Building on the success of the mRNA COVID-19 vaccines, scientists are aiming this technology at other infectious diseases, as well as cancer.
Before 2020, much of the public hadn’t even heard of messenger RNA (mRNA). Now, 2 years into a pandemic that has caused more than 5.5 million deaths worldwide, everyday conversations abound with mentions of two vaccines that use this molecule to safely induce an immune response to protect against COVID-19.
These vaccines — developed by Pfizer, Inc. in partnership with German biotechnology company BioNTech, and biotech company Moderna in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) — have changed the landscape of vaccinology.
Their rapid development and unexpectedly high effectiveness have given this vaccine technology a solid win — multiple wins, actually — that has spurred interest among scientists and the public alike.
Not only are these the to be approved for use in people in the United States, but this is the first time a coronavirus vaccine — using any vaccine technology — has been rolled out to the public.
The work, though, hasn’t stopped there.
Scientists have already tweaked these vaccines to better match variants of SARS-CoV-2, the coronavirus that causes COVID-19 — highlighting how relatively easy it is to update vaccines created with this technology.
They also have their mRNA vaccine sights set on other infectious diseases — such as respiratory syncytial virus (RSV) and HIV — as well as a number of cancers.
Some of this work began before the novel coronavirus upended the world. This research, along with new projects, continue with new enthusiasm, propelled by the successes of the COVID-19 vaccines.
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Speed of Development is a Key Strength for mRNA Vaccines
Many common vaccines induce a protective immune response using a weakened form of a virus (chickenpox and the combined measles, mumps, and rubella) or an inactivated virus (hepatitis A, rabies, polio).
When it comes to the seasonal flu, you can get either type: The flu shot is the inactivated version, while the intranasal flu vaccine is the weakened live version.
Other vaccines contain a piece of the microbe (hepatitis B, human papillomavirus, shingles, meningococcal disease) — these are known as subunit, recombinant, polysaccharide, or conjugate vaccines.
In contrast, mRNA vaccines use a single stranded mRNA molecule to teach our cells to produce a protein, also known as an antigen, which triggers an immune response.
The mRNA COVID-19 vaccines teach cells to produce a harmless piece of the spike protein, which the coronavirus uses to enter cells. Although harmless, the body recognizes this piece as foreign and produces antibodies.
One of the advantages of this technology is much of the work of designing an mRNA vaccine can be done on a computer, sometimes referred to as “in silico.”
This avoids the complex and time consuming laboratory steps — such as growing cells in culture — associated with other types of vaccine technologies.
"If COVID-19 had occurred a decade earlier, I don’t think we would have been as effective, as fast and as successful as we have been."
Peter Palese, PhD
To get started, scientists only need the genetic sequence of a virus — along with a deep understanding of that information.
The first cases of COVID-19 were reported in China on December 31, 2019, and initially described as “viral pneumonia.” Eleven days later, Chinese scientists published a draft genome — full genetic sequence — of the novel coronavirus.
By January 13, Moderna and NIAID had finalized the sequence for their candidate COVID-19 vaccine, known as mRNA-1273. The company began its phase 1 clinical trial in March.
The Food and Drug Administration (FDA) issued emergency use authorization for the Moderna-NIAID vaccine and the Pfizer-BioNTech vaccine for emergency use in December 2020, issuing full approval of the Pfizer-BioNTech vaccine in August 2021.
While scientists had to wait for the draft genome to be published before they could begin designing an mRNA vaccine candidate, they already knew a lot about coronaviruses similar to SARS-CoV-2.
The outbreaks of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 provided scientists with intimate details of how coronaviruses function, including the role of the virus’ spike protein in infecting cells.
In addition, researchers had been working on vaccines for SARS and MERS for years. None have been approved for use, but the knowledge gained during these efforts put the race for a COVID-19 vaccine on more solid footing.
Likewise, basic research that would eventually lead to mRNA vaccines began in the late 1980s. This was followed by a flurry of research activity on this technology over the next 3 decades.
“In the last 10 years, the scientific community has made enormous advances [in these areas],” said Peter Palese, PhD, a professor of microbiology and the chair of the department of microbiology at the Icahn School of Medicine at Mount Sinai.
“If COVID-19 had occurred a decade earlier, I don’t think we would have been as effective, as fast and as successful as we have been.”
The development of the COVID-19 vaccines was also aided by a rapidly spreading virus that provided an ample supply of potential clinical trial participants. This helped speed up the clinical trials.
In addition, governments, foundations, and industry funneled large amounts of money into research on COVID-19 vaccines and therapies.
“In the U.S., billions were poured into making a vaccine against COVID-19. [As a result], the mRNA vaccines, both from Moderna and Pfizer, have been an extraordinary success,” said Palese.
“I don't think there were any shortcuts [in the development of the COVID-19 vaccines],” he added. “There was just so much money put into the research and the clinical trials that instead of 7 to 10 years, the vaccines were developed in a year.”
Systems Aim mRNA Vaccines at Other Viruses
Given the success of the mRNA COVID-19 vaccines, many people are optimistic about future research along these lines, including for addressing future emerging pathogens.
“Now that the technology is available, it is fairly simple to put a piece of mRNA coding for a part of the pathogen into the mRNA technology platform, and make similar vaccines for the next pandemic,” said Dr. Monica Gandhi, an infectious diseases specialist with the University of California, San Francisco.
However, past performance is no guarantee of success, especially in vaccinology, where each pathogen is unique.
Even different variants of SARS-CoV-2 behave differently — some cause more severe disease, while others spread more easily. And some, like Omicron, have partially overcome the immunity gained through past infection or vaccination, highlighting the importance of a booster dose.
Palese emphasized that the companies and groups that developed the mRNA COVID-19 vaccines deserve credit for having achieved this in such a short time.
“On the other hand,” he added, “this [technology] is not the solution for every vaccine. We have a lot of pathogens where we don’t have any vaccines.”
Even after decades of research.
One of these is HIV, which researchers have been trying to develop a vaccine for since the late 1980s — without success.
Some groups are working on an mRNA HIV vaccine — hoping this vaccine platform will be the key to success — but the preclinical trials are still in the early stages.
“The mRNA vaccines have been very successful [with COVID-19],” said Palese, “but this technology is not a panacea, in terms of just plugging in the genetic information for every single pathogen.”
Other vaccine platforms will likely still be needed in the future.
As with the COVID-19 vaccines, the “best” vaccine depends on the situation. Cost, storage, number of doses, ease of use, and other factors determine how well a vaccine works for a population.
For example, the inactivated virus Salk polio vaccine is widely used in some parts of the world, but the weakened virus Sabin polio vaccine, which is an oral vaccine, is more appropriate for the developing world because it is easier to distribute.
Likewise, older adults receive a seasonal flu vaccine that is specifically tailored for a weaker immune response to vaccination.
Still, a lot of mRNA vaccine research is underway.
Last year there were 44 active clinical trials involving mRNA vaccines, according to GlobalData — of these, around half were related to infectious disease and the rest to oncology.
Moderna, which emerged during the pandemic ahead of a crowded pack of vaccine developers, is testing two non-COVID mRNA vaccines: one for RSV and one for cytomegalovirus (CMV).
The RSV vaccine is another one that researchers have been chasing unsuccessfully for decades. Moderna’s work on their mRNA RSV vaccine — now in a phase 1 clinical trial — began before SARS-CoV-2 appeared on the scene.
"Since the mRNA COVID-19 vaccines first received emergency use authorization, additional research has found that a longer gap between doses boosts the immune response."
The company’s CMV vaccine is further along in the research pipeline. The company is currently recruiting for a phase 3 clinical trial, during which people will be randomly assigned to receive either the candidate vaccine or an inactive placebo.
With less pressure to roll out the CMV vaccine quickly — compared to the COVID-19 vaccines, which were urgently needed during the pandemic — Moderna is testing a three-dose regimen over 5 and a half months.
This is similar to the interval used for other vaccines, such as the one against diphtheria, tetanus, and acellular pertussis (DTaP).
Since the mRNA COVID-19 vaccines first received emergency use authorization, additional research has found that a longer gap between doses boosts the immune response.
In addition, as we’ve seen with the Delta and Omicron variants, three doses provide stronger protection against infection than two — although two doses still provide strong protection against severe illness for most people.
BioNTech and Pfizer are also undertaking another collaboration, this one aimed at developing an mRNA-based “universal” flu vaccine that would work against a majority of seasonal influenza viruses.
Current flu vaccines have to be updated each year to match the influenza strains that are expected to be in circulation. Predictions about which strains to include are not always perfect, so the effectiveness of the flu vaccine varies from 20 to 60 percent.
BioNTech’s candidate vaccine targets part of the influenza virus that is the same on many strains. Researchers hope this will increase the chance that the vaccine works against the flu strains circulating that year.
This vaccine has proven effective in animal trials, and a phase 1 clinical trial was expected to start at the end of 2021.
In addition, CureVac is working on an mRNA vaccine for rabies that is currently being tested in a phase 1 clinical trial.
mRNA Vaccines Offer Promise as Cancer Treatment
While mRNA vaccines for infectious diseases are a key focus right now, scientists are also eyeing this technology as a potential treatment for cancer.
These vaccines don’t train the immune system to attack a virus, but instead to go after cancer cells.
mRNA cancer vaccines contain instructions for one or more cancer cell proteins, such as those found on the surface of tumor cells.
When the vaccine is injected, the immune system learns to recognize and attack cancer cells that carry those proteins, using antibodies, T cells, and other immune responses.
Some of this research began before the pandemic.
BioNTech, which was founded in 2008 with the goal of personalizing cancer treatments, has several mRNA cancer therapies in development, including four in phase 2 clinical trials — for melanoma, colorectal cancer, and head and neck cancer.
The company is not alone.
Moderna is also working on mRNA-based cancer therapies, including personalized treatments (something BioNTech is testing as well).
"It only takes around 6 weeks from tumor biopsy to having a personalized vaccine ready for the patient."
The first step in developing a personalized mRNA cancer therapy is analyzing the genetic sequence of a person’s tumor cells to look for mutations specific to their cancer.
Scientists then look for mutations that are associated with unique cancer cell proteins that can be targeted with an mRNA vaccine.
As with targeting emerging pathogens such as coronaviruses, an advantage of using an mRNA vaccine for cancer therapy is the speed at which the vaccine can be designed and produced.
It only takes around 6 weeks from tumor biopsy to having a personalized vaccine ready for the patient.
These vaccines are all still in clinical trials, with none further along than phase 2. But there are early signs that these vaccines — when used in conjunction with existing cancer treatments — might help.
Moderna’s mRNA-4157 showed promising results, when used alongside Merck’s Keytruda, in a phase 1 clinical trial for head and neck cancer. However, the combo came up short for colorectal cancer.
Vaccine Programs Only Work if Everyone has Access
Having effective vaccines doesn’t ensure that an infectious disease will be eradicated or even reduced to manageable levels.
In spite of the rapid development and testing of the COVID-19 vaccines, 60 percent of the world’s population has received at least one dose of a COVID-19 vaccine. However, in developing countries, this falls to under 10 percent.
Even in the United States, which has a glut of vaccines, over 20 percent of eligible Americans have not yet had a single dose.
"Experts say this vaccine access disparity will prolong the pandemic and could give rise to additional coronavirus variants."
“The rapidity with which the [COVID-19] vaccines were developed was remarkable,” said Jeffrey Levi, PhD, a professor of health policy and management at the Milken Institute School of Public Health at The George Washington University in Washington, D.C.
“But one issue that cannot be overstated is the fact that we have not shared this technology globally.”
Companies such as Moderna have come under fire for refusing to share the formula for their COVID-19 vaccine so that the vaccine can be produced in more countries, including developing ones.
Experts say this vaccine access disparity will prolong the pandemic and could give rise to additional coronavirus variants.
As long as the coronavirus is allowed to continue spreading widely, “variants are going to emerge all over the world,” said Levi. “We are only protected if everyone is protected.”
“While the United States is talking about boosting people a fourth time, there are huge populations [in the world] that still have not gotten a first dose,” he added. “And that inequity is not just a moral issue, it's a practical issue for being able to contain future pandemics.”
To help address this issue, the World Health Organization’s governing body has agreed to begin negotiating an international agreement to ensure that the world’s response to the next pandemic is more coherent and equitable.
The WHO director-general Dr. Tedros Adhanom Ghebreyesus said this decision represents “a once-in-a-generation opportunity to strengthen the global health architecture to protect and promote the well-being of all people.”
In spite of this step forward, the United States and other countries have pushed for a weaker mechanism that is not legally binding for countries, reports The New York Times.
This latest attempt by the WHO to address global vaccine inequity will likely come too late to help countries without access to the COVID-19 vaccines.
However, other groups have already stepped up to help.
A COVID-19 vaccine developed by researchers at Baylor College of Medicine and the Texas Children's Center for Vaccine Development was authorized in December for use in India.
The vaccine, called CORBEVAX, uses protein subunit technology, in which a piece of the virus is delivered to the body to induce an immune response without causing disease.
Clinical trials showed that the vaccine was 90 percent effective at preventing symptomatic infections caused by the original strain of the coronavirus — putting it on par with the two mRNA vaccines approved in the United States — and 80 percent effective against the Delta variant.
The vaccine is also durable, inexpensive — costing a dollar or two per dose — and patent-free.
"We can never hope that we will eliminate viruses from the animal kingdom. So as long as these viruses can occasionally jump into humans, we will have a problem."
Peter Palese, PhD
“We have not filed patents on this vaccine, our goal is to make [it] as freely available as possible to the world's poorest people,” Dr. Peter Hotez, professor and dean of the National School of Tropical Medicine at Baylor and co-director of the Texas Children’s Hospital Center for Vaccine Development, wrote on Twitter.
The release of this vaccine — dubbed by some as “the world’s vaccine” because of its patent-free status — comes as COVAX, the global COVID-19 vaccine-sharing program, missed a goal of delivering 2 billion doses to developing countries by the end of 2021.
COVAX recently reached a milestone of 1 billion doses shipped to 144 countries — about half of its original target.
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Strengthening Public Health Systems before Next Pandemic
Palese hopes that the COVID-19 pandemic has been an awakening for governments, politicians, and health organizations.
“It’s not a question of if, but only a question of when,” said Palese, referring to the potential for another epidemic or pandemic, “particularly in terms of influenza or coronaviruses.”
“There are several other viruses that have zoonotic properties,” he continued. “In other words, they occur in humans as well as in animals.”
“We can never hope that we will eliminate viruses from the animal kingdom. So as long as these viruses can occasionally jump into humans, we will have a problem.”
"A deep understanding of what it takes to overcome another pandemic is very important, and that takes money."
Peter Palese, PhD
Trillions of dollars were spent on the development of COVID-19 vaccines and therapies, along with supporting economic recovery and providing financial relief to people affected by the pandemic.
Not to mention the impact of the pandemic on the global economy.
“The economic cost [of the pandemic] is staggering,” said Palese.
If we had spent just a small amount of those trillions on research, vaccine development, and other preventive measures, he said, we would have already had ways to combat COVID-19 when the first cases appeared in 2019.
“A deep understanding of what it takes to overcome another pandemic is very important,” he said, “and that takes money.”
Beyond vaccine equity and continued funding for research, experts have called for a number of other steps to help prepare the world for the next pandemic.
A report released last year by the National Academies of Sciences, Engineering, and Medicine on the “lessons from COVID-19” focused on leveraging the scientific and technological breakthroughs that occurred over the past 2 years to improve future pandemic responses.
courtesy of Dr. Monica Gandhi
"We have a long way to go to get racial and ethnic minorities to trust [public health] in the U.S., given historical and earned distrust."
Monica Gandhi, PhD
Other experts say we need to strengthen our public health and health systems, what Jennifer B. Nuzzo, DrPH, and Lawrence O. Gostin, JD, refer to in a January 6 opinion piece in JAMA as the “bedrock of pandemic preparedness.”
They call for increasing testing capacity, rebuilding public trust in health agencies, encouraging risk mitigation behaviors during outbreaks, addressing health disparities, and strengthening cooperation among institutions and countries.
Gandhi agrees that future health emergencies will require stronger support for health agencies.
“Hopefully we can garner more trust in public health after this time of polarization,” she said, “and move forward in a better way, if and when another pandemic occurs.”
But, “we have a long way to go to get racial and ethnic minorities to trust [public health] in the U.S., given historical and earned distrust.”
In 2020, 7 in 10 Black adults believed that race-based discrimination occurred at least “somewhat often” in healthcare, according to a Kaiser Family Foundation survey. One in 5 Black people reported personally experiencing this kind of discrimination in the past year.
"Testing in the United States continues to fall short of the level many experts have called for."
A growing body of research shows the negative impact that this lack of trust has on the health of certain groups in the United States, including low COVID-19 vaccination rates.
As for testing capacity, the United States began the pandemic on the wrong foot when diagnostic testing kits issued by the Centers for Disease Control and Prevention were flawed.
“Certainly in the United States, but I think in many countries of the world, we've always been a little behind the curve in our ability to identify outbreaks,” said Levi, “to do the kind of genetic sequencing that is important.”
Testing in the United States continues to fall short of the level many experts have called for. The rapidly spreading Omicron variant has strained the testing supply even further.
Exacerbating the weak surveillance systems in the United States are equally insufficient public health data systems.
“Local health departments have tremendous variability in their ability to track a pandemic or an outbreak,” Levi said, “simply because they are not tied into their health information exchanges, they are not able to share information electronically across jurisdictions or other really fundamental issues.”
In addition, he said the decentralized nature of U.S. public health systems has made it difficult for the country to rapidly respond to the pandemic.
This has also led to a patchwork of public health responses across the country, not just from state to state, but also at the county and local levels.
Clearer Communication about Harm Reduction Strategies
Another area that Levi thinks needs to be improved before the next health emergency is public health communication. In particular, he thinks there should be more emphasis on communicating about harm reduction.
Harm reduction is a public health strategy in which people learn how to assess and reduce risks — to themselves and to others — rather than trying to eliminate these risks altogether.
Gandhi thinks that “applying principles of harm reduction to a pandemic will earn us way more trust [in public health] next time than [we had] this time.”
This approach, though, is very nuanced, something that was lost in the shuffle of highly politicized social media posts and network talk shows.
“The U.S. is not a society where we think about harm reduction other than in black or white,” said Levi. “Is this going to work, or is this not going work?”
"While much media coverage is made of vaccine research, less attention is paid to the thousands of peer-reviewed studies focused on vaccine hesitancy and refusal."
He said this hurt the country on the vaccination front, with many people thinking that the vaccines would completely eliminate the risk of infection. When they found out that this was not true, some people lost faith in the vaccines and public health communicators.
Similar communication missteps occurred as the messaging failed to keep up with a rapidly evolving pandemic.
“The messaging needed for how to protect ourselves and protect one another from the virus has changed over time,” said Levi, “given how both our knowledge of the virus and the virus and our tools have changed.”
However, miscommunication during the pandemic is not entirely to blame for vaccine hesitancy.
Some experts, such as science journalist Tara Haelle, have been warning for years about the rise in vaccine hesitancy in the United States.
And while much media coverage is made of vaccine research, less attention is paid to the thousands of peer-reviewed studies focused on vaccine hesitancy and refusal.
“My message to a room of scientists: ‘When will you start paying attention to sociology research [on vaccine hesitancy] as a real and valid scientific field?’” Haelle wrote on Twitter. “It's long past due. [Peter Hotez] knows it—he's been screaming it for years.”
One of Levi’s main concerns about the next pandemic is that the United States, which has a short attention span when it comes to public health emergencies, will not learn its lessons from the COVID-19 pandemic.
“We could see once again this huge drop-off in public health spending once the pandemic is behind us,” he said, “rather than the country trying to rebuild the system so that it is stronger for the next time.”