In a recent study posted to the medRxiv* preprint server, researchers investigated the interplay of all the factors responsible for within-host evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in immunocompromised patients.
Studies suggest that SARS-CoV-2 mutations associated with immune evasion, particularly within the spike (S) protein, the target of currently approved coronavirus disease 2019 (COVID-19) vaccines, can arise in immunocompromised patients with prolonged infection.
For instance, studies identified the E484K and Q493K mutations in the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) of SARS-CoV-2, which confer partial resistance to neutralizing antibodies (nAbs) in immunocompromised patients with prolonged infection. The occurrence of these mutations likely points to viral evolution within immunocompromised patients, which is a serious issue that needs to be addressed.
Since these mutations do not arise in all immunocompromised patients with prolonged infection, the role of additional selective pressure, such as exogenous monoclonal antibody (mAb) treatment, cannot be ruled out.
Hence, it becomes crucial to fully understand what factors within the host facilitate the emergence of immune evasion mutations in SARS-CoV-2 to guide future therapies against emerging SARS-CoV-2 variants and prevent their emergence.
About the study
In the present study, researchers recruited five immunocompromised patients (P1 to P5) with persistent SARS-CoV-2 infection (greater than 30 days) to examine the interplay between exogenous mAb treatment, within-host SARS-CoV-2 evolution, and host’s immune responses.
All these patients were under treatment with immunosuppressive medications, such as rituximab. One patient (P4) had Good Syndrome, which causes B-cell deficiency, hypogammaglobulinemia, and an imbalanced cluster of differentiation 4 (CD4)-CD8 T-cell ratio.
From the time of the first positive test, the reverse transcription-polymerase chain reaction (RT-PCR) test was positive for a period of 42 to 302 days for all the patients, with persistently low cycle threshold (CT) values throughout infection, indicating a prolonged SARS-CoV-2-infection in all the patients.
There were no known changes to any patients’ baseline immunosuppressive regimens. Patients P2 and P3 received the single-agent mAb bamlanivimab on day 4 and day 8 after SARS-CoV-2 infection. Two patients received high-titer convalescent plasma (CP), P4 on day 0 and day 104, and P5 on day 196. Patients P3 and P4 also received intravenous immunoglobulin (IVIG). Only patient P1 received steroids, while all the patients received remdesivir.
In patients with longitudinal infection, persistent SARS-CoV-2 replication combined with selective pressure due to mAb treatment (here bamlanivimab) resulted in nAb resistant S mutations. This finding raises the possibility that mAb therapies may contribute to the emergence of immune evasion mutations in SARS-CoV-2 at the population level.
The finding also explains why the United States Food and Drug Administration (FDA) revoked emergency use authorization (EUA) for single-agent bamlanivimab therapy. Subsequently, alternative multi-agent mAb therapies are being used for treatment, which are less likely to select for resistance against nAbs.
Some studies suggest that even CP exerts selective pressure during longitudinal SARS-CoV-2 infection. However, the present study findings do not support this, as the authors did not observe escape mutations in the two patients treated with CP.
In P2, the authors observed the rapid emergence of two neutralization resistant S mutations, Q493R and S494, suggesting that selective pressures other than bamlanivimab therapy were also at play in patients with longitudinal infection. Likewise, S RBM mutation E484K was detected at sub-consensus levels in P2 and transiently in P3 and did not alter the neutralization profile of SARS-CoV-2. Furthermore, the authors observed deletions of fluctuating length in the N-terminal domain (NTD) of S protein in patient P3.
Together, these findings suggested that although additional selective pressures were at play during within-host evolution, SARS-CoV-2 attains neutralization resistance via multiple pathways.
The study results also confirmed that immunocompromised patients with B cell deficiencies could elicit effector T (Teff) cells, suggesting an important role for CD8+ T cells in controlling infection, relevant to COVID-19 vaccines and therapeutics.
Accordingly, patients P4 and P5 who clinically recovered from COVID-19 had functional SARS-CoV-2-specific CD4+ and CD8+ T cell responses, with a higher magnitude of CD8+ T cell responses than hospitalized immunocompetent patients.
The current study highlights the need for large-scale clinical studies, including serial sampling, in immunocompromised individuals for in-depth insights into the implications of different mAb therapies and further elucidate therapies that promote immune evasion.
Most importantly, the study sheds light on how SARS-CoV-2 evolution occurs within the host and the factors which promote it, including persistent infection, absence of endogenous immune response, and selective pressure due to exogenous antibody treatment.
Hence, to prevent the onward transmission of SARS-CoV-2 variants with immune escape mutations, next-generation mAbs should be broad-spectrum, and vaccines should induce potent nAb responses and memory CD8+ T cell responses for enhanced efficacy.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.