Post by Nadica (She/Her) on Sept 3, 2024 1:31:25 GMT
Weighing up monoclonals and vaccination against COVID-19 - Published Sept 2, 2024
People most at risk of severe COVID-19 have been prioritised for both monoclonal antibody (mAb) therapy and vaccination. Although mAbs can provide levels of protection approaching that of vaccination, they require repeated administration, and ongoing evolution of SARS-CoV-2 has led to the prospect of sudden loss of neutralising ability as new variants emerge—in marked contrast to the broad polyclonal antibody response to vaccination that provides forward protection. Indeed, it remains challenging to divine whether a given mAb will be effective, with interpretations of in vitro and observational data differing considerably.
In The Lancet Infectious Diseases, Flonza Isa and colleagues5 report the outcome of a randomised, open-label study assessing SARS-CoV-2 neutralising antibody responses when two mAbs (casirivimab and imdevimab, Regeneron, Tarrytown, NY, USA) are administered with mRNA-1273 vaccination (Moderna, Boston, MA, USA).
Ideally, the short-term protection provided by mAbs can be complemented by vaccination for long-term protection. However, dual administration of mAbs and vaccination risks a potential interaction between mAbs and vaccine: either by mAb depletion of the Spike antigen encoded in vaccines, or by epitope masking of the Spike receptor binding domain (RBD) by the mAbs. Studying these effects in real-world settings has been challenging: observational studies are confounded by the differing times of monoclonal antibody administration overlapping with differing times of COVID-19 variant waves, and it is technically challenging to distinguish neutralising antibody responses elicited by vaccination from neutralisation by the administered mAb.
The work of Isa and colleagues presents a significant advance in three aspects. First, it examines a mAb and vaccine combination that was in widespread clinical use in the context of a purpose-built trial. Second, it controls for the varying risk of SARS-CoV-2 infection during waves of COVID-19 by administering mAbs at fixed times, and instead varying mAb dosage to mimic vaccination at different timepoints following mAb administration. Third, it specifically determines the neutralising antibody titres of vaccine-elicited antibodies by depleting the administered therapeutic mAbs before carrying out a pseudotyped virus neutralisation assay.
Isa and colleagues found that all participants developed neutralising antibodies following vaccination, however those in groups mimicking vaccination 0–12 weeks after mAb administration had up to a 4-fold reduction in vaccine-elicited neutralising antibody responses against ancestral SARS-CoV-2 (whose Spike protein is encoded by mRNA-1273) compared with those who did not receive mAbs. However, no significant reduction in neutralising titres was observed in groups mimicking vaccination 16 or more weeks after mAb administration, nor was a reduction observed for those who instead were vaccinated first and then given mAbs 7 days later.
Despite the reduction in neutralising antibody titres observed in some groups, total anti-Spike IgG levels were consistently high across all study groups, suggesting that the Spike antigen is not depleted by mAbs. Instead, this scenario is consistent with epitope masking of the Spike RBD by mAbs and with the selection of B cell clones with lower affinity in germinal centres, as previously reported by Schaefer-Babajew and colleagues.
The results from Isa and colleagues are in fact broadly in line with previous observational and preclinical studies, all of which report a modest decrease in RBD-specific antibodies (even if underpowered to assess statistical significance), but differ in their assessment of whether these changes are meaninigful.
Is a 4-fold reduction in neutralising titres significant enough to justify delaying vaccination or prophylactic mAb administration? In the case of rapidly evolving SARS-CoV-2, the answer might depend on whether a similar reduction might be seen against emerging variants; although Isa and colleagues measured total binding anti-variant Spike IgG, they did not measure neutralisation of these variants. Given that the correlation between binding antibody and neutralising antibody levels seen in healthy adults can be expected to be broken due to immune compromise or due to the administration of monoclonal antibodies themselves, further research into how mAb administration affects the landscape of immunity against different variants will be valuable.
It remains to be seen if similar interactions between mAbs and vaccination are observed with different mAbs (eg, those retaining Fc effector functions such as sotrovimab), and different vaccine platforms (eg, with different germinal centre responses from mRNA vaccines). The work of Isa and colleagues will be immediately applicable to understanding the management of other infectious diseases such as Influenza and Respiratory Syncytial Virus (in which its F glycoprotein is both the target of a recently approved mAb and the antigen of recently approved vaccines), and provides a well controlled insight into the development of humoral immunity within humans.
People most at risk of severe COVID-19 have been prioritised for both monoclonal antibody (mAb) therapy and vaccination. Although mAbs can provide levels of protection approaching that of vaccination, they require repeated administration, and ongoing evolution of SARS-CoV-2 has led to the prospect of sudden loss of neutralising ability as new variants emerge—in marked contrast to the broad polyclonal antibody response to vaccination that provides forward protection. Indeed, it remains challenging to divine whether a given mAb will be effective, with interpretations of in vitro and observational data differing considerably.
In The Lancet Infectious Diseases, Flonza Isa and colleagues5 report the outcome of a randomised, open-label study assessing SARS-CoV-2 neutralising antibody responses when two mAbs (casirivimab and imdevimab, Regeneron, Tarrytown, NY, USA) are administered with mRNA-1273 vaccination (Moderna, Boston, MA, USA).
Ideally, the short-term protection provided by mAbs can be complemented by vaccination for long-term protection. However, dual administration of mAbs and vaccination risks a potential interaction between mAbs and vaccine: either by mAb depletion of the Spike antigen encoded in vaccines, or by epitope masking of the Spike receptor binding domain (RBD) by the mAbs. Studying these effects in real-world settings has been challenging: observational studies are confounded by the differing times of monoclonal antibody administration overlapping with differing times of COVID-19 variant waves, and it is technically challenging to distinguish neutralising antibody responses elicited by vaccination from neutralisation by the administered mAb.
The work of Isa and colleagues presents a significant advance in three aspects. First, it examines a mAb and vaccine combination that was in widespread clinical use in the context of a purpose-built trial. Second, it controls for the varying risk of SARS-CoV-2 infection during waves of COVID-19 by administering mAbs at fixed times, and instead varying mAb dosage to mimic vaccination at different timepoints following mAb administration. Third, it specifically determines the neutralising antibody titres of vaccine-elicited antibodies by depleting the administered therapeutic mAbs before carrying out a pseudotyped virus neutralisation assay.
Isa and colleagues found that all participants developed neutralising antibodies following vaccination, however those in groups mimicking vaccination 0–12 weeks after mAb administration had up to a 4-fold reduction in vaccine-elicited neutralising antibody responses against ancestral SARS-CoV-2 (whose Spike protein is encoded by mRNA-1273) compared with those who did not receive mAbs. However, no significant reduction in neutralising titres was observed in groups mimicking vaccination 16 or more weeks after mAb administration, nor was a reduction observed for those who instead were vaccinated first and then given mAbs 7 days later.
Despite the reduction in neutralising antibody titres observed in some groups, total anti-Spike IgG levels were consistently high across all study groups, suggesting that the Spike antigen is not depleted by mAbs. Instead, this scenario is consistent with epitope masking of the Spike RBD by mAbs and with the selection of B cell clones with lower affinity in germinal centres, as previously reported by Schaefer-Babajew and colleagues.
The results from Isa and colleagues are in fact broadly in line with previous observational and preclinical studies, all of which report a modest decrease in RBD-specific antibodies (even if underpowered to assess statistical significance), but differ in their assessment of whether these changes are meaninigful.
Is a 4-fold reduction in neutralising titres significant enough to justify delaying vaccination or prophylactic mAb administration? In the case of rapidly evolving SARS-CoV-2, the answer might depend on whether a similar reduction might be seen against emerging variants; although Isa and colleagues measured total binding anti-variant Spike IgG, they did not measure neutralisation of these variants. Given that the correlation between binding antibody and neutralising antibody levels seen in healthy adults can be expected to be broken due to immune compromise or due to the administration of monoclonal antibodies themselves, further research into how mAb administration affects the landscape of immunity against different variants will be valuable.
It remains to be seen if similar interactions between mAbs and vaccination are observed with different mAbs (eg, those retaining Fc effector functions such as sotrovimab), and different vaccine platforms (eg, with different germinal centre responses from mRNA vaccines). The work of Isa and colleagues will be immediately applicable to understanding the management of other infectious diseases such as Influenza and Respiratory Syncytial Virus (in which its F glycoprotein is both the target of a recently approved mAb and the antigen of recently approved vaccines), and provides a well controlled insight into the development of humoral immunity within humans.