Biotechnology

Even when SARS-CoV-2 mutates, some human antibodies fight back

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LA JOLLA, CA—An anonymous San Diego resident has become a compelling example of how the human immune system fights SARS-CoV-2. In a new investigation, scientists from the La Jolla Institute for Immunology (LJI) have shown how antibodies, collected from volunteers for this clinical study, bind to the SARS-CoV-2 “Spike” protein to neutralize the virus.

LA JOLLA, CA—An anonymous San Diego resident has become a compelling example of how the human immune system fights SARS-CoV-2. In a new investigation, scientists from the La Jolla Institute for Immunology (LJI) have shown how antibodies, collected from volunteers for this clinical study, bind to the SARS-CoV-2 “Spike” protein to neutralize the virus.

Although studies have shown antibodies bound to Spike before, this new research reveals how the original Moderna SARS-CoV-2 vaccine can prompt the body to produce antibodies against the Omicron variant of the newer SARS-CoV-2. The researchers also captured the highly detailed 3D structures of three promising neutralizing antibodies bound to Spike.

This important work pinpoints where Spike is vulnerable to human antibodies — and how future vaccines and antibody therapies can exploit these weaknesses. In fact, research in mice suggests some of these antibodies may help prevent severe cases of COVID-19.

“To blunt the next pandemic and protect people from this one seasonal resurgence, we need antibodies with the widest possible capacity—which cannot escape,” said LJI President and CEO Erica Ollmann Saphire, Ph.D.new senior author Cell Report Study. “We found them in vaccinated San Diegan.”

“Studying the person’s immune response in detail found antibodies that were still effective against many Omicron variants,” added LJI Instructor Kathryn Hastie, Ph.D., one of the study leaders and Director of the LJI Antibody Discovery Center. “We now have to figure out how to increase the antibody we want rather than the other one that is less effective.”

Takes the virus variant

Throughout the pandemic, scientists at LJI have been collecting blood samples here in San Diego, and from laboratories around the world, with the goal of understanding the role of different immune cells in fighting SARS-CoV-2. (Learn more about the LJI leadership of the Coronavirus Immunotherapy Consortium (CoVIC))

Antibodies are one of the most elite fighters of the immune system. These molecules are made by B cells and each antibody has a specific structure meant to bind to a specific target on the pathogen. It is as if the B cells see the target in the pathogen and then go to work making their arrows.

For the new study, the antibodies came from clinical study volunteers who received two doses of the Moderna SARS-CoV-2 vaccine. Moderna’s vaccine works by prompting the body to make Spike protein—a flash bullseye virus—so it can start working on antibodies and other weapons against the real virus.

Samples from research volunteers were collected in early 2021—before the appearance of Omicron. That means any antibodies the volunteers make are the result of vaccination, not exposure to Omicron.

The Omicron variant of SARS-CoV-2 appeared in late 2021 and spread rapidly. Omicron stands out from the other variants because it contains mutations that help it evade the protection of immune cells. Many antibodies designed to fight against earlier variants of SARS-CoV-2 were unable to reach their target on Omicron.

Finding the winning antibody

Fortunately, not everyone produces the same type of antibodies. In fact, the composition of virus-fighting cells and antibodies varies greatly from person to person. For the new study, the researchers started with a pool of antibodies from San Diego volunteers. Like many people who received the first two shots of Moderna’s vaccine, this person produced a strong pool of antibodies capable of neutralizing the ancestral D614G variant of SARS-CoV-2.

When a new variant of the virus of concern emerges, the researchers test this pool to see how many of the antibodies can still bind to the mutated virus.

“We found that this set of antibodies can also neutralize other variants, such as Delta and Omicron,” said Hastie.

They found that the subjects maintained moderate to high levels of antibodies against the Beta, Delta and Omicron lineages BA.1, BA.1.1 and BA.2. Among these surviving antibodies, the researchers found five that actually reduced BA.1 infectivity by more than 85 percent.

The researchers then took these five remaining antibodies through another series of tests. One antibody, called 1C3, showed promise in blocking part of the infection process (when the viral receptor binding domain interacts with the human ACE2 protein) but only against the BA.1 and BA.2 lineages. Another antibody, 1H2, can also neutralize some Omicron lineages, but does so in a different way than 1C3. Meanwhile, the 2A10 antibody was reactive against all Omicron SARS-CoV-2 lineages tested, including the most common now: XBB and BQ1.

Mapping antibody targets

The scientists then mapped these vulnerabilities in Spike using a high-resolution imaging technique called cryo-electron microscopy. “We were very interested to see how this antibody recognizes Spike proteins and structures,” said LJI Postdoctoral Fellow Xiaoying Yu, who co-led the new study with Hastie. “This structural work allows us to see exactly how antibodies interact with proteins and how they can neutralize viruses.”

Imaging work revealed that two of the promising antibodies bind to the SARS-CoV-2 Spike by attaching to two parts of the protein at once. By capturing Spike in death’s arms, these antibodies lock onto the structure of the virus to stop infection. This finding is consistent with others latest Cell Report Study from Saphire Lab who demonstrated the importance of bivalent antibodies against variants of SARS-CoV-2.

Could these three promising antibodies be recreated in antibody therapy to treat COVID-19? The results from the mouse model are encouraging. The LJI team found that each antibody by itself could indeed reduce the viral load in the lungs of mice infected with SARS CoV-2 BA.1 and BA.2.

Going forward, the researchers plan to run more human antibodies through the same channels at LJI—from antibody isolation to screening, structural analysis, and animal model trials. “We can do the whole antibody discovery pathway now,” Yu said. “This research will help us combat the variants we currently have and give us targets for future vaccine development and therapy.”

Co-author of the study, “Strong omicron neutralizing antibody was isolated from patients vaccinated 6 months before the appearance of omicron,” are Fernanda A. Sosa Batiz, Dawid Zyla, Stephanie S. Harkins, Chitra Hariharan, Hal Wasserman, Michelle A. Zandonatti, Robyn Miller, Erin Maule, Kenneth Kim, Kristen Valentine, and Sujan Shresta.

This research was supported by the National Institutes of Health (NIH grant U19 AI142790-02S1), the GHR Foundation, the Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2EZP3_195680), Postdoc Mobility Fellowship (P500PB_210992), and the American Association of Immunologists Career Re-entry Scholarship.

DOI: 10.1016/j.celrep.2023.112421


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