Antibodies from recovered patients are a treatment option for Covid-19 – especially for patients with weakened immune systems. But doctors have long worried that the mutants could grow well then. If one’s immune system is weakened by chemotherapy, for example, the immune system is difficult to fight viruses successfully. “The antibodies that are then administered are hardly supported by cytotoxic T cells, which reduces the chances of eliminating the virus,” say British researchers in a study recently published in the journal Nature.
Infections 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 will prevail, in particular against which these antibodies are less effective. The result could be similar in the case of insufficiently effective vaccination.
More than three months, 23 genome sequences
The researchers from the Genomics UK consortium had the opportunity to monitor the link between chronic infection, mutations and serum therapy for 101 days in a patient with immunosuppressed Covid. The British patient was over 70 years old and was suffering from a cancer of the lymphatic system that appeared in the mucous membranes. His immune system was weakened by the chemotherapy. When he became infected with Sars-CoV-2, he initially received serum therapy, among other things. At first his condition stabilized, but then it deteriorated significantly. Despite further treatment, he died. During these 101 days, 23 virus samples were taken and their genomes were sequenced. This allowed us to see how the virus mutated
After two treatments with antibody serum therapy, the researchers observed the clearest change in the virus population between days 66 and 82. A virus variant that had survived antibody therapy became predominant. On the one hand, it has a double called deletion through which two amino acids are lost in the protein.
Evolutionary race with the effect of treatment
This change, called H69 / V70, is located near the receptor binding site of the protein spike, which the virus uses as a key to invading cells. There is also another mutation known as D796H. In combination, both cause a structural change in the protein. This leads to the fact that the administered antibodies do not fit well and neutralize the virus more difficult.
Initially, this variant of the virus took a back seat, but after the third round of treatment, it showed another increase in numbers. One of the study’s authors, Ravi Gupta of the Cambridge Institute for Therapeut Immunology and Infectious Diseases, said: “What we saw was essentially competition between different variants of viruses and we believe that this competition was fueled by serum therapy.”
In people with a normal immune system, the virus is not expected to be mutated as a result of serum therapy, as in immunocompromised patients. Because in these cases the antibodies are adequately supported by the cytotoxic T cells of the immune system. These can identify and eliminate infected cells. Antibodies and cytotoxic T cells are more likely to stop 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, British scientists have been able to determine what causes the mutations. In laboratory experiments without antibodies, deletion alone doubled the infectivity of the virus compared to the old variant of the virus. It is also important that the deletion of H69 / V70 occurs in the “British” variant B.1.1.7.
In contrast, the D796H is the so-called escape mutation. Here the site of receptor binding changes so that antibodies from healthy Covid 19 patients can no longer catch the virus there. This reduces the effectiveness of serum therapy. “Because both vaccines and therapies target the mutated protein spike in our patient, our study makes the most troubling choice of the virus to go beyond vaccines with the appropriate mutation,” says Ravi Gupta.
However, it is “unlikely that this virus formation will occur in patients with a functioning immune system, as fewer virus variants may occur due to better immune control”. However, serum therapy has promoted the selection of virus variants that are less sensitive or insensitive to antibodies to it and at least one other patient with immunosuppressed Covid-19 in the United States. “It shows how careful we need to be in treating immunocompromised patients in whom the virus has more time to multiply, which means it also has more opportunities for mutation,” the study authors wrote.
Given that data are no longer available, researchers suggest that serum therapy in immunocompromised patients be performed only as part of studies and preferably in single rooms with increased infection control precautions due to the increased risk of virus mutations. A special effort must be made to avoid infecting others. Continuous sequencing of the virus is also required.
Serum therapies are also known to be successful only under certain conditions, even in non-immunosuppressed Covid 19 patients. This is why the US Food and Drug Administration (FDA) has now restricted its use: in the future, it should only be used in the early stages of treatment, ie in the first 72 hours and in patients whose immune cells do not produce enough antibodies for defense.