Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses (preprint)

Humans display vast clinical variability upon SARS-CoV-2 infection, partly due to genetic and immunological factors. However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.

Humoral and Cellular Immunogenicity and Safety of 3 Doses of CoronaVac and BNT162b2 in Young Children and Adolescents with Kidney Diseases (preprint)

Background: Patients with kidney diseases are at risk of severe complications from COVID-19, yet little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. Methods: We investigated the immunogenicity and safety of an accelerated, 3-dose primary series of COVID-19 vaccines among 64 pediatric chronic kidney disease patients (mean age 12.2; 32 male) with or without immunosuppression, dialysis, or kidney transplant. CoronaVac was given to those aged <5 years, 0.1ml BNT162b2 to those aged 5-11 years, and 0.3ml BNT162b2 to those aged 11-18 years. Results: Antibody responses including S-RBD IgG (90.9-100% seropositive) and surrogate virus neutralization (geometric mean sVNT% level, 78.6-94.0%) were significantly elicited by 3 doses of any vaccine. T cell responses were also elicited. Weaker neutralization responses were observed among kidney transplant recipients and non-dialysis children receiving rituximab for glomerular diseases. Neutralization was reduced against Omicron BA.1 compared to wild-type (post-dose 3 sVNT% level; 84% vs 27.2%; p<0.0001). However, T cell response against Omicron BA.1 was preserved, which likely confer protection against severe COVID-19. Hybrid immunity was observed after vaccination in infected patients, as evidenced by higher Omicron BA.1 neutralization response among infected patients receiving 2 doses than those uninfected. Generally mild or moderate adverse reactions following vaccines were reported. Conclusions: Our findings support that an accelerated 3-dose primary series with CoronaVac and BNT162b2 is safe and immunogenic in young children and adolescents with kidney diseases.

Detection of a BA.1/BA.2 recombinant in travelers arriving in Hong Kong, February 2022 (preprint)

We studied SARS-CoV-2 genomes from travelers arriving in Hong Kong from November-2021 to February-2022. Apart from detecting Omicron (BA.1, BA1.1. and BA.2) and Delta variants, we detected a BA.1/BA.2 recombinant in two epidemiologically linked cases. This recombinant has a breakpoint near the 5 end of Spike gene (nucleotide position 20055-21618).

Surface-aerosol stability and pathogenicity of diverse MERS-CoV strains from 2012 - 2018 (preprint)

Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a coronavirus that infects both humans and dromedary camels and is responsible for an ongoing outbreak of severe respiratory illness in humans in the Middle East. While some mutations found in camel-derived MERS-CoV strains have been characterized, the majority of natural variation found across MERS-CoV isolates remains unstudied. Here we report on the environmental stability, replication kinetics and pathogenicity of several diverse isolates of MERS-CoV as well as SARS-CoV-2 to serve as a basis of comparison with other stability studies. While most of the MERS-CoV isolates exhibited similar stability and pathogenicity in our experiments, the camel derived isolate, C/KSA/13, exhibited reduced surface stability while another camel isolate, C/BF/15, had reduced pathogenicity in a small animal model. These results suggest that while betacoronaviruses may have similar environmental stability profiles, individual variation can influence this phenotype, underscoring the importance of continual, global viral surveillance.

Evidence of antigenic imprinting in sequential Sarbecovirus immunization (preprint)

Antigenic imprinting, which describes the bias of antibody response due to previous immune history, can influence vaccine effectiveness and has been reported in different viruses. Give that COVID-19 vaccine development is currently a major focus of the world, there is a lack of understanding of how background immunity influence antibody response to SARS-CoV-2. This study provides evidence for antigenic imprinting in Sarbecovirus, which is the subgenus that SARS-CoV-2 belongs to. Specifically, we sequentially immunized mice with two antigenically distinct Sarbecovirus strains, namely SARS-CoV and SARS-CoV-2. We found that the neutralizing antibodies triggered by the sequentially immunization are dominantly against the one that is used for priming. Given that the impact of the background immunity on COVID-19 is still unclear, our results will provide important insights into the pathogenesis of this disease as well as COVID-19 vaccination strategy.

Evaluation of a SARS-CoV-2 surrogate virus neutralization test for detection of antibody in human, canine, cat and hamster sera (preprint)

Surrogate neutralization assays for SARS-CoV-2 that can be done without biosafety-level-3 containment and across multiple species are desirable. We evaluate a recently developed surrogate virus neutralization test (sVNT) in comparison to 90% plaque reduction neutralization tests (PRNT90) in human, canine, cat and hamster sera and found excellent concordance between the two assays. Using a panel of immune sera to other coronaviruses, we confirm the lack of cross reactivity in sVNT and PRNT90 assays.

Multivariate Analyses of Codon Usage in 2019 Novel Coronavirus on the Genomic Landscape of Betacoronavirus (preprint)

Coronavirus disease 2019 (COVID-19) is a global health concern as it continues to spread within China and beyond. The causative agent of this disease, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to the genus Betacoronavirus which also includes severe acute respiratory syndrome related coronavirus (SARSr-CoV) and Middle East respiratory syndrome related coronavirus (MERSr-CoV). Codon usage of viral genes are believed to be subjected to different selection pressures in different host environments. Previous studies on codon usage of influenza A viruses can help identify viral host origins and evolution trends, however, similar studies on coronaviruses are lacking. In this study, global correspondence analysis (CA), within-group correspondence analysis (WCA) and between-group correspondence analysis (BCA) were performed among different genes in coronavirus viral sequences. The amino acid usage pattern of SARS-CoV-2 was generally found similar to bat and human SARSr-CoVs. However, we found greater synonymous codon usage differences between SARS-CoV-2 and its phylogenetic relatives on spike and membrane genes, suggesting these two genes of SARS-CoV-2 are subjected to different evolutionary pressures.