ABSTRACT
Due to the proliferation of new SARS-CoV-2 variants, most COVID-19 cases are now caused by post-vaccine infections and a substantial proportion are reinfections. While prior research on correlates of protection has focused on the role of anti-spike antibodies, the results of the corresponding antibody assays may not accurately predict the risk of infection with new SARS-CoV-2 variants. In this study, we investigated the association between live virus neutralising antibody activity and SARS-CoV-2 infection risk using self-administered capillary microsample blood tests from VirusWatch participants. The study was conducted during the transition between the dominance of the B.1.617.2 (Delta) and B.1.1.529 (Omicron BA.1) SARS-CoV-2 variants, enabling us to investigate the association between variant-specific virus inhibition and subsequent infections within each dominance period. Greater inhibition of Omicron BA.1 live virus was associated with a reduction in infection risk during both the Delta and Omicron BA.1 dominance periods. Delta virus inhibition was associated with infection risk reduction during the Delta dominance period, but we found no association between Delta inhibition and protection against infection during the Omicron BA.1 dominance period. Our results are consistent with earlier findings and suggest that variant-specific serosurveillance of immunity and protection against SARS-CoV-2 infection at the population level could inform public health policy in near-real time using inexpensive and accessible home-based testing.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
We analyzed the dynamics of the earliest T cell response to SARS-COV-2. A wave of TCRs strongly but transiently expand during infection, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Most epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains, but not with circulating human coronaviruses. Many expanding CDR3s were also present at high precursor frequency in pre-pandemic TCR repertoires. A similar set of early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the pre-infection naive repertoire. High frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection.
Subject(s)
Virus Diseases , Lymphocytic ChoriomeningitisABSTRACT
SARS-CoV-2, the agent of the COVID-19 pandemic, can infect a wide range of mammals. Since its spread in humans, secondary host jumps of SARS-CoV-2 from humans to a variety of domestic and wild populations of mammals have been documented. The evolution of SARS-CoV-2 in different host species is of fundamental interest while also providing indication of how SARS-CoV-2 may have adapted to human hosts soon after the initial host jump, a time window for which there are no genome sequences available. Moreover, the study of SARS-CoV-2 circulating in animals is critical to assess the risk that the transmission of animal-adapted viral lineages back into humans (i.e., spillback) may pose. Here, we compared the genomic landscapes of SARS-CoV-2 isolated from animal species relative to that in humans, profiling the mutational biases indicative of potentially different selective pressures in animals. We focused on viral genomes collected in infected mink (Neovison vison) and white-tailed deer (Odocoileus virginianus) for which reports of multiple independent spillover events and subsequent animal-to-animal transmission are available. We identified six candidate mutations for animal-specific adaptation in mink (NSP9_G37E, Spike_F486L, Spike_N501T, Spike_Y453F, ORF3a_T229I, ORF3a_L219V), and one in deer (NSP3a_L1035F), though these mutations appear to confer minimal advantage for circulation in humans. Additionally, circulation of SARS-CoV-2 in mink and deer has not caused considerable changes to the evolutionary trajectory of SARS-CoV-2 thus far. Finally, our results suggest that minimal adaptation was required for human-to-animal spillover and subsequent onward transmission in mink and deer, highlighting the ‘generalist’ nature of SARS-CoV-2 as a pathogen of mammalian hosts.
Subject(s)
COVID-19ABSTRACT
Individuals with likely exposure to the highly infectious SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-5. We hypothesised that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-26-12, would expand in vivo to mediate rapid viral control, potentially aborting infection. We studied T cells against the replication transcription complex (RTC) of SARS-CoV-2 since this is transcribed first in the viral life cycle13-15 and should be highly conserved. We measured SARS-CoV-2-reactive T cells in a cohort of intensively monitored healthcare workers (HCW) who remained repeatedly negative by PCR, antibody binding, and neutralisation for SARS-CoV-2 (exposed seronegative, ES). 16-weeks post-recruitment, ES had memory T cells that were stronger and more multispecific than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). The postulate that HCW with the strongest RTC-specific T cells had an abortive infection was supported by a low-level increase in IFI27 transcript, a robust early innate signature of SARS-CoV-2 infection16. We showed that the RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and was preferentially targeted by T cells from UK and Singapore pre-pandemic cohorts and from ES. RTC epitope-specific T cells capable of cross-recognising HCoV variants were identified in ES. Longitudinal samples from ES and an additional validation cohort, showed pre-existing RNA-polymerase-specific T cells expanded in vivo following SARS-CoV-2 exposure, becoming enriched in the memory response of those with abortive compared to overt infection. In summary, we provide evidence of abortive seronegative SARS-CoV-2 infection with expansion of cross-reactive RTC-specific T cells, highlighting these highly conserved proteins as targets for future vaccines against endemic and emerging Coronaviridae.
Subject(s)
COVID-19 , Abortion, SepticABSTRACT
The COVID-19 pandemic has led to an unprecedented global sequencing effort of its viral agent SARS-CoV-2. The first whole genome assembly of SARS-CoV-2 was published on January 5 2020. Since then, over 150,000 high-quality SARS-CoV-2 genomes have been made available. This large genomic resource has allowed tracing of the emergence and spread of mutations and phylogenetic reconstruction of SARS-CoV-2 lineages in near real time. Though, whether SARS-CoV-2 undergoes genetic recombination has been largely overlooked to date. Recombination-mediated rearrangement of variants that arose independently can be of major evolutionary importance. Moreover, the absence of recombination is a key assumption behind the application of phylogenetic inference methods. Here, we analyse the extant genomic diversity of SARS-CoV-2 and show that, to date, there is no detectable hallmark of recombination. We assess our detection power using simulations and validate our method on the related MERS-CoV for which we report evidence for widespread genetic recombination.
Subject(s)
COVID-19ABSTRACT
COVID-19 (Coronavirus disease 2019) is an emerging pneumonia-like respiratory disease of humans and is recently spreading across the globe. To analyze the genome sequence of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) isolated from Rwanda with other viral strains from African countries. We downloaded 75 genomes sequences of clinical SARS-CoV-2 from the GISAID (global initiative on sharing all influenza data) database and we comprehensively analyzed these SARS-CoV-2 genomes sequences alongside with Wuhan SARS-CoV-2 sequences as the reference strains. We analyzed 75 genomes sequences of SARS-CoV-2 isolated in different African countries including 10 samples of SARS-CoV-2 isolated in Rwanda between July and August 2020. The phylogenetic analysis of the genome sequence of SARS-CoV-2 revealed a strong identity with reference strains between 90-95%. We identified a missense mutation in four proteins including orf1ab polyprotein, NSP2, 2'-O-ribose methyltransferase and orf1a polyprotein. The most common changes in the base are C > T. We also found that all clinically SARS-CoV-2 isolated from Rwanda had genomes belonging to clade G and lineage B.1. Tracking the genetic evolution of SARS-CoV-2 over time is important to understand viral evolution pathogenesis. These findings may help to implement public health measures in curbing COVID-19 in Rwanda.
Subject(s)
Coronavirus Infections , Pneumonia , Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
Abstract: Previously, we have demonstrated that ACIS KEPTIDE, a chemically modified peptide, selectively binds to ACE-2 receptor and prevents the entry of SARS-CoV2 virions in vitro in primate kidney Cells. However, it is not known if ACIS KEPTIDE attenuates the entry of SARS-CoV2 virus in vivo in lung and kidney tissues, protects health, and prevent death once applied through intranasal route. In our current manuscript, we demonstrated that the intranasal administration of SARS-CoV2 (1*106) strongly induced the expression of ACE-2, promoted the entry of virions into the lung and kidney cells, caused acute histopathological toxicities, and mortality (28%). Interestingly, thirty-minutes of pre-treatment with 50 g/Kg Body weight ACIS normalized the expression of ACE-2 via receptor internalization, strongly mitigated that viral entry, and prevented mortality suggesting its prospect as a prophylactic therapy in the treatment of COVID-19. On the contrary, the peptide backbone of ACIS was unable to normalize the expression of ACE-2, failed to improve the health vital signs and histopathological abnormalities. In summary, our results suggest that ACIS is a potential vaccine-alternative, prophylactic agent that prevents entry of SARS-CoV2 in vivo, significantly improves respiratory health and also dramatically prevents acute mortality in K18-hACE2 humanized mice.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , COVID-19ABSTRACT
Severe acute respiratory coronavirus 2 (SARS-CoV-2), the agent of the ongoing COVID-19 pandemic, jumped into humans from an unknown animal reservoir in late 2019. In line with other coronaviruses, SARS-CoV-2 has the potential to infect a broad range of hosts. SARS-CoV-2 genomes have now been isolated from cats, dogs, lions, tigers and minks. SARS-CoV-2 seems to transmit particularly well in mink farms with outbreaks reported in Spain, Sweden, the Netherlands, Italy, the USA and Denmark. Genomic data from SARS-CoV-2 isolated from infected minks provides a natural case study of a secondary host jump of the virus, in this case from humans to animals, and occasionally back again. We screened published SARS-CoV-2 genomes isolated from minks for the presence of recurrent mutations common in mink but infrequent in SARS-CoV-2 genomes from human infections. We identify 23 recurrent mutations including three nonsynonymous mutations in the Receptor Binding Domain of the SARS-CoV-2 spike protein that independently emerged at least four times but are only very rarely observed in strains circulating in humans. The repeat emergence of mutations across phylogenetically distinct lineages of the virus isolated from minks points to ongoing adaptation of SARS-CoV-2 to a new host. The rapid acquisition and spread of SARS-CoV-2 mutations in minks suggests that if a similar phenomenon of host adaptation had occurred upon its jump into humans, those human-specific mutations would likely have reached fixation already before the first SARS-CoV-2 genomes were generated.
Subject(s)
Coronavirus Infections , COVID-19ABSTRACT
The current SARS-CoV-2 pandemic has emphasized the vulnerability of human populations to novel viral pressures, despite the vast array of epidemiological and biomedical tools now available. Notably, modern human genomes contain evolutionary information tracing back tens of thousands of years, which may help identify the viruses that have impacted our ancestors - pointing to which viruses have future pandemic potential. Here, we apply evolutionary analyses to human genomic datasets to recover selection events involving tens of human genes that interact with coronaviruses, including SARS-CoV-2, that started 25,000 years ago. These adaptive events were limited to ancestral East Asian populations, the geographical origin of several modern coronavirus epidemics. An arms race with an ancient corona-like virus may thus have taken place in ancestral East Asian populations. By learning more about our ancient viral foes, our study highlights the promise of evolutionary information to combat the pandemics of the future.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for the COVID-19 pandemic, continues to cause significant public health burden and disruption globally. Genomic epidemiology approaches point to most countries in the world having experienced many independent introductions of SARS-CoV-2 during the early stages of the pandemic. However, this situation may change with local lockdown policies and restrictions on travel leading to the emergence of more geographically structured viral populations and lineages transmitting locally. Here, we report the first SARS-CoV-2 genomes from Palestine sampled from early March, when the first cases were observed, through to August of 2020. SARS-CoV-2 genomes from Palestine fall across the diversity of the global phylogeny, consistent with at least nine independent introductions into the region. We identify one locally predominant lineage in circulation represented by 50 Palestinian SARS-CoV-2, grouping with isolated viral samples from patients in Israel and the UK. We estimate the age of introduction of this lineage to 05/02/2020 (16/01/2020 - 19/02/2020), suggesting SARS-CoV-2 was already in circulation in Palestine predating its first detection in Bethlehem in early March. Our work highlights the value of ongoing genomic surveillance and monitoring to reconstruct the epidemiology of COVID-19 at both local and global scales.
Subject(s)
COVID-19ABSTRACT
Motivation: Danchin et al. have pointed out that cytosine drives the evolution of SARS-CoV-2. A depletion of cytosine might lead to the attenuation of SARS-CoV-2. Results: We built a website to track the composition change of mono-, di-, and tri-nucleotide of SARS- CoV-2 over time. The website downloads new strains available from GISAID and updates its results daily. Our analysis suggests that the composition of cytosine in coronaviruses is related to their reported mortality. Using 137,315 SARS-CoV-2 strains collected in ten months, we observed cytosine depletion at a rate of about one cytosine loss per month from the whole genome. Availability: The website is available at http://www.bio8.cs.hku.hk/sarscov2/.
ABSTRACT
The COVID-19 pandemic is caused by the coronavirus SARS-CoV-2, which jumped into the human population in late 2019 from a currently uncharacterised reservoir. Due to this extremely recent association with humans, SARS-CoV-2 may not yet be fully adapted to its human host. This has led to speculations that some lineages of SARS-CoV-2 may be evolving towards higher transmissibility. The most plausible candidate mutations under putative natural selection are those which have emerged repeatedly and independently (homoplasies). Here, we formally test whether any of the recurrent mutations that have been observed in SARS-CoV-2 to date are significantly associated with increased viral transmission. To do so, we developed a phylogenetic index to quantify the relative number of descendants in sister clades with and without a specific allele. We apply this index to a carefully curated set of recurrent mutations identified within a dataset of over 23,000 SARS-CoV-2 genomes isolated from patients worldwide. We do not identify a single recurrent mutation in this set convincingly associated with increased viral transmission. Instead, recurrent SARS-CoV-2 mutations currently in circulation appear to be evolutionary neutral. Recurrent mutations also seem primarily induced by the human immune system via host RNA editing, rather than being signatures of adaption to the novel human host. We find no evidence at this stage for the emergence of more transmissible lineages of SARS-CoV-2 due to recurrent mutations.