What makes mRNA vaccines so effective against severe COVID-19?

Effective response with COVID vaccine

Shot triggers unique antibody response by activating central helper immune cells.

The first two vaccines created with mRNA vaccine technology – Pfizer / BioNTech and Moderna COVID-19 vaccines – are without a doubt two of the most effective COVID vaccines developed to date. In clinical trials, both were more than 90% effective in preventing symptomatic infection, and they easily exceeded the 50% threshold set by the Food and Drug Administration for COVID-19 vaccines to be considered for emergency use.

While breakthrough infections have increased with the advent of the delta and omicron variants, the vaccines remain quite effective in preventing hospitalizations and deaths. The success of the new technology has prompted scientists to try to figure out why mRNA vaccines are so effective and whether the protection they provide is likely to last as new variants emerge.

A new study from researchers at the Washington University School of Medicine in St. Louis and St. Jude Children’s Research Hospital sheds light on the quality of the immune response triggered by mRNA vaccines. The study shows that the Pfizer vaccine strongly and sustainably activates a kind of helper immune cell, which helps antibody-producing cells to create large amounts of increasingly strong antibodies, and which also drives the development of some forms of immune memory. These cells, known as T-follicular helper cells, last for up to six months after vaccination, helping the body extract better and better antibodies. Once the helper cells fall, long-lived antibody-producing cells and memory B cells help provide protection against serious illness and death, the researchers said.

Furthermore, many of the T-follicular helper cells are activated by a portion 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 elicits such high levels of neutralizing antibodies and suggests that vaccination may help many people continue to produce potent antibodies even if the virus changes.

“The longer the T-follicular helper cells provide help, the better the antibodies, and the more likely you are to have a good memory response,” said co-correspondent Philip Mudd, MD, PhD, an assistant professor of emergency medicine at Washington University. “In this study, we found that these T-follicular helper cell responses just go on and on. And what’s more, some of them respond to a portion of the virus’ peak protein, which has very little variation in it. With the variants, especially delta and now omicron, we have seen some breakthrough infections, but the vaccines have stayed very nice in terms of preventing serious illness and death.I think this strong T-follicle helper response is part of the reason why the mRNA vaccines continue with being so protective. “

The first antibodies produced in response to an infection or vaccination tend not to be very good. B cells have to go through a kind of boot camp in so-called germinal centers in the lymph nodes before they can produce really strong antibodies. T follicular auxiliary cells are the drilling sergeants in these boot camps. The helper cells instruct the antibody-producing cells to make increasingly potent antibodies and encourage them with the best antibodies to multiply and in some cases become long-lived antibody-producing cells or memory B cells. The longer the germinal centers last, the better and stronger the antibody response.

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

In this latest study, Mudd and co-corresponding authors Ellebedy and Paul Thomas, PhD, from St. Jude, on understanding the role of T-follicular 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 researchers working with Thomas at St. Jude, and others.

The researchers recruited 15 volunteers, each receiving two doses of the Pfizer vaccine three weeks apart. The volunteers underwent a procedure to extract germinal 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 T-follicular helper cells from the lymph nodes and analyzed them.

Researchers are now studying what happens after a booster dose and whether changes in T-follicular helper cells can explain why people with compromised immune systems, such as those with HIV infection, do not get a strong antibody response.

Reference: “SARS-CoV-2 mRNA vaccination elicits a robust and sustained human T helper cell response” by Philip A. Mudd, Anastasia A. Minervina, Mikhail V. Pogorelyy, Jackson S. Turner, Wooseob Kim, Elizaveta Kalaidina, Jan Petersen, Aaron J. Schmitz, Tingting Lei, Alem Haile, Allison M. Kirk, Robert C. Mettelman, Jeremy Chase Crawford, Thi HO Nguyen, Louise C. Rowntree, Elisa Rosati, Katherine A. Richards, Andrea J. Sant, Michael K. Klebert, Teresa Suessen, William D. Middleton, SJTRC Study Team, Joshua Wolf, Sharlene A. Teefey, Jane A. O’Halloran, Rachel M. Presti, Katherine Kedzierska, Jamie Rossjohn, Paul G. Thomas, and Ali H Ellebedy, December 23, 2021, Cell.
DOI: 10.1016 / j.cell.2021.12.026

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