New insights into hybrid immunity could enhance COVID-19 vaccination strategies

October 3, 2024

A recent study published in Cell Reports Medicine offers groundbreaking insights into how immunity to SARS-CoV-2, the virus that causes COVID-19, develops, functions and responds to infection with new variants of concern. The findings come following a summer of surging COVID-19 cases, with several SARS-CoV2 strains known as the “FLiRT” variants emphasizing the need to upgrade current mRNA vaccines.

Researchers found that hybrid immunity — achieved through a combination of both infection and vaccination — offers a broader protective antibody-based immunological response to COVID-19 than either type of immunity alone. In some individuals, hybrid immunological responses are capable of eliciting antibodies that neutralize all known COVID-19 variants (as well as distantly related SARS-like coronaviruses that infect other animals).

Dr. Ralph Baric

The collaborative study was conducted by a multi-institution research team co-led by Michael Mallory, MPH, from the Department of Epidemiology at the University of North Carolina at Chapel Hill’s Gillings School of Global Public Health, and William Voss, PhD, at the University of Texas at Austin. Senior authors Greggory Ippolito, PhD, and Jason Lavinder, PhD, at UT-Austin, and Ralph Baric, PhD, at UNC-Chapel Hill, guided the study’s state-of-the-art techniques.

More than four years following the discovery of SARS-CoV-2, several unique variants of concern have emerged. Each new variant displays slightly different characteristics from the last, which enables the virus to evade prior immunity from vaccination or natural exposure.

However, the authors describe a novel plasma antibody called SC27, elicited through hybrid immunity, which neutralizes every variant of SARS-CoV-2 circulating to date. SC27 also neutralized a large panel of zoonotic Sarbecoviruses and the 2003 SARS-CoV outbreak strain.

Protective antibodies like SC27 bind to a part of the coronavirus called the spike protein, which allows the virus to attach to and infect cells in the human body. When they fully block the spike protein from engaging with host cells, antibodies can prevent infection. This process is known as virus neutralization.

“A key strength within this study of virus neutralization is the combination of advanced techniques known as Ig-Seq, which was developed at UT-Austin and combines single-cell and proteomic approaches,” says Mallory. “This technique allows researchers to look at the relative abundance of different types of circulating antibodies within blood plasma and pair them with functional B-cells. Ultimately, this enables researchers to reproduce high concentrations of individual antibodies in a laboratory setting. When combining this approach with the incredibly broad panel of wildtype human and animal coronaviruses studied in the Baric Lab at UNC-Chapel Hill, we were able to identify SC27 and several other powerful antibodies uniquely elicited through hybrid immunity.”

Learning about the antibodies linked to hybrid immunity could eventually empower public health officials to design more effective vaccination strategies.

“One goal of this research is to develop a deeper understanding how the immune system responds to repetitive exposures with very similar but slightly different antigens,” Mallory explains. “This insight ultimately will inform how best to design universal vaccine candidates, as well as more efficacious vaccines that offer broader protection against viruses like SARS-CoV-2 that rapidly mutate and evolve.”

The study also highlights the need for continued research into immune responses to SARS-CoV-2, including studies on how long hybrid immunity lasts. For now, the findings provide additional proof that vaccines are highly protective, and they represent a step toward the ultimate goal of a universal vaccine.

“The incredible breadth and potency of SC27 and its mechanism of action support its potential as a new human COVID-19 therapeutic treatment,” says Baric. “Although many antibodies have lost potency against new SARS-CoV-2 variants of concern, SC27 has retained remarkable potency against them.”

Other members of the multi-institution collaboration behind the study are: Patrick O. Byrne, Sean A. Knudson, Douglas R. Townsend, Jessica Kain, Yimin Huang, Ed Satterwhite, Allison Seeger, Jeffrey M. Marchioni, and Chelsea Paresi at the University of Texas at Austin; John M. Powers, Sarah R. Leist, Jennifer E. Munt, Trevor Scobey, Izabella N. Castillo, Melissa Mattocks and Premkumar Lakshmanane at the University of North Carolina at Chapel Hill; and Bernadeta Dadonaite and Jesse D. Bloom of the Fred Hutchinson Cancer Center. The research team received funding from the National Institutes of Health and the Bill & Melinda Gates Foundation.

Contact the UNC Gillings School of Global Public Health communications team at sphcomm@unc.edu.