COVID-19: which monoclonal antibodies should be used for vulnerable individuals?

On October 1, 2020, US President Donald Trump was revealed to have tested positive for SARS-CoV-2. At the time there was no vaccine available and no antiviral treatments had shown compelling efficacy. The following day, the White House physician announced that Donald Trump had received an experimental cocktail of monoclonal antibodies, casirivimab/imdevimab. With this announcement, the general public discovered that the "next generation" messenger RNA vaccines that were about to be brought to market may not be the only means of protection against COVID-19.

A few weeks later, the first SARS-CoV-2 vaccines were granted marketing authorization in several countries, including in the European Union. They were reliable, offered strong protection and could be rapidly produced at scale, and they would go on to save millions of lives – nearly 20 million in 2021 alone, according to WHO. But for many people, vaccination proved to be an imperfect solution.

This was particularly the case for immunocompromised people (individuals with AIDS or cancer, transplant recipients or those with chronic illnesses, etc.), since their immune system is not sufficiently stimulated by vaccination. To avoid severe forms of COVID-19, they have to abide by health and hygiene measures like wearing masks and airing closed spaces even more scrupulously – a challenge at a time when the majority of people are starting to forget about them. Another possibility for immunocompromised individuals is treatment with an alternative therapeutic solution, the same one given to the former US President: the administration of monoclonal antibodies.

For COVID-19, monoclonal antibodies were designed to prevent SARS-CoV-2 entering the cell, by targeting the virus' spike protein. The spike protein, which gives SARS-CoV-2 its spiky appearance (the "corona" of coronaviruses), can be seen as the key that enables the virus to open the door to the cells in our body. By binding to the spike protein and stopping the cell from being infected, monoclonal antibodies neutralize the biological effects of the virus.

Characterizing monoclonal antibodies that are effective against SARS-CoV-2 variants

Several monoclonal antibodies, developed within a few months and authorized in late 2020 or early 2021 (depending on the country), initially demonstrated high protective efficacy against SARS-CoV-2. In France, two dual therapies for use in people at high risk of developing a severe form of COVID-19 were authorized in the first quarter of 2021. The casirivimab/imdevimab combination mentioned above was authorized as a preventive treatment from August 2021. Unfortunately, several SARS-CoV-2 variants (Alpha, Beta and Gamma) emerged in late 2020 and then spread across the globe. The Delta variant began circulating worldwide from spring 2021. What are the consequences of these mutated viruses for our immune response? Are the vaccines still effective? Do monoclonal antibodies still represent a relevant therapeutic solution? These are some of the main questions that scientists and clinicians have been exploring since the emergence of the variants, and the answers are crucial, especially when it comes to treating immunocompromised people.

Over the following months, the Institut Pasteur's scientists continued this painstaking task and even took it a step further. As well as in vitro studies, the scientists were determined to continue with in vivo studies using sera from people who had received monoclonal antibodies.

They also added new criteria to their research. The protective efficacy of monoclonal antibodies depends primarily, but not solely, on their neutralizing capability. Some monoclonal antibodies can also induce a key immune defense mechanism known as antibody-dependent cellular cytotoxicity (ADCC), which kills cells infected with SARS-CoV-2. In the case of COVID-19, natural killer (NK) cells in the immune system recognize the antibodies that bind to antigens on the surface of infected cells and then specifically lyse those cells. These antibodies are described as "polyfunctional." This characteristic is all the more interesting since the monoclonal antibodies with the highest neutralizing capability are not those that induce ADCC the most, as shown in a study published in December 2022. In short, to obtain protective antibody cocktails, it may be a good idea to include polyfunctional antibodies which combine a high neutralizing capability with a strong ability to induce immune defense mechanisms.

Monoclonal antibodies, still a relevant therapeutic solution

What is the situation today? Given their loss of efficacy, there are currently no monoclonal antibodies that are approved for preventive use. For infected individuals who may develop severe forms, the recommended treatments are antiviral drugs like the nirmatrelvir/ritonavir combination or remdesivir. But these drugs have some drawbacks: they may interact with other medication, they can have significant side effects, and they are not easy to administer, so as a therapeutic option they are limited. Where do monoclonal antibodies stand as a curative treatment? While sotrovimab has been recognized as a possible alternative for the SARS-CoV-2 variants that were circulating in early 2023, it is ineffective against some of the current variants.

So can we say that monoclonal antibodies no longer serve any purpose? No, since research is continuing to produce new, more effective monoclonal antibodies. In convalescent individuals, a team of scientists coordinated by Hugo Mouquet has identified powerful broadly neutralizing antibodies that are active for a wide range of SARS-CoV-2 variants. The corresponding monoclonal antibodies are currently under development by SpikImm, a start-up founded by Truffle Capital and the Institut Pasteur. SpikImm has already taken two of these antibodies through to Phase I completion and is now developing an optimized antibody that will be more effective against the current variants, which could soon be approved for clinical practice. Depending on the results, the antibodies developed could be fast-tracked for authorization to be used preventively against COVID-19 in immunocompromised individuals. Other monoclonal antibodies against new variants, developed by various pharmaceutical companies, are also undergoing clinical trials.

Finally, other potential strategies for the development of future monoclonal antibodies for COVID-19 are under exploration. Scientists are now aiming to prevent SARS-CoV-2 from entering the cell by obtaining neutralizing antibodies that target the spike protein. But this protein undergoes numerous mutations, considerably reducing the effectiveness of antibody recognition. Can other parts of the virus be targeted? "One might imagine that antibodies can be produced to target other viral proteins, and that these antibodies might have other functions than neutralization. But this requires a better understanding of the functions of monoclonal antibodies. Research in this area could help us expand our antibody toolkit so that we are more resilient when dealing with viral diversification," indicates Timothée Bruel.

So in this "reciprocal adaptation" between monoclonal antibodies and viral variants, scientists have not yet played their last card. This is a priority, since 230,000 to 300,000 people in France alone are immunocompromised and at risk of developing severe forms of COVID-19.