A recent study has used genomic sequencing of the SARS-CoV-2 virus to help understand how the virus evolves in hospital patients and learn more about the antiviral drug remdesivir.
The research set out to explore how the SARS-CoV-2 virus evolves over time in individual patients admitted to hospital with COVID-19. Nine children aged 0 to 14 were studied at Great Ormond Street Hospital for Children NHS Foundation Trust. Each child was tested for COVID-19 on admission and regularly during their stay using a PCR test. The positive test material was then used for genome sequencing so mutations in the virus could be tracked.
Run in collaboration by members of the COG-UK consortium at University College London, Great Ormond Street Hospital and the University of Sheffield, the study also aimed to assess the effectiveness of the antiviral drug remdesivir. The drug works by inhibiting the replication of viral RNA and has shown contradictory results in clinical trials. Remdesivir was given to three of the nine children and each patient’s COVID test material analysed to follow the amount of virus present during treatment.
The study found that four of the nine patients were infected by multiple variants of the virus. In other words, samples from these patients contained a number of different SARS-CoV-2 genetic sequences. Some of the viral variants were shared between individuals, and the researchers investigated if this was due to patients catching the virus from one another while in hospital. Additionally, the data were examined to see if the multiple variants present could be explained by patients being reinfected more than once, each time with a new variant or mix of variants. The investigations concluded that viral evolution within each patient was a more likely explanation than patient transmission or reinfection.
Given the SARS-CoV-2 mutation rate of, on average, one mutation per fortnight, an evolving virus population is expected in patients with long-term infections. However, the changes in variants observed over the course of the study indicated that the virus population was not uniform throughout each patient. Instead, it was consistent with multiple populations of the virus physically separated within the lungs of each individual. Different compartments in the lungs have previously been observed to act as distinct niches for influenza virus and Mycobacterium tuberculosis and are known to make drug treatment more challenging.
Responses to remdesivir varied between the four treated patients and were not found to be related to the viral variant present. For example, suppression of viral replication was observed in one patient receiving remdesivir, but not in another infected with an identical variant. The authors of the study speculate that the virus may have been more inaccessible to the drug in the patient showing no decrease in replication, owing to concealment in the lung.
Analysis of the mutations present in the viral populations focussed on two areas of clinical importance – immune resistance and drug resistance. Immune escape mutations tend to be located in the genetic material encoding regions of the virus that bind the antibody and T-cell receptor. Only one potential mutation was found in these regions, P812L, in a sequence predicted to bind the T-cell receptor, although the clinical impact of the mutation is not known. Remdesivir blocks RNA replication in the virus, and no mutations were found in sites known to interfere with drug action. The lack of evidence for drug resistance mutations is encouraging, but with only nine patients, the study was not designed to be comprehensive.
Overall, this study adds more evidence that distinct viral populations can exist in an individual patient and that these populations of virus can evolve separately to the others. This raises a number of potential challenges for patient treatment. First, the inaccessibility of some of the lung compartments in which SARS-CoV-2 replicates may compromise drug delivery and make studies of antiviral drugs difficult to interpret. Second, the separate evolution of each virus population gives rise to multiple opportunities for immune and drug resistance mutations to occur and makes it harder to unpick how different variants of virus might be related. Addressing these challenges is of immediate relevance as the UK’s first oral COVID-19 drug to be licensed, the antiviral molnupiravir, was approved this month (November 2021) and inhibits the same viral protein as remdesivir.
Looking forward, a potential approach to improve the effectiveness of antiviral drugs like remdesivir is to administer a combination of drugs together. This study supports the possibility that different compartments within the lungs could show distinct responses to each drug in a cocktail. Bedside genomics is one tool to help unravel this complexity and guide the individualised drug treatment of the future.
Boshier, F. A. T., Pang, J., Penner, J., Parker, M., Alders, N., Bamford, A., … & COVID‐19 Genomics UK (COG‐UK) consortium. (2021). Evolution of viral variants in remdesivir‐treated and untreated SARS‐CoV‐2‐infected pediatrics patients. Journal of Medical Virology. https://doi.org/10.1002/jmv.27285
