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Expand genome sequencing in many settings, Immunologists urge 

07 Jul 2021

  • Lab capability, bioinformatics capacity vital to track emergence of VOCs 

  • Attention needed for metadata collection, appropriate sampling strategies, sample collection to results feeding time

By Ruwan Laknath Jayakody   As all countries including Sri Lanka are grappling with controlling the various phases and stages of the Covid-19 pandemic in the form of waves, Lankan immunologists pointed out that the need of the hour is to expand and scale up genome sequencing efforts and programmes within a multitude of settings, including laboratory capability and bioinformatics capacity, to track the emergence of variants of concern (VOCs). Furthermore, in this regard, aspects pertaining to the collection of metadata, the adoption of appropriate sampling strategies, and deciding on how best to optimise the end-to-end turnaround time from sample collection to feeding the results to public health officials, requires more care in terms of both thought and attention. These recommendations were made in an editorial published in the Sri Lanka Journal of Medicine's 30th Volume's First Issue on 1 July 2021, titled “Expansion of SARS-CoV-2 sequencing capacity globally is vital for the future control of the Covid-19 pandemic” and authored by T.I. de Silva (attached to the UK Sheffield University's Infection, Immunity, and Cardiovascular Disease Department and the London School of Hygiene and Tropical Medicine's The Gambia's Medical Research Council Unit's Vaccines and Immunity Theme) and G.N. Malavige (attached to the Sri Jayewardenepura University Medical Sciences Faculty's Immunology and Molecular Medicine Department and the Oxford University MRC Weatherall Institute of Molecular Medicine's MRC Human Immunology Unit).  Highlighting the use of the rapid viral whole genome sequencing tool with regard to tracking and monitoring community outbreaks of the Covid-19 virus pandemic and its various existing and emerging variants, alongside the development of anti Covid-19 vaccines and large scale clinical trials (“Dexamethasone in Hospitalised Patients with Covid-19” by The RECOVERY Collaborative Group), de Silva and Malavige noted that it was certain technological advancements that had made such possible. These include reductions in the costs incurred for sequencing, the availability of user-friendly benchtop sequencing devices, and improvements in the computational capacity needed to handle and manage the increasing amounts of data generated.  In this regard, the need to publicly share rapidly-generated sequence data for the purpose of using such in aiding the public health response in terms of Covid-19 control efforts, through the sharing of such data freely by academic scientists involved in research and publication related work in publicly accessible repositories (platforms such as the Global Initiative on Sharing All Influenza Data [GISAID]) in a timely manner has been noted by de Silva and Malavige. According to S. Elbe and G. Buckland-Merrett’s “Data, disease and diplomacy: GISAID's innovative contribution to global health”, GISAID has, to date, over 1.5 million genomes deposited (21 high income countries have deposited sequences from over 5% of all reported cases), with the SARS-CoV-2 pathogen being the most sequenced. As explained by de Silva and Malavige, there are multiple ways in which viral sequencing has played a role in dealing with the Covid-19 pandemic. They emphasise that it was meta-genomic sequencing that helped identify and characterise SARS-CoV-2 as the causative agent of Covid-19, while it also paved the way for the immediate design of the first molecular diagnostic tests. With the spread of Covid-19, the genomic data were used to understand, through the field of genomic epidemiology, transmission related patterns at the local, national, and international level. This was done by using mutations occurring within the SARS-CoV-2 genome. These mutations, the duo point out, are, errors taking place during the cycle of viral replication, which in turn makes it easy to identify transmission patterns. “Establishment and lineage dynamics of the SARS-CoV-2 epidemic in the UK” by L. du Plessis, J.T. McCrone, A.E. Zarebski, V. Hill, C. Ruis, B. Gutierrez, J. Raghwani, J. Ashworth, R. Colquhoun, T.R. Connor, N.R. Faria, B. Jackson, N.J. Loman, A. O'Toole, S.M. Nicholls, K.V. Parag, E. Scher, T.I. Vasylyeva, E.M. Volz, A. Watts, I.I. Bogoch, K. Khan, the Covid-19 Genomics UK Consortium, D.M. Aanensen, M.U.G. Kraemer, A. Rambaut, and O.G. Pybus mentions that this was used to identify inter-continental spread and the importation of SARS-CoV-2 lineages into countries.  The importance of performing real time sequencing cannot be overemphasised, as the information obtained from such data can inform decisions and subsequent public health related measures taken with regard to Covid-19 control in connection with infection prevention in hospitals, and even as a guide in the case of implementing non-pharmaceutical interventions. De Silva and Malavige cited the case of the B.1.1.7 Alpha variant, first identified in the UK towards the latter part of 2020, which was found through gene sequencing to be the cause of the rapid and massive increase in infections. And as elaborated by N.G. Davies, C.I. Jarvis, the Centre for the Mathematical Modelling of Infectious Diseases Covid-19 Working Group, W.J. Edmunds, N.P. Jewell, K. Diaz-Ordaz and R.H. Keogh in “Increased mortality in community tested cases of SARS-CoV-2 lineage B.1.1.7”, the observation that a novel variant was more transmissible and potentially caused more severe disease, in turn assisted in directing decisions which called for stricter national control measures. The same is applicable in the case of the B.1.617.2 Delta variant, first identified in India, which is reported to be way more virulent than the Alpha variant. However, de Silva and Malavige also point out that the majority of the mutations in the SARS-CoV-2 genome have no functional relevance, and in this regard, cited du Plessis et al., and “Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the Covid-19 Virus” by B. Korber, W.M. Fischer, S. Gnanakaran, H. Yoon, J. Theiler, W. Abfalterer, N. Hengartner, E.E. Giorgi, T. Bhattacharya, B. Foley, K.M. Hastie, M.D. Parker, D.G. Partridge, C.M. Evans, T.M. Freeman, and T.I. de Silva, which noted that only the D614G mutation in the spike protein had been shown to result in a selective advantage for the spread of the virus during the first phase of the pandemic. de Silva and Malavige explained: “With increasing population immunity due to SARS-CoV-2 infection and vaccines, the occurrence of several spike mutations that may facilitate reduced antibody recognition have become increasingly relevant to pandemic control. Mutations demonstrated in laboratory experiments to cause reduction in neutralisation by convalescent or post-vaccine sera can be tracked as they appear in different SARS-CoV-2 lineages. The B.1.351 Beta variant appears to result in significant reduction in neutralisation titres and some reduction in clinical vaccine efficacy against infection (“Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 variant” by S.A. Madhi, V. Baillie, C.L. Cutland, M. Voysey, A.L. Koen, L. Fairlie, S.D. Padayachee, K. Dheda, S.L. Barnabas, Q.E. Bhorat, C. Briner, G. Kwatra, K. Ahmed, P. Aley, S. Bhika, J.N. Bhiman, A.E. Bhorat, J. du Plessis, A. Esmail, M. Groenewald, E. Home, S.H. Hwa, A. Jose, T. Lambe, M. Laubscher, M. Malahleha, M. Masenya, M. Masilela, S. McKenzie, K. Molapo, A. Moultrie, S. Oelofse, F. Patel, S. Pillay, S. Rhead, H. Rodel, L. Rossouw, C. Taoushanis, H. Tegally, A. Thombrayil, S.V. Eck, C.K. Wibmer, N.M. Durham, E.J. Kelley, T.L. Villafana, S. Gilbert, A.J. Pollard, T. de Oliveira, P.L. Moore, A. Sigal, A. Izu, the Network for Genomic Surveillance-South Africa Group and the Wits-VIDA Covid Group). Such variants that represent a potential threat to SARS-CoV-2 control due to an altered phenotype, which are mutations that are manifest in the form of increased transmissibility, severity, and immune escape, and impact on the performance of molecular diagnostic tests, have been defined as VOCs. While no VOC has so far been shown to significantly negate protection from a two dose vaccine course, especially against severe disease, the need for active prospective surveillance worldwide is clear".  The next aspect emphasised by de Silva and Malavige is the issue where there is significant variability in countries scientific capacity concerning the use of SARS-CoV-2 genome sequencing. They observed that the Covid-19 Genomics UK Consortium (COG-UK), which undertook large scale SARS-CoV-2 sequencing since March 2020, and has in the process harnessed the ability of public health organisations, the Wellcome Sanger Institute, and academic institutions under a decentralised model, has allowed for rapid feedback to be given on sequence data to both national public health organisations and local hospitals to aid in the control of outbreaks. At the same time, de Silva and Malavige explained that in the majority of the countries, sequencing is less systematic, with some countries having no capacity or having only the capacity to undertake sequencing in one national centre. With regard to the situation in Sri Lanka, sequencing (“Genomic and epidemiological analysis of SARS-CoV-2 Viruses in Sri Lanka” by C. Jeewandara, D. Jayathilaka, D. Ranasinghe, N.S. Hsu, D. Ariyaratne, T.T. Jayadas, D. Madushanka, B.B. Lindsey, L. Gomes, M.D. Parker, A. Wijewickrama, M. Karunaratne, G.S. Ogg, T.I. de Silva, and G.N. Malavige) found that the B.1.411 novel lineage, though not exhibiting any altered phenotype of concern, which emerged in country around late June 2020, was responsible for the wave of infections during October 2020 to January 2021. Further, a sharp rise in the number of infections and hospitalisations attributed to the Alpha variant since March 2021 has also been noted. Also, according to de Silva and Malavige, through the sequences submitted by Sri Lanka represents only 0.21% of the reported cases, currently, it is, as per them, higher than the same for others in the region including India, Nepal, and Pakistan. Therefore, de Silva and Malavige recommended the need to scale up SARS-CoV-2 sequencing, adding also that since the Delta variant is at present responsible for the majority of the infections in India, Nepal, and the Maldives, it is important that Sri Lanka too remains vigilant of this variant by way of prospective surveillance for the purpose of implementing adequate control measures.  The duo also noted the need to address inequity in vaccine rollout.  „The need to track the emergence of variants that may threaten national vaccine programmes through immune escape is vital. If there continues to be sequencing ‘blind spots’ worldwide, new VOCs will only be detected when they spill over into countries with high sequencing coverage, by which time it may be too late for effective public health measures. Scaling up sequencing programmes will require financial investment and effective planning to overcome multiple logistical challenges. To help with these processes, the World Health Organisation has produced a guide to implement SARS-CoV-2 sequencing,” de Silva and Malavige concluded.


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