SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children

Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with increased transmissibility, combined with fluctuating mask mandates and school reopenings, has led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remain unclear. Here, we aimed to deeply profile the vaccine-induced humoral immune response in 6-to 11-year-old children receiving either a pediatric (50 mu g) or adult (100 mu g) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children who experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100-mu g dose but more variable immunity at a 50-mu g dose. Irrespective of titer, children generated antibodies with enhanced Fc receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain, but robustly preserved omicron spike protein binding. Fc receptor binding capabilities were also preserved in a dose-dependent manner. These data indicate that both the 50-and 100-mu g doses of mRNA vaccination in children elicit robust cross-VOC antibody responses and that 100-mu g doses in children result in highly preserved omicron-specific functional humoral immunity.

Immunogenicity of SARS-CoV-2 vaccines in patients with breast cancer receiving CDK 4/6 inhibitors

Background: CDK 4/6 inhibitors have transformed the landscape of breast oncology. A CDK 4/6 inhibitor in combination with endocrine therapy is recommended as 1st line therapy for patients with metastatic hormone receptor positive breast cancer. CDK 4/6 inhibitors have purported immunomodulatory effects and while effective, myelosuppression is a common adverse effect of CDK 4/6 inhibitor treatment of breast cancer. The impact of CDK 4/6 inhibitor therapy on immunogenicity of vaccines is not known. In this study, we evaluated the spike antibody response to SARS-CoV-2 vaccines among patients with breast cancer receiving endocrine therapy with or without CDK 4/6 inhibitors. Methods: In the Cancer COVID and Vaccine (CANVAX) study eligible patients included patients with breast cancer who had completed all scheduled doses of SARS-CoV-2 vaccines. Chart review was conducted to identify patients who had received endocrine therapy with or without CDK 4/6 inhibitor. We used validated assays to measure anti-SARS-CoV-2 total IgA/M/G spike antibodies and virus neutralization. We evaluated the magnitude of antibody response based on geometric mean concentrations (GMCs) as well as the % of patients with inadequate seroconversion (defined as levels <100 U/ml). Independent T-test based on log-transformed antibody values was utilized to compare the spike antibody levels and p value of ≤ 0.05 Swas considered statistically significant. Results: Between April 2021 and June 2021, 203 patients with breast cancer were enrolled. As of the cut-off date (2nd July 2021), results were available for 73 patients treated with endocrine therapy alone (N = 23), or with CDK 4/6 inhibitor-based therapy (N = 50). Most were females (98.6%), white (83.6%), and had metastatic breast cancer (68.5%). 49.3% had received BNT162b2 (Pfizer), 37% mRNA1273 (Moderna), and 13.7% Ad26.COV2.S (Johnson and Johnson/Janssen) vaccines. Overall, the mean spike antibody levels were similar between patients treated with endocrine therapy alone vs CDK 4/6 inhibitor-based therapy (GMC: 326 vs. 719 U/mL;p=0.704). Mean spike antibody levels were higher in patients with early breast cancer vs. metastatic breast cancer (GMC: 555 vs. 465 U/mL;p=0.031). However, patients who received Ad26.COV2.S had lower levels of mean spike antibody levels (GMC 47 U/ml), compared with patients treated with BNT162b2 (GMC 400 U/ml) or mRNA1273 (GMC 2203 U/mL;P<0.01 for both comparisons). Comparison of neutralization titers in 66 individuals supported the above results. 11 (15.1%) patients had low antibody titers (<100U/ml) of seroconversion and 3 received a booster vaccine, with 1 having available repeat titer results thus far demonstrating a significant improvement. Conclusions: The majority of patients receiving CDK 4/6 inhibitor have adequate antibody response to SARS-CoV-2 vaccines, particularly mRNA vaccines. However, a minority of patients may require booster vaccine to augment immunity. Monitoring spike antibody levels could be helpful to identify patients with inadequate seroconversion and guide mitigation strategies for patients with breast cancer.

Allelic variation in class I HLA determines CD8(+) T cell repertoire shape and cross-reactive memory responses to SARS-CoV-2

[Figure: see text].

The Algerian Chapter of SARS-CoV-2 Pandemic: An Evolutionary, Genetic, and Epidemiological Prospect.

To explore the SARS-CoV-2 pandemic in Algeria, a dataset comprising ninety-five genomes originating from SARS-CoV-2 sampled from Algeria and other countries worldwide, from 24 December 2019, through 4 March 2021, was thoroughly examined. While performing a multi-component analysis regarding the Algerian outbreak, the toolkit of phylogenetic, phylogeographic, haplotype, and genomic analysis were effectively implemented. We estimated the Time to the Most Recent Common Ancestor (TMRCA) in reference to the Algerian pandemic and highlighted the multiple introductions of the disease and the missing data depicted in the transmission loop. In addition, we emphasized the significant role played by local and international travels in disease dissemination. Most importantly, we unveiled mutational patterns, the effect of unique mutations on corresponding proteins, and the relatedness regarding the Algerian sequences to other sequences worldwide. Our results revealed individual amino-acid replacements such as the deleterious replacement A23T in the orf3a gene in Algeria_EPI_ISL_418241. Additionally, a connection between Algeria_EPI_ISL_420037 and sequences originating from the USA was observed through a USA characteristic amino-acid replacement T1004I in the nsp3 gene, found in the aforementioned Algerian sequence. Similarly, successful tracing could be established, such as Algeria/G37318-8849/2020|EPI_ISL_766863, which was imported from Saudi Arabia during the pilgrimage. Lastly, we assessed the Algerian mitigation measures regarding disease containment using statistical analyses.

Particle Number Emissions of a Euro 6d-Temp Gasoline Vehicle under Extreme Temperatures and Driving Conditions

With the introduction of gasoline particulate filters (GPFs), the particle number (PN) emissions of gasoline direct-injection (GDI) vehicles are below the European regulatory limit of 6 x 10(11) p/km under certification conditions. Nevertheless, concerns have been raised regarding emission levels at the boundaries of ambient and driving conditions of the real-driving emissions (RDE) regulation. A Euro 6d-Temp GDI vehicle with a GPF was tested on the road and in the laboratory with cycles simulating congested urban traffic, dynamic driving, and towing a trailer uphill at 85% of maximum payload. The ambient temperatures covered a range from -30 to 50 degrees C. The solid PN emissions were 10 times lower than the PN limit under most conditions and temperatures. Only dynamic driving that regenerated the filter passively, and for the next cycle resulted in relatively high emissions although they were still below the limit. The results of this study confirmed the effectiveness of GPFs in controlling PN emissions under a wide range of conditions.

Escape of SARS-CoV-2 501y.v2 variants from neutralization by convalescent plasma

Background: New SARS-CoV-2 variants with mutations in the spike glycoprotein have arisen independently at multiple locations and may have functional significance. The combination of mutations in the 501Y.V2 variant first detected in South Africa include the N501Y, K417N, and E484K mutations in the receptor binding domain (RBD) as well as mutations in the N-terminal domain (NTD). Here we address whether the 501Y.V2 variant could escape the neutralizing antibody response elicited by natural infection with earlier variants. Methods: We were the first to outgrow two variants of 501Y.V2 from South Africa, designated 501Y.V2.HV001 and 501Y.V2.HVdF002. We examined the neutralizing effect of convalescent plasma collected from adults hospitalized with COVID-19 using a microneutralization assay with live (authentic) virus. Whole genome sequencing of the infecting virus of the plasma donors confirmed the absence of the spike mutations which characterize 501Y.V2. We infected with 501Y.V2.HV001 and 501Y.V2.HVdF002 and compared plasma neutralization to first wave virus which contained the D614G mutation but no RBD or NTD mutations. Results: We observed a reduction in antibody activity ranging from 6-fold to knockout for the 501Y.V2 (B.1.351) relative to the B.1.1 variant derived from the first wave of the pandemic in South Africa. Conclusion: This observation indicates that 501Y.V2 may escape the neutralizing antibody response elicited by prior natural infection. It raises a concern of potential reduced protection against re-infection and by vaccines designed to target the spike protein of earlier SARS-CoV-2 variants.

Effect of An 84-bp Deletion of the Receptor-Binding Domain on the ACE2 Binding Affinity of the SARS-CoV-2 Spike Protein: An In Silico Analysis.

SARS-CoV-2 is a recently emerged, novel human coronavirus responsible for the currently ongoing COVID-19 pandemic. Recombination is a well-known evolutionary strategy of coronaviruses, which may frequently result in significant genetic alterations, such as deletions throughout the genome. In this study we identified a co-infection with two genetically different SARS-CoV-2 viruses within a single patient sample via amplicon-based next generation sequencing in Hungary. The recessive strain contained an 84 base pair deletion in the receptor binding domain of the spike protein gene and was found to be gradually displaced by a dominant non-deleterious variant over-time. We have identified the region of the receptor-binding domain (RBD) that is affected by the mutation, created homology models of the RBDΔ84 mutant, and based on the available experimental data and calculations, we propose that the mutation has a deteriorating effect on the binding of RBD to the angiotensin-converting enzyme 2 (ACE2) receptor, which results in the negative selection of this variant. Extending the sequencing capacity toward the discovery of emerging recombinant or deleterious strains may facilitate the early recognition of novel strains with altered phenotypic attributes and understanding of key elements of spike protein evolution. Such studies may greatly contribute to future therapeutic research and general understanding of genomic processes of the virus.

Multiple SARS-CoV-2 Introductions Shaped the Early Outbreak in Central Eastern Europe: Comparing Hungarian Data to a Worldwide Sequence Data-Matrix.

Severe Acute Respiratory Syndrome Coronavirus 2 is the third highly pathogenic human coronavirus in history. Since the emergence in Hubei province, China, during late 2019, the situation evolved to pandemic level. Following China, Europe was the second epicenter of the pandemic. To better comprehend the detailed founder mechanisms of the epidemic evolution in Central-Eastern Europe, particularly in Hungary, we determined the full-length SARS-CoV-2 genomes from 32 clinical samples collected from laboratory confirmed COVID-19 patients over the first month of disease in Hungary. We applied a haplotype network analysis on all available complete genomic sequences of SARS-CoV-2 from GISAID database as of 21 April 2020. We performed additional phylogenetic and phylogeographic analyses to achieve the recognition of multiple and parallel introductory events into our region. Here, we present a publicly available network imaging of the worldwide haplotype relations of SARS-CoV-2 sequences and conclude the founder mechanisms of the outbreak in Central-Eastern Europe.