Antibody Treatment: Dangers of Mutants in Defence

Antibody treatment in defence molecules of recovered cells are an essential option in Covid therapy. But especially with particularly needy patients, there are serious problems.

Model of an antibody against the spike protein. Antibodies from recovered patients are a therapy option for Covid-19 – especially for patients with a weakened immune system. But doctors have long been concerned that then mutants could develop nicely.

If someone’s immune system is weakened due to chemotherapy, for example, the immune system can hardly fight viruses successfully. “Administered antibodies are then hardly supported by cytotoxic T cells, which reduces the chances of eliminating the virus,” write British researchers in a study recently published in the magazine “Nature”.

Infections then often become chronic, and there is an increased risk that the virus will mutate and create variants with new properties. In the case of serum therapy in contact with donor antibodies, those variants against which these antibodies are less effective will prevail. The effect could be similar in the case of insufficiently effective vaccination.

Antibody Treatment : More than three months, 23 genome sequencing
The researchers of the “Genomics UK” consortium had the opportunity to follow the connection between chronic infection, mutations and serum therapy for 101 days in an immunocompromised Covid patient. The British patient was over 70 years old and suffered from a tumour disease of the lymphatic system occurring in the mucous membranes. His immune system was weakened from chemotherapy. When he became infected with Sars-CoV-2, he was initially treated with serum therapy, among other things. At first, his condition stabilized but then deteriorated noticeably. Despite further treatment, he died. During those 101 days, 23 virus samples were taken, and their genomes were sequenced. This made it possible to see how the virus mutated.

After two treatments with antibody serum therapy, the researchers observed the most straightforward change in the virus population between the 66th and 82nd day. A virus variant that had survived the antibody therapy became dominant. On the one hand, it has a double-called deletion through which two amino acids are lost in the protein.

Antibody Treatment : Evolutionary race with the influence of therapy
This change, called H69 / V70, is located near the spike protein receptor binding site, which the virus uses as a key to invading cells. There is also another mutation nearby known as D796H. In combination, both cause a structural change in the protein. It leads to the fact that the administered antibodies are more difficult to match and more difficult to neutralize the virus.

Initially, this virus variant took a back seat, but after the third round of treatment-experienced a renewed increase in numbers. One of the study authors, Ravi Gupta of the Cambridge Institute for Therapeutic Immunology and Infectious Diseases, said: “What we saw was essentially a competition between different virus variants, and we think that this competition was fueled by serum therapy.”

In people with typical immune systems, it is not expected that the virus will mutate due to serum therapy, as in immunocompromised patients. Because in these cases, the antibodies are sufficiently supported by cytotoxic T cells of the immune system. These can recognize and eliminate infected cells. Antibodies and cytotoxic T cells together have more potential to shut down viruses.

Antibody Treatment : Isolate patients as best as possible
Using synthetically produced viruses that contain either the H69 / V70 deletion or the D796 mutation or both at the same time, the British scientists succeeded in determining what the mutations cause. In laboratory experiments without antibodies, the deletion alone doubled the virus’s infectivity compared to the old virus variant. It is also essential that the H69 / V70 deletion also occurs in the “British” variant B.1.1.7.

Model of an antibody against the spike protein

In contrast, D796H is a so-called escape mutation. Here the receptor binding site is changed so that antibodies from healthy Covid 19 patients can no longer catch the virus there as well. This reduces the effectiveness of serum therapy. “Given that both vaccines and therapeutics target the spike protein that was mutated in our patient, our study makes the more worrying option of the virus outsmarting the vaccines by mutating appropriately,” says Ravi Gupta.

It is, however, “untrue. unfortunately, this formation of virus variants occurs in patients with a functioning immune system, since fewer virus variants can arise due to better immune control”. But serum therapy has promoted the selection of virus variants that are less sensitive or insensitive to antibodies in this and at least one other immunocompromised Covid-19 patient in the USA. “It shows how careful we have to be when treating immunocompromised patients, in whom the virus has more time to multiply, which means that it also has more opportunities to mutate,” the study authors write.

Antibody Treatment : Limited use
As long as no more data are available, the researchers recommend that serum therapy in immunocompromised patients only be carried out as part of studies and preferably in single rooms with increased infection control precautions because of the increased risk of virus mutations. Special effort should be made to prevent others from becoming infected. Continuous sequencing of the virus is also required.

What artificial antibodies can do against Covid-19
A specialist works in the infectious diseases laboratory of the US company Regeron on cell culture in a microbiological workbench. The biotechnology company produces an experimental antibody cocktail against Covid-19.

It is now also known that serum therapies are only successful under certain conditions, even for Covid 19 patients who are not immunocompromised. The reason why the US Food and Drug Administration (FDA) has now restricted its use: In future, it should only be used in the early phase of treatment, i.e. in the first 72 hours, and in patients whose immune cells do not produce enough antibodies for the defence.