This is Part III in a series that explores the promise, challenges and future of mRNA.
In Part I of this series, I noted that mRNA vaccines were hustled into commercial viability by Operation Warp Speed, a federal program set up in 2020 to accelerate the development of any vaccine that might stave off COVID-19's most severe symptoms.
The sudden appearance of a brand new kind of vaccine has generated concerns ranging from the spurious to the undeniable. Like all vaccines, the ones for COVID-19 can cause side effects -- a problem that may have a lot to do with how mRNA currently gets delivered -- and, as readers of Part II of the series have learned, Stanford Medicine researchers are bent on minimizing them. While Part 1 explained how the new vaccines work and how they're packaged for delivery to our immune systems, Part II focused on potential improvements in mRNA vaccine delivery that could both minimize side effects and get more bang for the dose.
To sum it up, lipid nanoparticles -- the mRNA delivery vehicles in commercial use today -- don't always deliver their mRNA cargo to their target cells, and sometimes deliver it to the wrong places. And only about one-tenth of the mRNA that reaches a targeted cell is actually converted into the protein meant to trigger an immune response. Potentially superior delivery technologies, which I described in detail in Part II, may address those shortcomings.
The biggest source of mRNA vaccine skepticism, according to vaccinologist Bali Pulendran, PhD, the Violetta L. Horton Professor and professor of pathology and of microbiology and immunology, is rooted not in biology but in our own psychology -- specifically, an amorphous, free-floating fear of the unknown.
"The human mind rejects any new idea like the body rejects a transplanted organ," he said.
Everything, everywhere, all at once
COVID-19 was the launchpad for mRNA vaccine technology. As the world emerges from the worst of the pandemic, can the same platform dispatch mRNA vaccines aimed at pretty much any microbe of choice?
Pulendran answers with a resounding yes.
"Any vaccine you can think of, the mRNA companies are working on it," said Pulendran, who has consulted with Moderna, Pfizer and BioNTech, three companies closely associated with the new technology. "Their world view is that mRNA technology will replace all preceding ones. The future is extremely bright for mRNA vaccines."
Pulendran noted a couple of criticisms that have been leveled at the mRNA-based COVID-19 vaccines. "They've been very good at preventing severe disease, hospitalization and death," he said. "So far, they haven't been so good at preventing infection for long periods of time -- particularly in the face of ever-newer viral variants - and they haven't been great at preventing transmission."
But transmission, or the spreading of a virus from person to person, is a problem common to all respiratory infections, he said. It's tough to completely prevent infection of the nose and throat with any vaccine, considering these outward-facing cavities' cells are constantly exposed to the air -- and, consequently, the microbes -- we inhale.
"To me, the most critical goal of a vaccine is to prevent severe or even moderate disease," Pulendran said. "A mild COVID 'cold' may even benefit us by keeping our immune system on its toes." On the other hand, he said, mRNA vaccines employing delivery systems that target the mucus-secreting linings of our airways and gut may prove more effective at durably preventing infection.
Was the technology that rescued people most susceptible to depredations of SARS-CoV-2 -- the virus that causes COVID-19 -- a one-hit wonder, or was it a cornucopia conferring protection from microbial menaces of every stripe? Time will tell.
And it won't take long. Clinical testing is underway for mRNA-based vaccines for influenza, HIV, cytomegalovirus (a ubiquitous microbe that usually causes no symptoms but can harm immunocompromised people), dengue, rabies and several other viruses, as well as for malaria, tuberculosis and other non-viral microbes. Moderna is submitting its mRNA-based vaccine directed at respiratory syncytial virus to the FDA for approval. Moderna and Merck are collaborating on a personalized skin-cancer vaccine employing mRNA, now in clinical trials.
These are all familiar, if uninvited, maladies. What humanity should most fear -- and what the plug-and-play mRNA vaccine technology promises to provide the most valiant and rapid defense against -- are those next unfamiliar monsters climbing over the hill toward us, which science-fiction movies always seem to depict as giants but are actually microscopic.
Read all the stories in this series:
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