The Sars-Cov-2 coronavirus is constantly developing new mutations and thus undermining our immune system. Vaccines and therapeutic antibodies are only partially effective against the current omicron variant. But now a research team has identified an antibody that can neutralize all previously known virus variants. The broad effect is based on the fact that this antibody, which is produced in mice with human immune cells, does not attach to the binding site of the coronavirus, which is highly variable due to mutations. Instead, it binds to a different site on the viral spike protein, thereby blocking the virus from fusing with the cell membrane – and thus the infection.
The Sars-CoV-2 coronavirus has developed significantly since it first appeared in Wuhan, China, a good two and a half years ago. A relatively high mutation rate and the infection and multiplication in more than 590 million people mean that the virus variants that are more infectious and are more easily transmitted from person to person have prevailed. At the same time, there are also variants that have adapted to our immune system: They have mutated in such a way that the antibodies produced by previous infections or a vaccination can no longer dock to their spike protein. That is why those who have been vaccinated and those who have recovered are largely protected against severe courses of Covid-19, but not against renewed infection. Most therapeutic antibodies for the treatment of Covid-19 are also no longer effective against the currently circulating omicron variants.
Searching for more broadly effective antibodies
Scientists are therefore always on the lookout for new, more broadly effective antibodies against Sars-CoV-2. A team led by Sai Luo from Harvard Medical School in Boston has now struck gold. The researchers have identified an antibody that can neutralize all of the current variants of Sars-CoV-2. They developed it with the help of mice that developed human immune cells through genetic manipulation. They 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 with only its binding site.
Through this exposure to viral material, 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 scientists then carried out neutralization tests with one monoclonal antibody from each line. 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 created omicron subvariants BA.1, BA.2, BA .3, BA.4/5 and BA.2.12.1,” report Luo and his colleagues. Analysis using cryo-electron microscopy showed that SP1-77 does not bind to the receptor binding site of the coronavirus like most other antibodies. Instead, the antibody binds to the opposite side of the ACE2 binding site – a site on the spike protein that is rarely affected by the mutations in the coronavirus. This could explain the broad effect of the new antibody against all known coronavirus variants.
Blocked membrane fusion
Further investigations also revealed how the new antibody prevents the coronavirus from infecting: SP1-77 allows the virus to dock to the ACE2 receptor on the cell surface, but it blocks the fusion of the outer virus membrane with the cell membrane – an essential step for the cell entry of the virus. 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. “If this broad and potent effect against Sars-CoV-2 variants is also confirmed in vivo, then this antibody has the potential for therapy against current and emerging variants of concern,” they state. The new antibody could then be administered to Covid-19 patients with severe courses 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.
Source: Sai Luo (Harvard Medical School, Boston) et al., Science Immunology, doi: 10.1126/sciimmunol.add5446