Why viral variants in the vaccinated matter

Artistic rendering of genetic variations of a virus.
Artistic rendering of genetic variations of a virus. (Shutterstock)

Think back to January 2021, when COVID vaccines offered a fresh hope after the pandemic’s first year. Effective and safe vaccines offered a key tool to tame the pandemic.

But not long after the public began to recover from their initial vaccination hangovers, questions emerged about breakthrough infections. Soon, researchers across the nation began to suspect that vaccinated individuals could become infected with SARS-CoV-2, the virus that causes COVID, sooner than previously thought. 

Researchers in UF professor Marco Salemi’s viral evolution lab were eager to learn more. Long focused on HIV and related viruses, the Salemi lab turned its attention early in the pandemic to SARS-CoV-2. Using their expertise in studying the evolution and relatedness of viruses, they used genomic sequencing to better understand how the new coronavirus was changing in real time. 

Salemi is a professor of experimental pathology at the UF College of Medicine, Department of Pathology, Immunology, and Laboratory Medicine. He is also the Holloway Chair for research in chronic and infectious diseases, and he is a faculty member of the UF Emerging Pathogens Institute. 

“We were curious to measure infection rates in vaccinated individuals, determine what kinds of mutations might be floating around in these individuals, and whether they could transmit to others,” recalled Salemi lab member Britany Rife Magalis, reflecting upon where the state of knowledge was a year and a half ago. Rife Magalis is a research assistant scientist in the UF College of Medicine, Department of Pathology, Immunology, and Laboratory Medicine and is also affiliated with the EPI.

Vaccinated, and infected

With funding from the Rockefeller Foundation, and support and collaboration from UF and the UF EPI, Salemi’s lab became involved very early in the pandemic with efforts to detect genomic variations in viral variants and trace their evolutionary history, or phylogeny, over time.

“At UF, we have the capacity, equipment, workforce, and knowledge in place to do this type of genomic sequence monitoring,” Rife Magalis said. 

Between January and June 2021, a research team detected 23 cases of breakthrough COVID-19 infections in vaccinated individuals in Alachua County, Fla. The infected individuals had only mild symptoms. 

Contact tracing revealed that 21 of these did not pass the virus on further, but in two cases the vaccinated individuals did pass their virus to others. It was among some of the earliest work to show that breakthrough infections could occur, and that onward transmission was possible. 

The team obtained viral genomic sequences from 11 of the 23 breakthrough cases and found that variants of concern, while present, were not the primary cause. 

“We were expecting only variants of concern to be present at this time in the vaccinated individuals but what we also found at the time were minor variants,” Magalis said. “Back then, this had not been investigated yet, it had not popped up anywhere else.” 

Emerging variants, in the vaccinated

The minor variants detected included ones that were present at a low rate of occurrence in 878 infected individuals from the surrounding community. 

Coauthor David Ostrov, UF associate professor in the College of Medicine, Department of Pathology, Immunology, and Laboratory Medicine, led a mutational structural analysis of the 11 sequenced viruses from the vaccinated individuals. 

“A lot of the mutations we see are the result of genetic drift,” Rife Magalis said. “The virus gets introduced to a new geographical area and has one mutation that is neutral and it doesn’t do any harm, but through the act of transmission, it continues to grow and spread in the population and become prevalent.”

But when a viral variant contains a change that makes it able to grow faster, cause more severe symptoms, or transmit more easily, then it becomes a variant of interest and/or concern.

Results showed that some of the low-frequency variants found in vaccinated individuals had changes in areas of the virus that positively affected its ability to grow in a person or to be transmitted. Some of these went on to become variants of concern, in time between when the team first detected them in spring 2021 and when the study was published this March in the journal of Medical Virology. 

“We expected that the vaccinated, because they were vaccinated, would be a little more difficult to infect,” Rife Magalis said. “Therefore, we thought it would require a full-fledged variant of concern to infect them, to penetrate their immunity.”

Instead, the team found many more minor and emerging variants than they anticipated. 

“What we found was the emergence of these seemingly not-so-significant variants in the vaccinated, but this was potentially a problem owing to their lack of symptoms – they might go undetected until it’s too late,” Magalis said. 

This shows that the vaccinated can contribute, in a small way, to the propagation of new viral variants that can then go on to become variants of concern.

Public health messaging

The results pose a challenge for public health messaging. Health care practitioners and public health authorities unanimously agree that people should get vaccinated and boosted against COVID-19. 

But it’s also important for those who receive vaccines to understand that their status does not make them fully immune from transmitting the virus to others, who may not be vaccinated. 

On the one hand, being vaccinated significantly reduces the severity of COVID if someone experiences a breakthrough infection. But on the other, when a breakthrough infection occurs in someone who is vaccinated, their symptoms tend to be very mild. They may mistake it for allergies, or a cold, and not get tested or even know they had COVID. Which means the emergence of new variants via breakthrough infections may go undetected.

“We still encourage vaccines for everyone. But this work shows you should continually be aware of how you are feeling,” Rife Magalis said. “Maybe you would opt to get tested before you go visit your grandfather in a nursing home, for example.” 

The results also underscore the importance of continuous community monitoring and genetic sequencing – even in the vaccinated.

“As we become more relaxed in our public health mitigation strategies, and we stop testing everyone and encouraging testing, we may see these minor variants and emerging new variants pop up which can accumulate in vaccinated individuals,” Magalis said. “Because the vaccines, while effective, are not perfect.”

As we learn to live with this virus, the lessons learned from influenza and the past two years of the pandemic will be critical, according to coauthor Ostrov.

“Continued sequencing of circulating variants, in both vaccinated and unvaccinated individuals, is necessary for the continual improvement of the vaccines and boosters, similar to seasonal influenza,” said Ostrov.

Despite the nuance of the results, Rife Magalis said the overriding message is that everyone should still get vaccinated to prevent severe disease, reduce transmission, and protect those who are not able to receive the vaccine. 

Acknowledgments: This study relied on collaboration and funding from the UF Emerging Pathogens Institute along with support from the UF Interdisciplinary Center for Biotechnology Research. EPI collaborators include Carla Mavian, Massimiliano Tagliamonte, Michael Norris, John Lednicky, EPI Director J. Glenn Morris, and EPI Deputy Director Michael Lauzardo. 

By: DeLene Beeland