2023-04-26 16:45:52
An anonymous person has become a fascinating example of how the human immune system fights SARS-CoV-2, the virus that causes Covid-19. Research conducted by scientists at the La Jolla Institute for Immunology (USA) has shown how antibodies, collected from this clinical study volunteer, bind to the SARS-CoV-2 “Spike” protein to neutralize the virus. .
While previous studies have shown that antibodies bind to Spike, this new research reveals how Moderna’s original SARS-CoV-2 vaccine could induce the body to produce antibodies against later Omicron variants of SARS-CoV-2 . The researchers also capture highly detailed three-dimensional structures of three promising neutralizing antibodies bound to Spike. In fact, studies in mice suggest that some of these antibodies could help prevent severe cases of Covid-19.
“To stop the next pandemic and protect the population from the seasonal recurrence of the current one, we need antibodies with the highest possible response capacity, that is, antibodies that do not escape,” says Erica Ollmann Saphire, lead author of the new study that publishes in “Cell Reports”.
“Detailed analysis of that person’s immune response uncovered antibodies that remain effective against many Omicron variants,” adds Kathryn Hastie, co-leader of the study and director of the La Jolla Institute for Immunology’s Antibody Discovery Center. “Now we have to figure out how to boost these antibodies that we want against others that are less effective.”
Throughout the pandemic, scientists at this center have collected blood samples from people in San Diego, and from laboratories around the world, with the goal of understanding the roles of different immune cells in the fight against SARS- CoV-2.
Antibodies are among the elite of the immune system. These molecules are produced by B lymphocytes and each antibody has a specific structure designed to bind to a specific target of a pathogen. It is as if the B lymphocytes saw a target in a pathogen and began to make their arrows.
The antibodies tested were from a clinical study volunteer who received two doses of the Moderna SARS-CoV-2 vaccine. The Moderna vaccine works by prompting the body to manufacture the Spike protein – a fragment of the viral target – so that it can start working on its antibodies and other weapons against the real virus.
The samples from the study volunteer were collected in early 2021, before the appearance of the Omicron. This means that the antibodies produced by the volunteer were due to the vaccination and not to the exposure to the Omicron.
The Omicron variant of SARS-CoV-2 appeared in late 2021 and spread rapidly. Omicron differed from other variants because it contained mutations that helped it evade protection from immune cells. Many antibodies designed to fight earlier variants of SARS-CoV-2 did not work against Omicron.
Fortunately, not everyone produces the same types 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 the San Diego volunteer. Like many of the people who received the first two injections of the Moderna vaccine, this person produced a robust set of antibodies capable of neutralizing the ancestral D614G variant of SARS-CoV-2.
As worrisome new virus variants emerged, the researchers tested this pool to see how many antibodies could continue to bind to the mutated virus.
“We found that this set of antibodies could also neutralize other variants, such as delta and Omicron,” Hastie explains.
They found that the subject 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 discovered five antibodies that decreased BA.1 infectivity by more than 85%.
They then put these remaining five antibodies through another battery of tests, and some of them proved effective.
This research will help us combat the variants we have now and give us targets for the development of future vaccines and therapies.
The scientists mapped these vulnerabilities in Spike using a high-resolution imaging technique called cryoelectron microscopy. “We were very interested to see how these antibodies recognize the Spike protein and its structure,” explains Xiaoying Yu, a postdoctoral researcher. “This structural work allows us to see exactly how the antibodies interact with the protein and how they can neutralize the virus.”
The imaging work revealed that two of the promising antibodies bind to the SARS-CoV-2 Spike by latching on to two parts of the protein at once. Capturing Spike in a sort of death grip, these antibodies lock onto the viral structure to stop the infection. This finding is consistent with another recent study by “Cell Reports” from the Saphire laboratory that shows the importance of bivalent antibodies against SARS-CoV-2 variants.
Could these three promising antibodies be recreated into a therapeutic antibody to treat Covid-19? The results obtained in a mouse model are encouraging. The team found that each antibody alone could reduce the viral load in the lungs of mice infected with SARS CoV-2 BA.1 and BA.2.
In the future, the researchers plan to put more human antibodies through this same process, from antibody isolation to screening, structural analysis, and experiments with animal models. “Now we can carry out the entire antibody discovery process,” says Yu. “This research will help us fight the variants we have now and give us targets for the development of future vaccines and therapies.”
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