key: cord-0982109-yhn63dhb
authors: Malick, M. Shaheen S.; Fernandes, Helen
title: The Genomic Landscape of SARS-CoV-2: Surveillance of Variants of Concern
date: 2021-07-08
journal: Advances in Molecular Pathology
DOI: 10.1016/j.yamp.2021.06.006
sha: a50b7efcc09bd4a072568e329fee1a04af9878a3
doc_id: 982109
cord_uid: yhn63dhb

Novel mutations that drive the evolution of SARS-CoV-2 variants, are constantly emerging. Given the acquired mutations of some of these variants compared to wild-type virus, identifying and monitoring variants through sequence-based surveillance is essential to control their spread. Prompt stratification of new variants into level of concern based on the mutational signatures, is important for understanding their response to current therapeutics and vaccines. Variants of concern have increased levels of infectivity, pathogenicity and transmissibility that enable the spread of the virus globally. Epidemiological investigations are extremely helpful for understanding the impact of these variants on the COVID-19 pandemic. Moreover, in light of recent surges in India and Brazil, by the Delta and Gamma variants respectively despite high levels of seroprevalance , current mathematical models for herd immunity may need to be re-evaluated.

As we continue to sequence SARS-CoV-2 genomes, novel mutations that drive viral evolution are constantly emerging. Such mutations generate a rich diversity of viral strains and lineages with varying degrees of transmissibility, virulence and pathogenicity. As these variants evolve, it is essential to monitor the efficacy of current diagnostics, therapeutics, and vaccines in efforts to control their spread.

Mutations are random events that naturally occur during replication of the error-prone viral genome. The host-pathogen interaction drives the selective pressure by which variants capable of escaping aspects of the natural and, perhaps, induced immunity subsequently start to dominate the circulating pool of infecting strains. 1 variants of concern are now Alpha, Beta, Gamma and Delta respectively (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Some variants appear to have enhanced transmissibility or infectivity than the wild-type virus and other circulating strains. These acquired characteristics of the SARS CoV2 virus have been responsible for the continued surge of cases and the increased fatality in different parts of the globe ( Figure 2 ). Additionally, early clinical trials have demonstrated reduced vaccine efficacy against novel strains compared to original strain, most notable being the 501Y.V2 (B1.351) variant in South Africa. As several nations enter into a second wave of cases, reports of reinfection with the new circulating variants arise regularly, generating concern on the status of acquired immunity from prior exposure.

Variants of concern in resource limited settings:

India and Brazil represent two important locations to examine given the recent surge in cases primarily due to novel variants of concern. The B. concern as India battles this variant is despite high levels of seroprevalence, indicating prior infection, in regions such as Delhi (56%), Mumbai (up to 75%) and Hyderabad (54%) the number of cases in these cities is once again surging. 4 This pattern is not at all unique to India.

In Manaus, Brazil, a variant with an E484K substitution was associated with a recent surge in cases despite a reported seroprevalence of 76% as of October 2020. 5 An important caveat to seroprevalence studies is that detectable humoral immunity does not capture the entire scope of immunity, including T cell reactivity. However, the estimated infection rate in Manaus is above the theoretical herd immunity threshold of 67% using a case reproduction number (R0) of 3. 6 The abrupt surge in hospitalizations that hit Manaus in January 2021, followed a period during which physical distancing requirements were eased (see ref. 5). This surge that surprisingly included SARS-CoV-2 reinfection of individuals in addition to new individuals, was attributed to a novel strain containing an E484K substitution. 7 Reinfection in the city of Manaus has been associated with the P.1 lineage characterized by ten unique spike protein mutations, including E484K and N501K. 8 In one Brazilian case of re-infection 9 months after initial infection, the reinfecting virus carried all lineage-defining mutations of P.1 but 11 additional amino acid substitutions in the S-protein relative to the primary infecting virus.

Interestingly, the unique molecular signatures that characterize the novel strains appear to be responsible for the lack of protection in previously infected individuals. Variants with E484Q or E484K substitutions have been found to have reduced neutralization by protective antibodies, or are, in other words, able to escape optimal protection by humoral immunity. This has been demonstrated effectively by an international research collaboration led by the Africa Health Research Institute (Durban, South Africa). This team employed in vitro live-viral neutralization assays, with plasma from individuals infected during the country's first and second waves. They clearly demonstrated that convalescent plasma from individuals infected with wild-type virus during the first wave, was unable to neutralize the 501Y.V2 (B1.1.351) virus that was responsible for roughly 97% of cases during the second wave in South Africa. 9

Returning to the idea of herd immunity, the resurgence in Brazil and India despite a seroprevalance of >70% causes us to reconsider our current mathematical models for herd immunity. This model is represented by the equation R = (1pc)(1 -pI)R0, where R is the effective reproduction number, pc, is the relative reduction in transmission due to nonpharmaceutical measures, pI is the proportion of immune individuals, and R0 is the reproduction number in the absence of controls in a fully susceptible population. In this model, herd immunity is achieved when R < 1, hopefully indicating an end to future large outbreaks. If this model holds true then the only way to explain the surges in Brazil and India is if current seroprevalance studies no longer accurately represent the proportion of immune individuals, or pI, since seropositivity of an older strain would not represent immunity to a novel variant of concern. The other potential explanation would be if the R0 of these variants were greater than that of the prior circulating strains. Potentially both of these may be true. Whatever the explanation, given the 

Representative, quality, timely and continuous genetic surveillance of SARS-CoV-2 is critical to the COVID-19 outbreak response. In addition to acquiring information on the infectivity and virulence of the virus, quick identification genomic alterations helps to elucidate the molecular mechanisms that allow variants of concern to evade vaccine-induced immunity and/or targeted therapy. Sequencing can also potentially alert us to variants that may eventually render current diagnostic tests ineffective.

Currently there is a lack of capacity for genomic surveillance globally. Rapid progress is occurring in scaling up genomic surveillance. However, the level of surveillance has not reached the necessary breadth to track and manage the pandemic. Large numbers of samples were sequenced in the UK, the USA, Australia, and Iceland and data were shared promptly. However, data are hurdles that need to be addressed. A study published on medRxiv preprint server, has predicted that sequencing at least 5% of all cases is necessary to detect emerging variants. As of May 22, the last 7-day average reported cases was 27,789, meaning that at 750 samples per week we are below the recommended 5%. Further strengthening of the sequencing capacity at a global level would help in the fight against not only the current pandemic but also future outbreaks of viral diseases. Low-and middle-income countries some of which are even now struggling to find adequate numbers of vaccines, have an even greater deficiency in genomic surveillance. 13 The public-health mantra of the pandemic since the outset has been 'test, trace, and isolate.' As the phylogenetic tree of SARS-CoV-2 blossoms it is now abundantly clear that genomic surveillance must buttress our testing. Otherwise, we may be unsuccessful in tackling this to the best of our capacity. Perhaps the greatest aspect of human creativity is the ability to do highly impactful work with limited resources, making the best of what we have available. With J o u r n a l P r e -p r o o f The Genomic Landscape of SARS-CoV-2: Surveillance of Variants of Concern diagnostic stewardship, it is possible to scale up genomic surveillance worldwide, though we will need to be strategic about how the scarce genomic sequencing resources are utilized and shared globally. In areas where this infrastructure is limited, genomic surveillance still can and must be done, though it will need to be much more targeted. For example, in resource limited settings genomic surveillance may be limited to only patients who present with reinfections. This can then be broadened to entire geographical areas that develop surges in infection despite having reached herd immunity, or regions with unexpectedly high rates of transmission. It is also important to correlate variant and lineage details with epidemiological data to inform public health decisions. We have entered a new era in the COVID-19 pandemic. However, it may also be a promising turning point in pandemic preparedness.

1 Genomic Surveillance for SARS-CoV-2 Variants -CDC. May 17, 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance.html. Accessed May 21, 2021.

COVID-19 herd immunity: where are we?

Reinfection Involving E484K Spike Mutation, Brazil. Emerg Infect Dis

Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings

Network for Genomic Surveillance in South Africa; COMMIT-KZN Team, Lessells RJ, de Oliveira T, Sigal A. Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant

Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant

Global sequencing coverage, COVID-19 CoV Genetics, Enabled by data from GISAID

Alarming COVID variants show vital role of genomic surveillance