Use with caution. Monoclonal antibodies (which recognize one dot of the virus) such as GlaxoSmithKline’s sotrovimab and Eli Lilly’s bamlanivimab are part of the arsenal available to fight Covid-19. Mainly for patients who have not been vaccinated or who have not developed a sufficient immune response to fight the virus, in particular for immunocompromised patients. Very effective against previous variants, these monoclonal antibodies have lost effectiveness against Omicron and its sub-variants due to their significant ability to evade the immune response. Thus, only sotrovimab is effective against BA.1 (the first strain of Omicron). Therefore, it is only natural that this monoclonal antibody is used to treat immunocompromised patients infected with the coronavirus. Problem: This treatment appears to be able to generate resistant variants in these patients.
Resistance mutations selected after this treatment in immunocompromised patients
“We have been interested in immunocompromised patients since the beginning of the pandemic, because immunocompromised people can be reservoirs for SARS-CoV-2, because they have a hard time clearing it, and therefore it can develop in their bodies,” Lawrence explains to us. Josse, Research Fellow at the Infectious Agents Institute of the Lyon Hospices, a laboratory associated with the National Reference Center for Respiratory Infection Viruses. The virus replicates at a faster rate in these patients and stays there longer, which increases the risk of mutations in the virus and thus evolution. In this context, only viruses that can escape the antibody used will replicate, creating selection for that resistance.”
Indeed, Lawrence Josse and colleagues have demonstrated that treatment with sotrovimab creates a selection pressure that may promote certain resistance mutations to this antibody. In particular, mutations at positions 340 and 337 of the Spike protein are known to significantly reduce the effectiveness of this antibody.
After analyzing almost 23,000 Omicron sequences collected in France between December 2021 and March 2022, the researchers found these mutations in 25 sequences in 18 patients. Clinical information was only available for 8 of these patients, all of whom were immunocompromised and treated with sotrovimab. According to their analysis, published online in a (not yet peer-reviewed) preprint on April 16, 2022, these mutations appeared one to two weeks after treatment. Due to this persistence, the treatment failed to eliminate the coronavirus, which was still detectable up to 43 days after infection. With the exception of one patient who was subsequently treated with convalescent plasma.
Use with caution. Monoclonal antibodies (which recognize one dot of the virus) such as GlaxoSmithKline’s sotrovimab and Eli Lilly’s bamlanivimab are part of the arsenal available to fight Covid-19. Mainly for patients who have not been vaccinated or who have not developed a sufficient immune response to fight the virus, in particular for immunocompromised patients. Very effective against previous variants, these monoclonal antibodies have lost effectiveness against Omicron and its sub-variants due to their significant ability to evade the immune response. Thus, only sotrovimab is effective against BA.1 (the first strain of Omicron). Therefore, it is only natural that this monoclonal antibody is used to treat immunocompromised patients infected with the coronavirus. Problem: This treatment appears to be able to generate resistant variants in these patients.
Resistance mutations selected after this treatment in immunocompromised patients
“We have been interested in immunocompromised patients since the beginning of the pandemic, because immunocompromised people can be reservoirs for SARS-CoV-2, because they have a hard time clearing it, and therefore it can develop in their bodies,” Lawrence explains to us. Josse, Research Fellow at the Infectious Agents Institute of the Lyon Hospices, a laboratory associated with the National Reference Center for Respiratory Infection Viruses. The virus replicates at a faster rate in these patients and stays there longer, which increases the risk of mutations in the virus and thus evolution. In this context, only viruses that can escape the antibody used will replicate, creating selection for that resistance.”
Indeed, Lawrence Josse and colleagues have demonstrated that treatment with sotrovimab creates a selection pressure that may promote certain resistance mutations to this antibody. In particular, mutations at positions 340 and 337 of the Spike protein are known to significantly reduce the effectiveness of this antibody.
After analyzing almost 23,000 Omicron sequences collected in France between December 2021 and March 2022, the researchers found these mutations in 25 sequences in 18 patients. Clinical information was only available for 8 of these patients, all of whom were immunocompromised and treated with sotrovimab. According to their analysis, published online in a (not yet peer-reviewed) preprint on April 16, 2022, these mutations appeared one to two weeks after treatment. Due to this persistence, the treatment failed to eliminate the coronavirus, which was still detectable up to 43 days after infection. With the exception of one patient who was subsequently treated with convalescent plasma.
The best alternative is the plasma of patients treated with Omicron.
“Monoclonal antibodies remain effective, but you just shouldn’t use just one,” she reassures. An alternative would be to combine multiple monoclonal antibodies (in dual therapy, as in the case of AstraZeneca’s Evucheld) that recognize the virus in multiple locations, but none currently effective against all variants, although there are currently several in clinical trials . Therefore, at the moment, the best alternative is plasma from patients treated with Omicron, collected shortly after infection, when antibody levels are still high.” Because after infection, the immune system produces antibodies that target multiple locations in the virus, so many mutations would be required to escape this army of antibodies present in convalescent plasma, reducing the risk of resistance.
A rare event, but with Omicron it seems to be more frequent.
This selection of resistance mutations has already been demonstrated by Australian researchers in delta-infected patients treated with sotrovimab in a letter published in the New England Journal of Medicine on 14 April 2022. In their study, these mutations were selected in 4 out of 100 patients.
But this event seems to be more frequent with Omicron. According to a preprint published online by Dutch researchers on April 6, 2022, these mutations were selected from 13% of immunocompromised patients treated with sotrovimab (6 out of 47 patients). “This remains a rare event, and these immunocompromised patients are not a major source of risk for the appearance of variants,” says Lawrence Josse. Rather, these are regions of the world that are very poorly vaccinated, because it is in these populations that the virus is likely to develop rapidly.
No risk of resistance with vaccination
On the other hand, vaccination does not pose the same risk of emergence of resistant variants in immunocompromised patients. “Vaccination produces multiple antibodies that target different sites, so there is no risk of isolating viruses that are resistant to antibodies produced by vaccination,” she recalls. The problem, rather, is that vaccination does not elicit a sufficient immune response in all immunocompromised patients to protect them from infection or disease: the vaccine protects some of these patients, but there are 20 to 60% who are refractory (or poorly) responsive to vaccination. among the immunocompromised. They depend on the protection of those around them to avoid infection.” And if infection is unfortunately unavoidable, it would be better to treat these patients with convalescent plasma instead of monoclonal antibodies until new therapies hit the market.