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Selective adaptation of SARS-CoV-2 Omicron under booster vaccine pressure: a multicentre observational study

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Wang, Guiqing; François, Fritz; Ortigoza, Mila B; Iturrate, Eduardo; Samanovic, Marie I; Mulligan, Mark J; Heguy, Adriana
BACKGROUND:High rates of vaccination and natural infection drive immunity and redirect selective viral adaptation. Updated boosters are installed to cope with drifted viruses, yet data on adaptive evolution under increasing immune pressure in a real-world situation are lacking. METHODS:Cross-sectional study to characterise SARS-CoV-2 mutational dynamics and selective adaptation over >1 year in relation to vaccine status, viral phylogenetics, and associated clinical and demographic variables. FINDINGS/RESULTS:The study of >5400 SARS-CoV-2 infections between July 2021 and August 2022 in metropolitan New York portrayed the evolutionary transition from Delta to Omicron BA.1-BA.5 variants. Booster vaccinations were implemented during the Delta wave, yet booster breakthrough infections and SARS-CoV-2 re-infections were almost exclusive to Omicron. In adjusted logistic regression analyses, BA.1, BA.2, and BA.5 had a significant growth advantage over co-occurring lineages in the boosted population, unlike BA.2.12.1 or BA.4. Selection pressure by booster shots translated into diffuse adaptive evolution in Delta spike, contrasting with strong, receptor-binding motif-focused adaptive evolution in BA.2-BA.5 spike (Fisher Exact tests; non-synonymous/synonymous mutation rates per site). Convergent evolution has become common in Omicron, engaging spike positions crucial for immune escape, receptor binding, or cleavage. INTERPRETATION/CONCLUSIONS:Booster shots are required to cope with gaps in immunity. Their discriminative immune pressure contributes to their effectiveness but also requires monitoring of selective viral adaptation processes. Omicron BA.2 and BA.5 had a selective advantage under booster vaccination pressure, contributing to the evolution of BA.2 and BA.5 sublineages and recombinant forms that predominate in 2023. FUNDING/BACKGROUND:The study was supported by NYU institutional funds and partly by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.
PMCID:10623172
PMID: 37866115
ISSN: 2352-3964
CID: 5609742

Delta-Omicron recombinant escapes therapeutic antibody neutralization

Duerr, Ralf; Zhou, Hao; Tada, Takuya; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Wang, Guiqing; Plitnick, Jonathan; Griesemer, Sara B.; Girardin, Roxanne; Machowski, Jessica; Bialosuknia, Sean; Lasek-Nesselquist, Erica; Hong, Samuel L.; Baele, Guy; Dittmann, Meike; Ortigoza, Mila B.; Prasad, Prithiv J.; McDonough, Kathleen; Landau, Nathaniel R.; St George, Kirsten; Heguy, Adriana
The emergence of recombinant viruses is a threat to public health, as recombination may integrate variant-specific features that together result in escape from treatment or immunity. The selective advantages of recombinant SARS-CoV-2 isolates over their parental lineages remain unknown. We identified a Delta-Omicron (AY.45-BA.1) recombinant in an immunosuppressed transplant recipient treated with monoclonal antibody Sotrovimab. The single recombination breakpoint is located in the spike N-terminal domain adjacent to the Sotrovimab binding site. While Delta and BA.1 are sensitive to Sotrovimab neutralization, the Delta-Omicron recombinant is highly resistant. To our knowledge, this is the first described instance of recombination between circulating SARS-CoV-2 variants as a functional mechanism of resistance to treatment and immune escape.
SCOPUS:85148349152
ISSN: 2589-0042
CID: 5425942

Remdesivir resistance in transplant recipients with persistent COVID-19

Hogan, John I; Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Hochman, Sarah E; Mehta, Sapna; Wang, Guiqing; Heguy, Adriana
New mutations conferring resistance to SARS-CoV-2 therapeutics have important clinical implications. We describe the first cases of an independently acquired V792I RNA-dependent RNA polymerase mutation developing in renal transplant recipients after remdesivir exposure. Our work underscores the need for augmented efforts to identify concerning mutations and address their clinical implications.
PMID: 36156117
ISSN: 1537-6591
CID: 5333962

Delta-Omicron recombinant SARS-CoV-2 in a transplant patient treated with Sotrovimab [PrePrint]

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Wang, Guiqing; Plitnick, Jonathan; Griesemer, Sara B; Lasek-Nesselquist, Erica; Dittmann, Meike; Ortigoza, Mila B; Prasad, Prithiv J; St George, Kirsten; Heguy, Adriana
We identified a Delta-Omicron SARS-CoV-2 recombinant in an unvaccinated, immunosuppressed kidney transplant recipient who had positive COVID-19 tests in December 2021 and February 2022 and was initially treated with Sotrovimab. Viral sequencing in February 2022 revealed a 5' Delta AY.45 portion and a 3' Omicron BA.1 portion with a recombination breakpoint in the spike N-terminal domain, adjacent to the Sotrovimab quaternary binding site. The recombinant virus induced cytopathic effects with characteristics of both Delta (large cells) and Omicron (cell rounding/detachment). Monitoring of immunosuppressed COVID-19 patients treated with antiviral monoclonal antibodies is crucial to detect potential selection of recombinant variants.
PMCID:8996620
PMID: 35411351
ISSN: 2692-8205
CID: 5192442

Clinical and genomic signatures of SARS-CoV-2 Delta breakthrough infections in New York

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Levine, Samuel; Francois, Fritz; Iturrate, Eduardo; Wang, Guiqing; Dittmann, Meike; Lighter, Jennifer; Elbel, Brian; Troxel, Andrea B; Goldfeld, Keith S; Heguy, Adriana
BACKGROUND:In 2021, Delta became the predominant SARS-CoV-2 variant worldwide. While vaccines have effectively prevented COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occurred. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contributed to increased rates of breakthrough infections compared to unvaccinated controls. METHODS:We studied SARS-CoV-2 variant distribution, dynamics, and adaptive selection over time in relation to vaccine status, phylogenetic relatedness of viruses, full genome mutation profiles, and associated clinical and demographic parameters. FINDINGS/RESULTS:We show a steep and near-complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25 (14% in vaccinated, 7% in unvaccinated), its spike mutation S112L, and AY.44 (8% in vaccinated, 2% in unvaccinated) with its nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthrough infections increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. INTERPRETATION/CONCLUSIONS:We observed a modest adaptation of Delta genomes in breakthrough infections in New York, suggesting an improved genomic framework to support Delta's epidemic growth in times of waning vaccine protection despite limited impact on vaccine escape. FUNDING/BACKGROUND:The study was supported by NYU institutional funds. The NYULH Genome Technology Center is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.
PMCID:9323230
PMID: 35906172
ISSN: 2352-3964
CID: 5277042

Amplification Artifact in SARS-CoV-2 Omicron Sequences Carrying P681R Mutation, New York, USA

Heguy, Adriana; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Guzman, Emily; Duerr, Ralf; Wang, Guiqing; Plitnick, Jonathan; Russell, Alexis; Lamson, Daryl M; St George, Kirsten
Of 379 severe acute respiratory syndrome coronavirus 2 samples collected in New York, USA, we detected 86 Omicron variant sequences containing Delta variant mutation P681R. Probable explanations were co-infection with 2 viruses or contamination/amplification artifact. Repeated library preparation with fewer cycles showed the P681R calls were artifactual. Unusual mutations should be interpreted with caution.
PMCID:8962901
PMID: 35130474
ISSN: 1080-6059
CID: 5200142

Clinical and genomic signatures of rising SARS-CoV-2 Delta breakthrough infections in New York

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Levine, Samuel; François, Fritz; Iturrate, Eduardo; Wang, Guiqing; Dittmann, Meike; Lighter, Jennifer; Elbel, Brian; Troxel, Andrea B; Goldfeld, Keith S; Heguy, Adriana
In 2021, Delta has become the predominant SARS-CoV-2 variant worldwide. While vaccines effectively prevent COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occur. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contribute to increased rates of breakthrough infections compared to unvaccinated controls. Here, we show a steep and near complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25, its spike mutation S112L, and nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthroughs increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. Our data indicate a limited impact of vaccine escape in favor of Delta's increased epidemic growth in times of waning vaccine protection.
PMCID:8669846
PMID: 34909779
ISSN: n/a
CID: 5085062

Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Wang, Guiqing; Lighter, Jennifer; Elbel, Brian; Troxel, Andrea B; Heguy, Adriana
The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February-April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. The median age of patients in the study was 48 years; 7 required hospitalization and 1 died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in χ2 and McNemar tests (P > 0.1), highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.
PMCID:8439605
PMID: 34375308
ISSN: 1558-8238
CID: 5010772

Advanced nanomaterials for hypoxia tumor therapy: challenges and solutions

Sundaram, Aravindkumar; Peng, Ling; Chai, Luxiao; Xie, Zhongjian; Ponraj, Joice Sophia; Wang, Xiangjiang; Wang, Guiqing; Zhang, Bin; Nie, Guohui; Xie, Ni; Rajesh Kumar, Manavalan; Zhang, Han
In recent years, nanomaterials and nanotechnology have emerged as vital factors in the medical field with a unique contribution to cancer medicine. Given the increasing number of cancer patients, it is necessarily required to develop innovative strategies and therapeutic modalities to tackle hypoxia, which forms a hallmark and great barrier in treating solid tumors. The present review details the challenges in nanotechnology-based hypoxia, targeting the strategies and solutions for better therapeutic performances. The interaction between hypoxia and tumor is firstly introduced. Then, we review the recently developed engineered nanomaterials towards multimodal hypoxia tumor therapies, including chemotherapy, radiotherapy, and sonodynamic treatment. In the next part, we summarize the nanotechnology-based strategies for overcoming hypoxia problems. Finally, current challenges and future directions are proposed for successfully overcoming the hypoxia tumor problems.
PMID: 33094770
ISSN: 2040-3372
CID: 4690212

Therapeutic effect of metformin in the treatment of endometrial cancer

Mu, Nan; Xu, Tingting; Gao, Mingxiao; Dong, Mei; Tang, Qing; Hao, Li; Wang, Guiqing; Li, Zenghui; Wang, Wenshuang; Yang, Ying; Hou, Jianqing
The present review aims at reviewing the role of metformin in the treatment of endometrial cancer (EC). According to the literature, excessive estrogen levels and insulin resistance are established risk factors of EC. As a traditional insulin sensitizer and newly discovered anticancer agent, metformin directly and indirectly inhibits the development of EC. The direct mechanisms of metformin include inhibition of the LKB1-AMP-activated protein kinase-mTOR, PI3K-Akt and insulin-like growth factor 1-related signaling pathways, which reduces the proliferation and promotes the apoptosis of EC cells. In the indirect mechanism, metformin increases the insulin sensitivity of body tissues and decreases circulating insulin levels. Decreased levels of insulin increase the blood levels of sex hormone binding globulin, which leads to reductions in circulating estrogen and androgens. The aforementioned findings suggest that metformin serves an important role in the treatment of EC. Increased understanding of the mechanism of metformin in EC may provide novel insights into the treatment of this malignancy.
PMCID:7471738
PMID: 32934724
ISSN: 1792-1074
CID: 4690202