stage III colorectal cancer who test positive for ctDNA. After surgery, tumor tissue is removed from the patient’s body and tested for genetic mutations that fuel cancer growth.
Morris says anywhere from five to 20 mutations specific to a patient’s tumor can be identified during testing. The mutations are then prioritized by the most common to the least common, and an mRNA vaccine is created based on that ranking.
As with COVID-19 vaccines, this mRNA vaccine instructs a patient’s cells to produce protein fragments based off the genetic mutations identified during testing. The immune system then searches for other cells with the mutated proteins and clears out any remaining circulating tumor cells.
“Each patient receives a personalized mRNA vaccine based on the individual mutation test results from their tumor,” Morris says. “We’re hopeful that with the personalized vaccine, we’re priming the immune system to go after the residual tumor cells, clear them out and cure the patient.”
Compared to this time just last year, mRNA vaccines are in their infancy but they seem poised to bring about a revolution in vaccinology.
“It’s an evolving technology,” said Morris. “It’s new and exciting, and we know it can help us.”
Photo: A B-cell displaying antibodies created in response to foreign protein fragments produced from a personalized mRNA vaccine recognizes a colorectal cancer cell and signals killer T-cells to destroy it. Credit: MD Anderson Cancer Center.