Interim Report of the Reactogenicity and Immunogenicity of Severe Acute Respiratory Syndrome Coronavirus 2 XBB-Containing Vaccines.

BACKGROUND: Monovalent Omicron XBB.1.5-containing vaccines were approved for coronavirus disease 2019 (COVID-19) 2023-2024 immunizations. METHODS: This ongoing, open-label, phase 2/3 study evaluated messenger RNA (mRNA)-1273.815 monovalent (50-µg Omicron XBB.1.5 spike mRNA) and mRNA-1273.231 bivalent (25-µg each Omicron XBB.1.5 and BA.4/BA.5 spike mRNAs) vaccines, administered as fifth doses to adults who previously received primary series, third doses of an original mRNA COVID-19 vaccine, and fourth doses of an Omicron BA.4/BA.5 bivalent vaccine. Interim safety and immunogenicity 29 days after vaccination are reported. RESULTS: Participants (randomized 1:1) received 50-µg of mRNA-1273.815 (n = 50) or mRNA-1273.231 (n = 51); median intervals (interquartile range) from prior BA.4/BA.5 bivalent doses were 8.2 (8.1-8.3) and 8.3 (8.1-8.4) months, respectively. Fold increases in neutralizing antibody (nAb) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants from prebooster nAb levels were numerically higher against XBB.1.5, XBB.1.16, EG.5.1, BA.2.86, and JN.1 than BA.4/BA.5, BQ.1.1, or D614G on day 29. Monovalent vaccine also cross-neutralized FL.1.5.1, EG.5.1, BA.2.86, HK.3.1, HV.1, and JN.1 variants in a participant subset (n = 20) 15 days after vaccination. Reactogenicity was similar to that of mRNA-1273 vaccines. CONCLUSIONS: XBB.1.5-containing mRNA-1273 vaccines elicit robust, diverse nAb responses against more recent SARS-CoV-2 variants, including JN.1, supporting the XBB.1.5-spike update for COVID-19 vaccines.

Protection of the receptor binding domain (RBD) dimer against SARS-CoV-2 and its variants.

IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants achieved immune escape and became less virulent and easily transmissible through rapid mutation in the spike protein, thus the efficacy of vaccines on the market or in development continues to be challenged. Updating the vaccine, exploring compromise vaccination strategies, and evaluating the efficacy of candidate vaccines for the emerging variants in a timely manner are important to combat complex and volatile SARS-CoV-2. This study reports that vaccines prepared from the dimeric receptor-binding domain (RBD) recombinant protein, which can be quickly produced using a mature and stable process platform, had both good immunogenicity and protection in vivo and could completely protect rodents from lethal challenge by SARS-CoV-2 and its variants, including the emerging Omicron XBB.1.16, highlighting the value of dimeric recombinant vaccines in the post-COVID-19 era.

Epidemiological characteristics and antibody kinetics of elderly population with booster vaccination following both Omicron BA.5 and XBB waves in China.

After the termination of zero-COVID-19 policy, the populace in China has experienced both Omicron BA.5 and XBB waves. Considering the poor antibody responses and severe outcomes observed among the elderly following infection, we conducted a longitudinal investigation to examine the epidemiological characteristics and antibody kinetics among 107 boosted elderly participants following the Omicron BA.5 and XBB waves. We observed that 96 participants (89.7%) were infected with Omicron BA.5, while 59 (55.1%) participants were infected with Omicron XBB. Notably, 52 participants (48.6%) experienced dual infections of both Omicron BA.5 and XBB. The proportion of symptomatic cases appeared to decrease following the XBB wave (18.6%) compared to that after the BA.5 wave (59.3%). Omicron BA.5 breakthrough infection induced lower neutralizing antibody titers against XBB.1.5, BA.2.86, and JN.1, while reinfection with Omicron XBB broadened the antibody responses against all measured Omicron subvariants and may alleviate the wild type-vaccination induced immune imprinting. Boosted vaccination type and comorbidities were the significant factors associated with antibody responses. Updated vaccines based on emerging severe acute respiratory syndrome coronavirus 2 variants are needed to control the Coronavirus Disease 2019 pandemic in the elderly.

Marine sulfated glycans inhibit the interaction of heparin with S-protein of SARS-CoV-2 Omicron XBB variant.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide COVID-19 pandemic, leading to 6.8 million deaths. Numerous variants have emerged since its outbreak, resulting in its significantly enhanced ability to spread among humans. As with many other viruses, SARS­CoV­2 utilizes heparan sulfate (HS) glycosaminoglycan (GAG) on the surface of host cells to facilitate viral attachment and initiate cellular entry through the ACE2 receptor. Therefore, interfering with virion-HS interactions represents a promising target to develop broad-spectrum antiviral therapeutics. Sulfated glycans derived from marine organisms have been proven to be exceptional reservoirs of naturally existing HS mimetics, which exhibit remarkable therapeutic properties encompassing antiviral/microbial, antitumor, anticoagulant, and anti-inflammatory activities. In the current study, the interactions between the receptor-binding domain (RBD) of S-protein of SARS-CoV-2 (both WT and XBB.1.5 variants) and heparin were applied to assess the inhibitory activity of 10 marine-sourced glycans including three sulfated fucans, three fucosylated chondroitin sulfates and two fucoidans derived from sea cucumbers, sea urchin and seaweed Saccharina japonica, respectively. The inhibitory activity of these marine derived sulfated glycans on the interactions between RBD of S-protein and heparin was evaluated using Surface Plasmon Resonance (SPR). The RBDs of S-proteins from both Omicrion XBB.1.5 and wild-type (WT) were found to bind to heparin, which is a highly sulfated form of HS. All the tested marine-sourced sulfated glycans exhibited strong inhibition of WT and XBB.1.5 S-protein binding to heparin. We believe the study on the molecular interactions between S-proteins and host cell glycosaminoglycans provides valuable insight for the development of marine-sourced, glycan-based inhibitors as potential anti-SARS-CoV-2 agents.

COVID-19 prophylaxis, diagnostics, and treatment in patients with rheumatic diseases. The Polish experts panel opinion.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves, infection management in vulnerable populations requires formalized guidance. Although low-virulence variants of SARS-CoV-2 remain predominant, they pose an increased risk of severe illness in adults with rheumatic and musculoskeletal diseases (RMDs). Several disease-specific (chronic long-grade inflammation, concomitant immunosuppression) and individual (advanced age, multimorbidity, pregnancy, vaccination status) factors contribute to excess risk in RMD populations. Various post-COVID-19 manifestations are also increasingly reported and appear more commonly than in the general population. At a pathogenetic level, complex interplay involving innate and acquired immune dysregulation, viral persistence, and genetic predisposition shapes a unique susceptibility profile. Moreover, incident cases of SARS-CoV-2 infection as a trigger factor for the development of autoimmune conditions have been reported. Vaccination remains a key preventive strategy, and encouraging active education and awareness will be crucial for rheumatologists in the upcoming years. In patients with RMDs, COVID-19 vaccines' benefits outweigh the risks. Derivation of specialized diagnostic and therapeutic protocols within a comprehensive COVID-19 care plan represents an ideal scenario for healthcare system organization. Vigilance for symptoms of infection and rapid diagnosis are key for introducing antiviral treatment in patients with RMDs in a timely manner. This review provides updated guidance on optimal immunization, diagnosis, and antiviral treatment strategies.

SARS-CoV-2 Omicron XBB subvariants exhibit enhanced fusogenicity and substantial immune evasion in elderly population, but high sensitivity to pan-coronavirus fusion inhibitors.

Numerous emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants have shown significant immune evasion capacity and caused a large number of infections, as well as vaccine-breakthrough infections, especially in elderly populations. Recently emerged Omicron XBB was derived from the BA.2 lineage, but bears a distinct mutant profile in its spike (S) protein. In this study, we found that Omicron XBB S protein drove more efficient membrane-fusion kinetics on human lung-derived cells (Calu-3). Considering the high susceptibility of the elderly to the current Omicron pandemic, we performed a comprehensive neutralization assessment of elderly convalescent or vaccine sera against XBB infection. We found that the sera from elderly convalescent patients who experienced with BA.2 infection or breakthrough infection potently inhibited BA.2 infection, but showed significantly reduced efficacy against XBB. Moreover, recently emerged XBB.1.5 subvariant also showed more significant resistance to the convalescent sera of BA.2- or BA.5-infected elderly. On the other hand, we found that the pan-CoV fusion inhibitors EK1 and EK1C4 can potently block either XBB-S- or XBB.1.5-S-mediated fusion process and viral entry. Moreover, EK1 fusion inhibitor showed potent synergism when combined with convalescent sera of BA.2- or BA.5-infected patients against XBB and XBB.1.5 infection, further indicating that EK1-based pan-CoV fusion inhibitors are promising candidates for development as clinical antiviral agents to combat the Omicron XBB subvariants.

Relative effectiveness of bivalent Original/Omicron BA.4-5 mRNA vaccine in preventing severe COVID-19 in persons 60 years and above during SARS-CoV-2 Omicron XBB.1.5 and other XBB sublineages circulation, Italy, April to June 2023.

During predominant circulation of SARS-CoV-2 Omicron XBB.1.5 and other XBB sublineages (April-June 2023), we found that a second or third booster of Comirnaty bivalent Original/Omicron BA.4-5 mRNA vaccine, versus a first booster received at least 120 days earlier, was effective in preventing severe COVID-19 for more than 6 months post-administration in persons 60 years and above. In view of autumn 2023 vaccination campaigns, use of bivalent Original/Omicron BA.4-5 mRNA vaccines might be warranted until monovalent COVID-19 vaccines targeting Omicron XBB.1 sublineages become available.

Long-Term Immunity against SARS-CoV-2 Wild-Type and Omicron XBB.1.5 in Indonesian Residents after Vaccination and Infection.

In the post-pandemic era, evaluating long-term immunity against COVID-19 has become increasingly critical, particularly in light of continuous SARS-CoV-2 mutations. This study aimed to assess the long-term humoral immune response in sera collected in Makassar. We measured anti-RBD IgG levels and neutralization capacity (NC) against both the Wild-Type (WT) Wuhan-Hu and Omicron XBB.1.5 variants across groups of COVID-19-vaccinated individuals with no booster (NB), single booster (SB), and double booster (DB). The mean durations since the last vaccination were 25.11 months, 19.24 months, and 16.9 months for the NB, SB, and DB group, respectively. Additionally, we evaluated the effect of breakthrough infection (BTI) history, with a mean duration since the last confirmed infection of 21.72 months. Our findings indicate fair long-term WT antibody (Ab) titers, with the DB group showing a significantly higher level than the other groups. Similarly, the DB group demonstrated the highest anti-Omicron XBB.1.5 Ab titer, yet it was insignificantly different from the other groups. Although the level of anti-WT Ab titers was moderate, we observed near-complete (96-97%) long-term neutralization against the WT pseudo-virus for all groups. There was a slight decrease in NC against Omicron XBB.1.5 compared to the WT among all groups, as DB group, SB group, and NB group showed 80.71 ± 3.9%, 74.29 ± 6.7%, and 67.2 ± 6.3% neutralization activity, respectively. A breakdown analysis based on infection and vaccine status showed that booster doses increase the NC against XBB.1.5, particularly in individuals without BTI. Individuals with BTI demonstrate a better NC compared to their counterpart uninfected individuals with the same number of booster doses. Our findings suggest that long-term immunity against SARS-CoV-2 persists and is effective against the mutant variant. Booster doses enhance the NC, especially among uninfected individuals.

Differentiating Cell Entry Potentials of SARS-CoV-2 Omicron Subvariants on Human Lung Epithelium Cells.

The surface spike (S) glycoprotein mediates cell entry of SARS-CoV-2 into the host through fusion at the plasma membrane or endocytosis. Omicron lineages/sublineages have acquired extensive mutations in S to gain transmissibility advantages and altered antigenicity. The fusogenicity, antigenicity, and evasion of Omicron subvariants have been extensively investigated at unprecedented speed to align with the mutation rate of S. Cells that overexpress receptors/cofactors are mostly used as hosts to amplify infection sensitivity to tested variants. However, systematic cell entry comparisons of most prior dominant Omicron subvariants using human lung epithelium cells are yet to be well-studied. Here, with human bronchial epithelium BEAS-2B cells as the host, we compared single-round virus-to-cell entry and cell-to-cell fusion of Omicron BA.1, BA.5, BQ.1.1, CH.1.1, XBB.1.5, and XBB.1.16 based upon split NanoLuc fusion readout assays and the S-pseudotyped lentivirus system. Virus-to-cell entry of tested S variants exhibited cell-type dependence. The parental Omicron BA.1 required more time to develop full entry to HEK293T-ACE2-TMPRSS2 than BEAS-2B cells. Compared to unchanged P681, S-cleavage constructs of P681H/R did not have any noticeable advantages in cell entry. Omicron BA.1 and its descendants entered BEAS-2B cells more efficiently than D614G, and it was slightly less or comparable to that of Delta. Serine protease-pretreated Omicron subvariants enhanced virus-to-cell entry in a dose-dependent manner, suggesting fusion at the plasma membrane persists as a productive cell entry route. Spike-mediated cell-to-cell fusion and total S1/S2 processing of Omicron descendants were similar. Our results indicate no obvious entry or fusion advantages of recent Omicron descendants over preceding variants since Delta, thus supporting immune evasion conferred by antigenicity shifts due to altered S sequences as probably the primary viral fitness driver.

Dynamic changes of neutralizing antibody and memory T cell responses six months post Omicron XBB reinfection.

Introduction: With the continued prevalence of COVID-19, repeated infection caused by SARS-CoV-2 has become common. However, studies on immune persistence post Omicron XBB reinfection are limited. Methods: We prospectively studied the durability and cross-reactivity of neutralizing antibodies (NAbs) and T cell responses among 20 subjects who suffered Omicron BA.5 infection with or without Omicron XBB reinfection over 6-month through the pseudovirus neutralization test and the fluorospot assay. Results: NAbs against EG.5.1, BA.2.86, and JN.1 subvariants were decreased and undetectable at 6-month post Omicron BA.5 infection, while those elicited by Omicron XBB reinfection were significant increased and remained detectable against all detected variants within 6-month. Furthermore, in subjects with Omicron XBB reinfection, memory T cell responses could cross-recognized wild-type and Omicron spike peptides and reached peak at 3-month. Interestingly, comparable robust T cell responses were observed among non-seroconverted subjects post Omicron XBB exposure. Conclusion: Though the NAbs against various emerging Omicron subvariants elicited by Omicron XBB reinfection can persist for at least 6-month, the HCWs should strengthen personal protection and timely be immunized with updated vaccines upon current circulating variants or conserved T epitope.

Analysis of B-cell receptor repertoire to evaluate immunogenicity of monovalent Omicron XBB.1.5 mRNA vaccines.

Monovalent Omicron XBB.1.5 mRNA vaccines were newly developed and approved by the FDA in Autumn 2023 for preventing COVID-19. However, clinical efficacy for these vaccines is currently lacking. We previously established the quantification of antigen-specific antibody sequence (QASAS) method to assess the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the coronavirus antibody database (CoV-AbDab). Here, we used this method to evaluate the immunogenicity of monovalent XBB.1.5 vaccines. We analyzed repeated blood samples of healthy volunteers before and after monovalent XBB.1.5 vaccination (BNT162b2 XBB.1.5 or mRNA-1273.815) for the BCR repertoire to assess BCR/antibody sequences that matched SARS-CoV-2-specific sequences in the database. The number of matched unique sequences and their total reads quickly increased 1 week after vaccination. Matched sequences included those bound to the Omicron strain and Omicron XBB sublineage. The antibody sequences that can bind to the Omicron strain and XBB sublineage revealed that the monovalent XBB.1.5 vaccines showed a stronger response than previous vaccines or SARS-CoV-2 infection before the emergence of XBB sublineage. The QASAS method was able to demonstrate the immunogenic effect of monovalent XBB.1.5 vaccines for the 2023-2024 COVID-19 vaccination campaign.

The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease.

Introduction: The severity of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often dictated by a range of comorbidities. A considerable literature suggests iron deficiency and iron overload may contribute to increased infection, inflammation and disease severity, although direct causal relationships have been difficult to establish. Methods: Here we generate iron deficient and iron loaded C57BL/6 J mice by feeding standard low and high iron diets, with mice on a normal iron diet representing controls. All mice were infected with a primary SARS-CoV-2 omicron XBB isolate and lung inflammatory responses were analyzed by histology, immunohistochemistry and RNA-Seq. Results: Compared with controls, iron deficient mice showed no significant changes in lung viral loads or histopathology, whereas, iron loaded mice showed slightly, but significantly, reduced lung viral loads and histopathology. Transcriptional changes were modest, but illustrated widespread dysregulation of inflammation signatures for both iron deficient vs. controls, and iron loaded vs. controls. Some of these changes could be associated with detrimental outcomes, whereas others would be viewed as beneficial. Discussion: Diet-associated iron deficiency or overload thus induced modest modulations of inflammatory signatures, but no significant histopathologically detectable disease exacerbations.

Efficacy, immunogenicity, and safety of a monovalent mRNA vaccine, ABO1020, in adults: A randomized, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ABO1020 is a monovalent COVID-19 mRNA vaccine. Results from a phase 1 trial showed ABO1020 was safe and well tolerated, and phase 3 trials to evaluate the efficacy, immunogenicity, and safety of ABO1020 in healthy adults are urgently needed. METHODS: We conducted a multinational, randomized, placebo-controlled, double-blind, phase 3 trial among healthy adults (ClinicalTrials.gov: NCT05636319). Participants were randomly assigned (1:1) to receive either 2 doses of ABO1020 (15 µg per dose) or placebo, administered 28 days apart. The primary endpoint was the vaccine efficacy in preventing symptomatic COVID-19 cases that occurred at least 14 days post-full vaccination. The second endpoint included the neutralizing antibody titers against Omicron BA.5 and XBB and safety assessments. FINDINGS: A total of 14,138 participants were randomly assigned to receive either vaccine or placebo (7,069 participants in each group). A total of 366 symptomatic COVID-19 cases were confirmed 14 days after the second dose among 93 participants in the ABO1020 group and 273 participants in the placebo group, yielding a vaccine efficacy of 66.18% (95% confidence interval: 57.21-73.27, p < 0.0001). A single dose or two doses of ABO1020 elicited potent neutralizing antibodies against both BA.5 and XBB.1.5. The safety profile of ABO1020 was characterized by transient, mild-to-moderate fever, pain at the injection site, and headache. CONCLUSION: ABO1020 was well tolerated and conferred 66.18% protection against symptomatic COVID-19 in adults. FUNDING: National Key Research and Development Project of China, Innovation Fund for Medical Sciences from the CAMS, National Natural Science Foundation of China.

An updated review of epidemiological characteristics, immune escape, and therapeutic advances of SARS-CoV-2 Omicron XBB.1.5 and other mutants.

The rapid evolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the emergence of new variants with different genetic profiles, with important implications for public health. The continued emergence of new variants with unique genetic features and potential changes in biological properties poses significant challenges to public health strategies, vaccine development, and therapeutic interventions. Omicron variants have attracted particular attention due to their rapid spread and numerous mutations in key viral proteins. This review aims to provide an updated and comprehensive assessment of the epidemiological characteristics, immune escape potential, and therapeutic advances of the SARS-CoV-2 Omicron XBB.1.5 variant, as well as other variants.

Targeted amplicon sequencing of wastewater samples for detecting SARS-CoV-2 variants with high sensitivity and resolution.

Wastewater-based epidemiology (WBE) is a promising approach for monitoring the spread of SARS-CoV-2 within communities. Although qPCR-based WBE is powerful in that it allows quick and highly sensitive detection of this virus, it can provide limited information about which variants are responsible for the overall increase or decrease of this virus in sewage, and this hinders accurate risk assessments. To resolve this problem, we developed a next generation sequencing (NGS)-based method to determine the identity and composition of individual SARS-CoV-2 variants in wastewater samples. Combination and optimization of targeted amplicon-sequencing and nested PCR allowed detection of each variant with sensitivity comparable to that of qPCR. In addition, by targeting the receptor binding domain (RBD) of the S protein, which has mutations informative for variant classification, we could discriminate most variants of concern (VOC) and even sublineages of Omicron (BA.1, BA.2, BA.4/5, BA.2.75, BQ.1.1 and XBB.1). Focusing on a limited domain has a benefit of decreasing the sequencing reads. We applied this method to wastewater samples collected from a wastewater treatment plant in Kyoto city throughout 13 months (from January 2021 to February 2022) and successfully identified lineages of wild-type, alpha, delta, omicron BA.1 and BA.2 as well as their compositions in the samples. The transition of these variants was in good agreement with the epidemic situation reported in Kyoto city during that period based on clinical testing. These data indicate that our NGS-based method is useful for detecting and tracking emerging variants of SARS-CoV-2 in sewage samples. Coupled with the advantages of WBE, this method has the potential to serve as an efficient and low cost means for the community risk assessment of SARS-CoV-2 infection.