Help against Covid-19: A research team has identified an antibody that can neutralize all known variants of SARS-CoV-2 – this opens up new possibilities for Covid-19 therapy, but also for a more widely effective vaccination. The antibody generated in mice with human immune cells does not attach to the binding site of the coronavirus, which can be greatly altered by mutations, but binds to a different region of the spike protein. There it blocks the fusion of the virus with our cell membranes – and thus neutralizes the infection.
That Coronavirus SARS-CoV-2 is constantly changing due to mutations – and thus undermines our immune system. The currently circulating worldwide Omikron-Variante Above all, its receptor binding site has changed so much that many antibodies generated by our immune system through infection or vaccination no longer fit. As a result, piling up re-infections and the vaccines and antibody preparations against Covid-19 are only partially effective.
New antibodies against the corona virus
But now there could be a remedy: A team led by Sai Luo from Harvard Medical School in Boston has identified an antibody that can neutralize all common variants of SARS-CoV-2. It was developed with the help of mice that use gene manipulation to develop human immune cells. The team modified the mouse genome in such a way that the animals develop a particularly large number of different human B cells – the cells that produce the antibodies.
Luo and his team then injected the mice twice, four weeks apart, with the spike protein of the Wuhan strain of SARS-CoV-2 or nanoparticles containing only its binding site. As a result, the mice’s humanized immune systems produced nine different strains of antibodies against the coronavirus. In order to determine how well these defense proteins work against the different virus variants, the researchers then carried out neutralization tests with one monoclonal antibody from each line.
Potent action against all virus variants
The result: One of these antibodies, SP1-77, proved to be particularly effective: “SP1-77 very potently neutralized all previously known SARS-CoV-2 variants, including the recently emerged omicron subvariants BA.1, BA.2 , BA.3, BA.4/5 and BA.2.12.1,” report Luo and his colleagues. This effective effect was demonstrated in three different types of neutralization tests.
To find out why this particular antibody was so potent, the researchers used cryo-electron microscopy to examine its binding to the spike protein of SARS-CoV-2. It was shown that SP1-77 does not dock at the receptor binding site of the coronavirus like most other antibodies. “The structural analyzes confirmed that the antibody binds on the side opposite the ACE2 binding site,” the team writes.
Virus membrane fusion blocked
Exactly this could explain the broad effect of the new antibody against all known coronavirus variants: “Most mutations of SARS-CoV-2 are outside the point of attachment of SP1-77,” explain Luo and his colleagues. This makes this antibody robust against mutation-related changes. Because the mutations in the recently emerged omicron variant 2.75 also lie outside the binding zone of SP1-77, the team is confident that this antibody will also be effective against this new variant.
But how does the antibody block the virus infection? More detailed analyzes revealed that SP1-77 does not prevent the virus from docking to the ACE2 receptor on the cell surface. In return, however, it blocks the fusion of the outer virus membrane with the cell membrane – an essential step for the virus to enter the cell. The coronavirus can thus bind to human cells, but cannot get inside. The new antibody SP1-77 thus starts at a point that has not previously been used by any therapeutic or vaccine-generated antibody, as the scientists explain.
New opportunity for therapy and broadly effective vaccines
According to Luo and his team, this antibody could open up new possibilities for treating Covid-19. “If this broad and potent effect against SARS-CoV-2 variants is also confirmed in vivo, then it has the potential for therapy against current and emerging variants of concern,” the researchers state. The new antibody could then be administered to patients with severe illnesses alone or in a cocktail with other monoclonal antibodies.
At the same time, the new antibody also provides valuable clues as to where future vaccines could start: “The non-traditional neutralization mechanism of SP1-77 could trigger the development of new vaccination strategies that provide broader protection against BA.5 and other virus variants,” explain Luo and his colleagues. However, the antibody must first be tested for its effectiveness in further animal experiments. (Science Immunology, 2022; doi: 10.1126/sciimmunol.add5446)
Quelle: Boston Children’s Hospital