COVID-19 vaccines have quickly come to the rescue. Scientists created a vaccine to prevent the new virus using foundational research and technology developed at Penn. Today, as we race to vaccinate more people in more places against COVID-19, the biology behind these vaccines is poised to change the world again: With the promise of a whole new class of vaccines based on mRNA, the story of this novel treatment continues at Penn where researchers and labs are investigating other infectious diseases, including influenza and sexually transmitted infections, that could be prevented with an effective mRNA vaccine.

What are mRNA Vaccines?

The vaccine uses messenger RNA, or mRNA, to instruct the body to produce specific proteins called spike proteins. These proteins look similar to those of the virus, and this antigen triggers the body’s immune system to create specific antibodies that can fight off the real virus should the body become exposed. Drew Weissman, MD, PhD, and Katalin Karikó, PhD, helped pave the way for the COVID-19 vaccines from Pfizer/BioNTech and Moderna with their 2005 mRNA discoveries.

What are the Advantages of mRNA Vaccines?

“There are a few crucial benefits of using mRNA vaccines versus other types of vaccines,” said Weissman, a professor of Infectious Diseases at the Perelman School of Medicine.

Weissman points out that mRNA vaccines are both easier to make and may be more effective than other types of vaccines.

As seen with the COVID-19 vaccine, it’s possible to construct a new vaccine quickly: “mRNA vaccines are essentially plug and play. We believe you can change the part of the mRNA that encodes a protein, plugging in new code specific to the virus we hope to protect against, and cause one’s body to produce proteins that match that virus’ proteins. We do not have to develop and manufacture an entirely new formula.”

Another benefit is the speed at which mRNA vaccines can be made. With other vaccine types, like live attenuated vaccines (think measles, mumps, rubella vaccine) or inactivated vaccines (think flu and polio vaccines), actual pathogens must be transported and replicated during the manufacturing process, Weissman said. “This equates to faster production, which is important should a new infectious disease pop up that we need to quickly protect ourselves against.”

Both clinical trials and real-world studies investigating the capabilities of mRNA COVID-19 vaccines have shown enormous efficacy. The likelihood of contracting COVID-19 if you’ve been fully vaccinated with an mRNA vaccine is less than 10 percent, Weissman said. And the latest data says that if you do catch COVID-19, your symptoms will not be severe enough to require hospitalization.

“That level of protection is far greater than many other vaccines for other diseases,” Weissman said.

How Can Foundational Research Make Better mRNA Vaccines in the Future?

James Eberwine, PhD, a professor of Systems Pharmacology and Translational Therapeutics at Penn whose work largely focuses on foundational and basic research related to neurobiology, has been a long-time believer in mRNA’s promise.

“We saw that if you put the RNA from cell A into cell B, then cell B will become cell A,” Eberwine explained of experiments in his lab from decades ago. “RNA and mRNAs have a figurative cellular memory and a literal transformational quality.”

Eberwine’s work to understand how translating different RNA molecules into proteins affects different cells dates back to 27 years ago at Penn, before Weissman and Karikó’s groundbreaking research. Eberwine and his colleagues were the first to “transfect” RNA into cells when they put RNA into a region of a neuron to determine what the protein made from that RNA did in that region of the neuron.

Although the current mRNA-based COVID-19 vaccines each instruct the body to make only one type of spike protein, Eberwine believes that the benefit of mRNA vaccines lies in their ability to be crafted to create several different proteins within the body, and those proteins in turn would lead to antibodies that target various aspects of invading viruses; ultimately, that means the body has different weapons to attack threatening viruses.

Among other things, he and his lab are working on developing better ways to see the shape of viral and other disease-related proteins by making solution-based protein structures rather than crystal structures. That will lead to a clearer picture of what regions of mRNA are most effective and useful as building blocks of cellular therapies and vaccines.

Vaccines for many other diseases beyond COVID-19 are already in the works. Below is a quick look at just some of the mRNA research happening at Penn to fight infectious diseases.

Can mRNA Vaccines Prevent the Flu or Replace Seasonal Flu Vaccination?

Responsible for typically tens of thousands of deaths in the United States each year, seasonal influenza is a constant source of infectious disease risk, said Scott Hensley, PhD, a professor of Microbiology at Penn. Pandemics can also occur when new influenza viruses jump from animals to humans. Hensley has been developing new influenza vaccines since launching his laboratory over 10 years ago and now directs Penn’s new NIH-funded Center of Excellence for Influenza Research and Response (CEIRR).

“Influenza viruses are constantly changing,” Hensley said. “We need to develop new vaccines that elicit immunity against diverse viral strains and we need new vaccine technologies that can be updated quickly to keep up with these fast moving viruses.”

Currently, scientists and vaccine manufacturers have to study the virus and mutation trends to predict and conceive what the virus will look like in order to create new seasonal vaccines each year.

“The mRNA technology checks all the right boxes for influenza vaccines,” Hensley said. “These vaccines elicit high levels of antibodies that recognize antigenically diverse viral strains and the vaccines themselves can be updated easily.”

Together, Hensley and Weissman developed an H1N1 mRNA vaccine and found it evoked persistently high levels of antibodies in mice and ferrets. It comes down to epitopes, parts of antigens to which antibodies attach (such as the spike protein in the case of COVID-19 vaccines). Importantly, their H1N1 flu vaccine elicits antibodies that target epitopes that are conserved among many different influenza virus strains and therefore might offer universal protection against many varieties of influenza.

Small human trials studying influenza virus mRNA vaccines have already been conducted and this area is likely to expand given the success of SARS-CoV-2 mRNA vaccines in humans.   

Can mRNA Vaccines Prevent Sexually-Transmitted Diseases?

The most common sexually-transmitted disease (STD), herpes simplex virus 2 (HSV-2) is a non-curable disease that can be painful, can increase risk of other infections (like HIV), and can be fatal to the newborns and fetuses of mothers infected with the virus. Another danger of the disease: HSV-2 is often undetected.

“HSV-2 affects mental and emotional health, too,” said Harvey Friedman, MD, a professor of Infectious Diseases and a HSV researcher. “Those with the disease have to worry about passing it to others and engaging in sexual relationships. And while there are treatments and ways to limit spreading the disease to sexual partners, there are no current treatments that make it completely safe to have sex with someone who has HSV-2.”

In order to address the many different negative impacts of HSV-2, Friedman, Weissman, and their colleagues are developing an mRNA HSV-2 vaccine. Prior to the COVID-19 pandemic, a study of their mRNA herpes vaccine in mice showed that almost all mice that were vaccinated and then exposed to HSV-2 had sterilizing immunity, which meant there was no amount of the disease present in the body after the exposure.

This mRNA herpes vaccine has the potential to be so effective because it stimulates antibodies to three different HSV-2 proteins, which an mRNA vaccine easily allows.

“One antibody prevents the herpes virus from entering cells, and two others keep the virus from essentially turning off typical protective immune-system functions,” Friedman said. “Other vaccines being developed for HSV-2 elsewhere are only targeting that first antibody.”

Friedman and Weissman are on track to begin human clinical trials of their HSV-2 mRNA vaccine in 2022.

All STDs are different, so this exact vaccine for HSV-2 wouldn’t protect against other STDs, but Friedman believes that once targets are identified for other specific STDs, mRNA “may be the best way to develop an effective vaccine.”

Can mRNA Vaccines Prevent Future COVID Variants or Other Coronaviruses?

Since the COVID-19 pandemic is not over and new variants continue to emerge, the value remains huge for a vaccine, like the mRNA COVID-19 vaccine, which can be more easily adapted to cover new variants compared to other vaccine formats. Weissman’s lab is researching new formulas that may cover a wider spectrum of coronaviruses and COVID-19 variants.

The need for reliable vaccines will also continue to be a need, for the foreseeable future, in countries with fewer financial resources.

“As we’ve seen, richer nations have been able to put money behind the manufacturing and purchasing of vaccines,” Weissman said. “But everyone deserves and needs access to COVID-19 vaccines.”

In the spring of 2020, Kiat Ruxrungtham, MD, from Chulalongkorn University in Thailand, contacted Weissman and his lab asking about how Ruxrungtham’s lab, supported by the Thai government, could develop their own mRNA vaccine for COVID-19. Ruxrungtham, his colleagues, and the Thai government imagined that their citizens and people in surrounding, poorer countries would have difficulty securing COVID vaccines. They had read the research from Weissman’s lab and felt it was a vaccine that would work well and that could be created fairly quickly.

Weissman and his lab have since collaborated with Ruxrungtham’s lab to create a brand new COVID-19 mRNA vaccine that will be manufactured specifically for people in Thailand and neighboring low-resource countries. Weissman’s lab and his Penn colleagues have supported Chulalongkorn’s efforts without compensation. Among other things, they meet with them virtually, review data and mRNA “code,” and assist with production and testing. Thailand plans to start phase 1 trials of the new vaccine there within roughly a month.

“I pursued scientific research as a career because I wanted to help people,” Weissman said. “I am not only concerned about America and our own self-interests. I want the whole world to be vaccinated. Regardless, to put this pandemic behind us, we need as many people vaccinated as possible. COVID has reiterated that we do not live in a bubble.”