What makes an mRNA vaccine so effective against severe COVID-19? – Washington University School of Medicine in Saint-Louis

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Injections trigger an exceptional immune response by activating key helper immune cells

Matt miller

The first two vaccines created with mRNA vaccine technology – the Pfizer / BioNTech and Moderna COVID-19 vaccines – are arguably two of the most effective COVID vaccines developed to date. In clinical trials, both were over 90% effective at preventing symptomatic infections, easily exceeding the 50% threshold that the Food and Drug Administration set for COVID-19 vaccines to be considered for clearance. emergency use.

While breakthrough infections have increased with the emergence of the delta and omicron variants, vaccines remain effective enough to prevent hospitalizations and deaths. The success of the new technology has led scientists to try to understand why mRNA vaccines are so effective and whether the protection they offer is likely to last as new variants emerge.

A new study by researchers at Washington University School of Medicine in St. Louis and St. Jude Children’s Research Hospital sheds light on the quality of the immune response elicited by mRNA vaccines. The study shows that the Pfizer vaccine strongly and persistently activates a kind of helper immune cell that helps antibody-producing cells create large amounts of increasingly powerful antibodies, and also stimulates the development of certain types. immune memory. Known as follicular T helper cells, these cells last for up to six months after vaccination, helping the body to make antibodies better and better. Once helper cells decline, long-lived antibody-producing cells and memory B cells help provide protection against serious illness and death, the researchers said.

Additionally, many follicular T helper cells are activated by part of the virus that does not appear to detect mutations, even in the highly mutated omicron variant. The results, published online December 22, 2021 in the journal Cell, help explain why the Pfizer vaccine causes such high levels of neutralizing antibodies and suggest that vaccination can help many people continue to produce strong antibodies even though the virus changes.

“The more help the follicular T helper cells provide, the better the antibodies are and the more likely you are to have a good memory response,” said co-correspondent author Philip Mudd, MD, PhD, professor emergency medicine assistant in Washington. University. “In this study, we found that these follicular T helper cell responses continue to continue. And what’s more, some of them react to a part of the virus spike protein which shows very little variation. With the variants, especially delta and now omicron, we have seen breakthrough infections, but the vaccines have held up very well in terms of preventing serious illness and death. I think this strong T follicular assist response is part of the reason mRNA vaccines continue to be so protective. “

The first antibodies produced in response to infection or vaccination tend not to be very good. B cells have to go through some sort of boot camp in the so-called germinal centers in the lymph nodes before they can produce really strong antibodies. The T follicular helper cells are the drill sergeants at these training camps. Helper cells provide instructions to antibody-producing cells to make ever stronger antibodies and encourage those with the best antibodies to multiply and, in some cases, turn into long-lived antibody-producing cells. or in memory B cells. The longer the germinal centers last, the better and stronger the antibody response will be.

Earlier this year, Ali Ellebedy, PhD, associate professor of pathology and immunology, medicine and molecular microbiology at the University of Washington, reported that almost four months after people received the first dose of Pfizer vaccine, they still had germinal centers in their lymph nodes which were pouring out. immune cells directed against SARS-CoV-2, the virus that causes COVID-19.

In this latest study, Mudd and co-corresponding authors Ellebedy and Paul Thomas, PhD, of St. Jude, aimed to understand the role of follicular T helper cells in producing such a strong germinal center response. The research team also included co-first authors Anastasia Minervina, PhD, and Mikhail Pogorelyy, PhD, postdoctoral fellows working with Thomas at St. Jude, and others.

The researchers recruited 15 volunteers who each received two doses of the Pfizer vaccine three weeks apart. The volunteers underwent a procedure to extract germ centers from their lymph nodes 21 days after the first dose, just before the second dose; then on days 28, 35, 60, 110 and 200 after the initial dose. None of the volunteers had been infected with SARS-CoV-2 at the start of the study. The researchers obtained follicular T helper cells from the lymph nodes and analyzed them.

Researchers are now studying what happens after a booster dose and whether changes in follicular T helper cells might explain why people with weakened immune systems, such as those infected with HIV, do not develop a strong antibody response.

Mudd PA, Minervina AA, Pogorelyy MV, Turner JS, Kim W, Kalaidina E, Petersen J, Schmitz AJ, Lei Tingting, Haile A, Kirk AM, Mettelman RC, Crawford JC, Nguyen THO, Rowntree LC, Rosati E, Richards KA , Sant AJ, Klenert MK, Suessen T, Middleton WD, SJTRC Study Team, Wolf J, Teefey SA, O’Halloran JA, Presti RM, Kedzierska K, Rossjohn J, Thomas PG, Ellebedy AH. Vaccination with SARS-CoV-2 mRNA elicits a robust and persistent follicular T helper cell response in humans. Cell. December 22, 2021. DOI: https://doi.org/10.1016/j.cell.2021.12.026

This study was funded by the Washington University Institute for Clinical and Translational Sciences, grant number UL1TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH); Australian Research Council Laureate Fellowship; Australian National Council of Health and Medical Research, grant numbers 1173871 and 1194036; Syrian Lebanese American Charities in St. Jude; the Center for Influenza Vaccine Research for High-Risk Populations, contract number 75N93019C00052; the St. Jude Center of Excellence for Influenza Research and Surveillance; contract number HHSN272201400006C; the St. Jude Center of Excellence for Influenza Research and Response, contract numbers 75N93021C00016, U01AI150747, U01AI144616-02S1 and R01AI136514; the National Institute of Allergy and Infectious Diseases (NIAID), grant numbers U01AI141990 and U01AI150747; NIAID Centers of Excellence for Influenza Research and Surveillance, contract numbers HHSN272201400006C and HHSN272201400008C; and NIAID Collaborative Influenza Vaccine Innovation Centers, contract number 75N93019C00051.

The 1,700 physicians on the Washington University School of Medicine faculty are also on the medical staff of Barnes-jew and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, education, and patient care, and is among the top recipients of research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals, the School of Medicine is linked to BJC Healthcare.

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