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 well. If someone’s immune system is weakened due to chemotherapy, for example, the immune system is hardly able to 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 develop variants with new properties. In the case of serum therapy in contact with donor antibodies, those variants in particular against which these antibodies are less effective will prevail. The effect could be similar in the case of an insufficiently effective vaccination.
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 tumor disease of the lymphatic system in the mucous membranes. Due to chemotherapy, his immune system was weakened. 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 therapy, 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 clearest 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 so-called deletion through which two amino acids are lost in the protein.
Evolutionary race with the influence of therapy
This change, called H69 / V70, is close to the receptor binding site of the spike protein, 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 less suitable and more difficult to neutralize the virus.
Initially, this virus variant took a back seat, but after the third round of treatment, it experienced another upswing in numbers. As one of the study authors, Ravi Gupta of the Cambridge Institute for Therapeutic Immunology and Infectious Diseases, says, “What we saw was essentially competition between different virus variants and we think that this competition was fueled by serum therapy.”
In people with normal immune systems, it is not expected that the virus will mutate as a result of 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.
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 infectivity of the virus compared to the old virus variant. It is also important that the H69 / V70 deletion also occurs in the “British” variant B.1.1.7.
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 the serum therapy. “Given that both vaccines and therapeutics target the spike protein that was mutated in our patient, our study makes the more troubling option that the virus outsmarts the vaccines by mutating appropriately,” says Ravi Gupta .
However, it is “unlikely that 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.
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.
It is now also known that serum therapies are only successful under certain conditions, even in Covid 19 patients who are not immunocompromised. This is 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 defense.