Preventing the next pandemic: mRNA vaccines and siRNA oligo therapies

Investing in promising new pharmaceutical platforms like oligonucleotide therapies could reduce the gap between first detection and total eradication in future pandemics.

The battle against our current pandemic is playing out in multiple arenas: in government assemblies, lawmakers are issuing travel bans and dusting off ancient quarantine legislation to control the disease’s spread. In local communities, neighbors are avoiding contact under the auspices of social distancing. Distilleries are producing hand sanitizer, clothing manufacturers are making PPE, and clandestine online groups are crowdsourcing new ventilator designs.

Collectively, these efforts should be applauded and will help to keep us protected while the pharmaceutical world closes in on vaccines. But at what cost? Travel bans, mass quarantines, and social distancing are often insufficient and difficult to enforce—and we’ve seen what they do to the global economy. These are blunt tools that leave heavy scarring and are sure to have lasting impacts after the virus has run its course.

We have to do better than that. To me, a “better” response doesn’t mean, “Let’s get ready for the next pandemic.” It means, “Let’s prevent pandemics altogether.” Let’s leave those blunt tools to the history books and invest instead in the promising new pharmaceutical platforms that could reduce the gap between first detection and total eradication.

A new response: mRNA vaccines and siRNA oligo therapies

Many leading pharmaceutical companies are pouring resources into the development of traditional live-attenuated or inactive vaccines against SARS-CoV-2, which could lead to the cure our world needs. These are mature, well-understood therapeutic platforms that have already spared countless people from deadly infectious diseases. The downside? It can take anywhere from 18 months to three years (or more) to develop a safe and effective “live viral” vaccine, and another several years to build and license a manufacturing facility capable of producing the billions of doses that we’ll need. Although regulators and drug companies are working together to accelerate that timeline as much as possible, there’s only so much speed that we can expect from a platform that depends on culturing cells and must demonstrate efficacy and safety with each new application.

Meanwhile, two new kids in town are attracting a lot of serious attention and excitement: mRNA vaccines and siRNA oligo therapies. These modalities are so new, in fact, that no mRNA vaccine has ever advanced to commercial production, and siRNA has never been approved in an antiviral inclination or with the lungs as the target tissue. These challenges haven’t stopped biopharmaceutical innovators like Moderna, CureVac, and BioNTech/Pfizer from pursuing an mRNA vaccine against SARS-CoV-2, or partners Alnylam Pharmaceuticals and Vir Biotechnology from doubling down on a siRNA prophylactic therapy to treat those exposed to the virus.

What makes these therapies different from traditional platforms, and why are so many pharmaceutical leaders interested in their potential?


Traditional Vaccines

The historic approach is to propagate a mammalian cell culture, infect it with SARS-CoV-2 (in this case), then isolate and chemically inactivate the virus. Some vaccines are “live-attenuated,” meaning the virus itself is genetically modified and rendered non-pathogenic throughout its lifecycle. Both approaches result in a vaccine used to trigger an immune response in healthy individuals.

This is a well-understood platform, already used to prevent deadly infectious diseases around the world.

The process varies to weaken the virus in order to develop immunity without the downsides of an infection. Thus, both the safety and efficacy of each new inactivated and attenuated vaccine must be demonstrated independently. This regulatory hurdle, combined with the longer process of cell culture-based manufacturing pushes out development timelines.

Chinese State-backed Sinovac and Wuhan Biological Projects have the early lead. Sinovac started human trials on April 16th and has demonstrated successful immunization in primates.

mRNA Vaccines

This approach eliminates the need for a cell culture and spares patients from exposure to a live-attenuated or inactivated virus. Instead, the concept is to directly introduce the immune system to a sequence of messenger RNAs (mRNAs) that expresses the proteins characteristic of SARS-CoV-2 and thereby triggers an immune response.

By synthesizing mRNA in the lab, developers can leapfrog the biological processes that slow down traditional vaccine development and production.  Differences between mRNA vaccines are so minor, demonstrating the safety of each new mRNA vaccine may require less scrutiny, accelerating the approval process.

Although scientists are confident in the safety and efficacy of mRNA vaccine technology based on small sample sizes, no such vaccine has yet received approval and licensing. More study is needed. 

Working with The National Institute of Allergy and Infectious Diseases (NIAID), biotech innovator Moderna made headlines when the first vials of their proposed SARS-CoV-2 mRNA vaccine were ready for human testing just a few weeks after Chinese scientists sequenced the SARS-CoV-2 RNA genome.


Traditional Antiviral

These prophylactic therapies are designed to inhibit the replication of viral pathogens in an infected host.

Reformulations of existing broad-spectrum antivirals show promise against SARS-CoV-2. 

Broad-spectrum antivirals are often limited in their effectiveness and are likelier to trigger adverse side effects. More specific antivirals are possible, but only after years of studying behaviors in the target virus.

Gilead’s remdesivir treatment, originally indicated for ebola, shows promise as a treatment for improving lung function in patients with COVID-19.

Hydroxychloroquine, a general antiviral originally developed against malaria, attracted early attention as a potential treatment against COVID-19. However, the National Institutes of Health is no longer recommending its use for this new indication after recent studies showed mixed results.

siRNA oligo antiviral

This platform uses a short strand of synthetic RNA to interfere with the viral replication process (hence the “si” insignia, which refers to “small interfering”). This halts the infection before it spreads through the body.

Once the viral genome is sequenced, a targeted oligo therapy can be synthesized relatively quickly using existing siRNA manufacturing platforms.

Developers have been grappling with the question of how best to ensure delivery of the siRNA therapy to the targeted tissue. siRNA has demonstrated efficacy in treating genetic disorders, but not yet as an antiviral.

An existing collaboration between Vir Biotechnology and Alnylam Pharmaceuticals, which was recently expanded in response to COVID-19, has yielded a promising development: an siRNA that greatly reduced viral replication in lab tests. The partners are now advancing through an ongoing phase 1 and 2 studies.

Dressed” and ready for an ideal pharmaceutical response

I don’t have a crystal ball to tell me which type of vaccine will save us from SARS-CoV-2, or what the future holds for siRNA oligo antiviral therapies. What I do have is a set of criteria that define the ideal drug campaign for preventing future pandemics before they’ve made the news…and it so happens that mRNA vaccines and siRNA oligo therapies either meet each criterion already or show significant promise that with a little bit more development they’ll get there.


The acronym DRESS stands for Development Time, Rapid Deployment Time, Efficacy and Safety, Specificity and Flexibility, Stability and Shelf Life
Development Time

Ideally, new infectious diseases are stopped before they become endemic, let alone pandemic. This depends in part on how quickly we can develop vaccines and therapies once a new disease is identified.

  • mRNA vaccines: Once we’ve identified the viral proteins that cause the body’s immune response (this took just weeks in the case of SARS-CoV-2), developers can pursue multiple, simultaneous paths toward complementary mRNA sequences for each protein. Pursuing several possibilities at once is a major time advantage—one that’s not typically possible in traditional vaccine development.
  • Oligo therapies: Knowing the genetic sequence of the virus is all that’s required to identify targets for disrupting viral replication. From there, established siRNA manufacturing platforms can produce specific siRNA sequences to prevent the propagation of viral proteins.
Rapid Deployment Time

It won’t matter how quickly we develop vaccines and treatments if we can’t manufacture them fast enough to meet the population’s needs.

  • mRNA vaccines: Because manufacturing does not depend on cell cultures, the process requires fewer steps and is less susceptible to contamination. mRNA manufacturing facilities are capable of making more than just vaccines, and they have the equipment and raw materials at the ready—all they need is the correct sequence, which is as easy to share as sending an email.
  • Oligo therapies: Current oligo manufacturing facilities are often designed to produce multiple different oligos, so switching production from genetic disorder treatments to antiviral treatments would require little, if any, modification. This means virtually all existing manufacturing capacity could be used to ramp up antiviral production and switch back to other products once the need has been met. This decentralizes the potential manufacturing landscape and facilitates faster, more productive knowledge-sharing, which in turn could save countless lives. In other words, you don’t need a new kitchen to switch cookie recipes!
Efficacy with Safety

Obviously, vaccines and therapies must be effective, and they must be safe. Healthy people depend on vaccines to keep them that way; if the vaccine isn’t safe, it fails. Therapies accelerate recovery in those already exposed to the disease by killing the virus, which they usually accomplish by killing the host cell—but we’re talking about treatments, not weapons, so they too must be safe.

  • mRNA vaccines: Proving the efficacy of these vaccines is a major challenge. Ensuring the immune response targets the viral protein, not the mRNA itself, is essential to building patients’ immunity, and developers are still clinically proving the safety of this biological process. They’re confident that early clinical trials will succeed, especially given that mRNA by itself is harmless and that these vaccines spare humans from exposure to a live contamination, unlike attenuated vaccines. This lowers the risk of adverse reactions, such as an inadvertent infection.
  • Oligo therapies: We know from FDA-approved oligo therapies that when interfering RNA successfully reaches infected tissue, it disrupts the production of target proteins as designed. In the case of SARS-CoV-2, this means delivering sufficient qualities of siRNA directly to the lungs, which is today’s big challenge. Along with targeted delivery, we also know that early intervention is key to safety; studies suggest that local administration is more successful than systemwide administration, which requires nabbing the infection before it spreads through the body—another challenge. The third major factor in ensuring the safety and efficacy of oligos is the body’s unintended systemic response to human protein modulation, although developers expect that disrupting a viral protein that’s unrelated to normal functions will not trigger this issue.
Specificity with flexibility

In principle, a specific drug is more effective and delivers fewer side effects than a broad-spectrum therapy, but specificity comes at a price. Just look at current antiviral treatments: many vaccines circulating today are produced from scratch for each new and specific virus, which is a time-consuming and very inflexible process. Ideally, new vaccines and therapies will take advantage of a flexible platform that can pivot from one disease to another with only minor alterations.

  • mRNA vaccines: When (okay—if) the safety concerns are cleared, an mRNA vaccine developed for one virus will be easily adaptable to another. This is sharply different from traditional vaccine development, which requires reinventing the process anew according to the unique properties of each virus. Rather than depending on what makes each virus different, mRNA vaccines exploit what every virus has in common—that is, all viruses use the same process to enlist host cells as factories for making viral proteins. mRNAs work at the level of that common process, which means that shifting an mRNA vaccine from one virus to another should be as easy as modifying the sequence to match the corresponding viral protein.
  • Oligo therapies: Unlike most current antivirals, siRNA therapies are designed to specifically target the viral proteins of the disease they’re fighting. Despite the specificity of a certain RNA sequence against a target protein, the platform for delivering the siRNA treatment into body tissue would be the same from one virus to another. Much oligo research is focused on developing these delivery techniques in order to potentially target each of the body’s tissues, which would broaden the applicability of an oligo therapy. Recent progress towards clearing this hurdle suggests it’s a matter of “when,” not “if.”
Stability and shelf life

You can order ice cream from New York and it will arrive on your doorstep in San Francisco still frozen and delicious, so clearly cold-chain shipping is possible. It’s just that it’s expensive and complicated, especially when we’re talking about drug therapies as opposed to Rocky Road. Drug therapies with a longer shelf life are easier to move and store, which means regions can proactively stock key vaccines and treatments—no more lag between identifying the need and supplying the product.

  • mRNA vaccines: Although shelf life isn’t a current priority for teams working on this platform, the science of mRNA naturally favors a long shelf life because nucleic acids with the correct formulation are relatively stable. This suggests that mRNA vaccines could offer greater stability at room temperature than traditional vaccines—a major benefit.
  • Oligo therapies: Many current antivirals are solid dose (pill) formulations, which are well-suited for long stability and shelf life. Doing better than current antivirals could be a challenge. siRNA, which is partnered with a “passenger” strand, is more stable than single-stranded antisense oligos (ASOs), with a “room temperature” shelf life hovering somewhere around three to six months (some studies have suggested the potential shelf life would be much longer). Developments in ideal final formulations and delivery mechanisms for all oligo drugs will continue to push out the “expired by” date to an acceptable time frame.

Bottom line: We need to invest in promising pharmaceutical motifs

If we’re serious about preparedness, we need to invest significant resources in mRNA vaccines and siRNA oligo treatments. Whether they play a starring role in ending this particular pandemic or not, they offer our best chance at eliminating future health threats. They can be developed and deployed quickly, they’re well-suited for targeting specific indications effectively and safely, and they’re potentially stable enough to move around the world without the complexities of cold-chain storage and distribution. If I were a betting man, this is where I’d wager our future as a healthy, pandemic-free population.

If you’re part of the growing offensive against this health threat and those that may emerge in the future, call on us.

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