Vaccination-Route-Dependent Adjuvanticity of Antigen-Carrying Nanoparticles for Enhanced Vaccine Efficacy.

Vaccination-route-dependent adjuvanticity was identified as being associated with the specific features of antigen-carrying nanoparticles (NPs) in the present work. Here, we demonstrated that the mechanical properties and the decomposability of NP adjuvants play key roles in determining the antigen accessibility and thus the overall vaccine efficacy in the immune system when different vaccination routes were employed. We showed that soft nano-vaccines were associated with more efficient antigen uptake when administering subcutaneous (S.C.) vaccination, while the slow decomposition of hard nano-vaccines promoted antigen uptake when intravenous (I.V.) vaccination was employed. In comparison to the clinically used aluminum (Alum) adjuvant, the NP adjuvants were found to stimulate both humoral and cellular immune responses efficiently, irrespective of the vaccination route. For vaccination via S.C. and I.V. alike, the NP-based vaccines show excellent protection for mice from Staphylococcus aureus (S. aureus) infection, and their survival rates are 100% after lethal challenge, being much superior to the clinically used Alum adjuvant.

Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways.

Interferons (IFNs) are critical for immune defense against pathogens. While type-I and -III IFNs have been reported to inhibit SARS-CoV-2 replication, the antiviral effect and mechanism of type-II IFN against SARS-CoV-2 remain largely unknown. Here, we evaluate the antiviral activity of type-II IFN (IFNγ) using human lung epithelial cells (Calu3) and ex vivo human lung tissues. In this study, we found that IFNγ suppresses SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Moreover, IFNγ treatment does not significantly modulate the expression of SARS-CoV-2 entry-related factors and induces a similar level of pro-inflammatory response in human lung tissues when compared with IFNß treatment. Mechanistically, we show that overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts the replication of ancestral SARS-CoV-2 and the Alpha and Delta variants. Meanwhile, loss-of-function study reveals that IDO1 knockdown restores SARS-CoV-2 replication restricted by IFNγ in Calu3 cells. We further found that the treatment of l-tryptophan, a substrate of IDO1, partially rescues the IFNγ-mediated inhibitory effect on SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Collectively, these results suggest that type-II IFN potently inhibits SARS-CoV-2 replication through IDO1-mediated antiviral response.

Enhancing immune responses of ESC-based TAA cancer vaccines with a novel OMV delivery system.

Embryonic stem cell (ESC)-derived epitopes can act as therapeutic tumor vaccines against different types of tumors Jin (Adv Healthc Mater 2023). However, these epitopes have poor immunogenicity and stimulate insufficient CD8+ T cell responses, which motivated us to develop a new method to deliver and enhance their effectiveness. Bacterial outer membrane vesicles (OMVs) can serve as immunoadjuvants and act as a delivery vector for tumor antigens. In the current study, we engineered a new OMV platform for the co-delivery of ESC-derived tumor antigens and immune checkpoint inhibitors (PD-L1 antibody). An engineered Staphylococcal Protein A (SpA) was created to non-specifically bind to anti-PD-L1 antibody. SpyCatcher (SpC) and SpA were fused into the cell outer membrane protein OmpA to capture SpyTag-attached peptides and PD-L1 antibody, respectively. The modified OMV was able to efficiently conjugate with ESC-derived TAAs and PD-L1 antibody (SpC-OMVs + SpT-peptides + anti-PD-L1), increasing the residence time of TAAs in the body. The results showed that the combination therapy of ESC-based TAAs and PD-L1 antibody delivered by OMV had significant inhibitory effects in mouse tumor model. Specifically, it was effective in reducing tumor growth by enhancing IFN-γ-CD8+ T cell responses and increasing the number of CD8+ memory cells and antigen-specific T cells. Overall, the new OMV delivery system is a versatile platform that can enhance the immune responses of ESC-based TAA cancer vaccines.

Divergent trajectory of replication and intrinsic pathogenicity of SARS-CoV-2 Omicron post-BA.2/5 subvariants in the upper and lower respiratory tract.

BACKGROUND: Earlier Omicron subvariants including BA.1, BA.2, and BA.5 emerged in waves, with a subvariant replacing the previous one every few months. More recently, the post-BA.2/5 subvariants have acquired convergent substitutions in spike that facilitated their escape from humoral immunity and gained ACE2 binding capacity. However, the intrinsic pathogenicity and replication fitness of the evaluated post-BA.2/5 subvariants are not fully understood. METHODS: We systemically investigated the replication fitness and intrinsic pathogenicity of representative post-BA.2/5 subvariants (BL.1, BQ.1, BQ.1.1, XBB.1, CH.1.1, and XBB.1.5) in weanling (3-4 weeks), adult (8-10 weeks), and aged (10-12 months) mice. In addition, to better model Omicron replication in the human nasal epithelium, we further investigated the replication capacity of the post-BA.2/5 subvariants in human primary nasal epithelial cells. FINDINGS: We found that the evaluated post-BA.2/5 subvariants are consistently attenuated in mouse lungs but not in nasal turbinates when compared with their ancestral subvariants BA.2/5. Further investigations in primary human nasal epithelial cells revealed a gained replication fitness of XBB.1 and XBB.1.5 when compared to BA.2 and BA.5.2. INTERPRETATION: Our study revealed that the post-BA.2/5 subvariants are attenuated in lungs while increased in replication fitness in the nasal epithelium, indicating rapid adaptation of the circulating Omicron subvariants in the human populations. FUNDING: The full list of funding can be found at the Acknowledgements section.

Family-Specific Training Improves Linear B Cell Epitope Prediction for Emerging Viruses.

The rational design of vaccines and antibody-based therapeutics against newly emerging viruses relies on B cell epitopes mainly. To predict the B cell epitopes of a novel virus, several algorithms have been developed. While most existing algorithms are trained on a dataset in which B cell epitopes are classified as 'Positive' or 'Negative'. However, we found that training on such data contaminates the target pattern of specific viruses, leading to inaccurate predictions in some cases. In this paper, we introduce a novel framework for predicting linear B cell epitopes of novel viruses by exclusively using highly similar viruses for training data. We employed kernel regression based on seropositive rates, which are the percentages of seropositive samples among the population, to predict the potential epitopes. To assess our method, we conducted simulations and utilized two real-world datasets. Our method significantly outperformed other existing methods on the testing data of four viruses with seropositive rates. Also, our strategy showed a better prediction in a larger dataset from the IEDB. Thus, a novel framework providing better linear B cell prediction of newly emerging viruses is established, which will benefit the rational design of vaccines and antibody-based therapeutics in the future.

Rational design of a booster vaccine against COVID-19 based on antigenic distance.

Current COVID-19 vaccines are highly effective against symptomatic disease, but repeated booster doses using vaccines based on the ancestral strain offer limited additional protection against SARS-CoV-2 variants of concern (VOCs). To address this, we used antigenic distance to in silico select optimized booster vaccine seed strains effective against both current and future VOCs. Our model suggests that a SARS-CoV-1-based booster vaccine has the potential to cover a broader range of VOCs. Candidate vaccines including the spike protein from ancestral SARS-CoV-2, Delta, Omicron (BA.1), SARS-CoV-1, or MERS-CoV were experimentally evaluated in mice following two doses of the BNT162b2 vaccine. The SARS-CoV-1-based booster vaccine outperformed other candidates in terms of neutralizing antibody breadth and duration, as well as protective activity against Omicron (BA.2) challenge. This study suggests a unique strategy for selecting booster vaccines based on antigenic distance, which may be useful in designing future booster vaccines as new SARS-CoV-2 variants emerge.

The viral fitness and intrinsic pathogenicity of dominant SARS-CoV-2 Omicron sublineages BA.1, BA.2, and BA.5.

BACKGROUND: Among the Omicron sublineages that have emerged, BA.1, BA.2, BA.5, and their related sublineages have resulted in the largest number of infections. While recent studies demonstrated that all Omicron sublineages robustly escape neutralizing antibody response, it remains unclear on whether these Omicron sublineages share any pattern of evolutionary trajectory on their replication efficiency and intrinsic pathogenicity along the respiratory tract. METHODS: We compared the virological features, replication capacity of dominant Omicron sublineages BA.1, BA.2 and BA.5 in the human nasal epithelium, and characterized their pathogenicity in K18-hACE2, A129, young C57BL/6, and aged C57BL/6 mice. FINDINGS: We found that BA.5 replicated most robustly, followed by BA.2 and BA.1, in the differentiated human nasal epithelium. Consistently, BA.5 infection resulted in higher viral gene copies, infectious viral titres and more abundant viral antigen expression in the nasal turbinates of the infected K18-hACE2 transgenic mice. In contrast, the Omicron sublineages are continuously attenuated in lungs of infected K18-hACE2 and C57BL/6 mice, leading to decreased pathogenicity. Nevertheless, lung manifestations remain severe in Omicron sublineages-infected A129 and aged C57BL/6 mice. INTERPRETATION: Our results suggested that the Omicron sublineages might be gaining intrinsic replication fitness in the upper respiratory tract, therefore highlighting the importance of global surveillance of the emergence of hyper-transmissive Omicron sublineages. On the contrary, replication and intrinsic pathogenicity of Omicron is suggested to be further attenuated in the lower respiratory tract. Effective vaccination and other precautions should be in place to prevent severe infections in the immunocompromised populations at risk. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response.

The overall success of worldwide mass vaccination in limiting the negative effect of the COVID-19 pandemics is inevitable, however, recent SARS-CoV-2 variants of concern, especially Omicron and its sub-lineages, efficiently evade humoral immunity mounted upon vaccination or previous infection. Thus, it is an important question whether these variants, or vaccines against them, induce anti-viral cellular immunity. Here we show that the mRNA vaccine BNT162b2 induces robust protective immunity in K18-hACE2 transgenic B-cell deficient (µMT) mice. We further demonstrate that the protection is attributed to cellular immunity depending on robust IFN-γ production. Viral challenge with SARS-CoV-2 Omicron BA.1 and BA.5.2 sub-variants induce boosted cellular responses in vaccinated µMT mice, which highlights the significance of cellular immunity against the ever-emerging SARS-CoV-2 variants evading antibody-mediated immunity. Our work, by providing evidence that BNT162b2 can induce significant protective immunity in mice that are unable to produce antibodies, thus highlights the importance of cellular immunity in the protection against SARS-CoV-2.

Altered host protease determinants for SARS-CoV-2 Omicron.

Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While the role of the host transmembrane protease serine 2 in SARS-CoV-2 infection is widely recognized, the involvement of other proteases capable of facilitating SARS-CoV-2 entry remains incompletely explored. Here, we show that multiple members from the membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin and metalloproteinase families can mediate SARS-CoV-2 entry. Inhibition of MT-MMPs significantly reduces SARS-CoV-2 replication in vitro and in vivo. Mechanistically, we show that MT-MMPs can cleave SARS-CoV-2 spike and angiotensin-converting enzyme 2 and facilitate spike-mediated fusion. We further demonstrate that Omicron BA.1 has an increased efficiency on MT-MMP usage, while an altered efficiency on transmembrane serine protease usage for virus entry compared with that of ancestral SARS-CoV-2. These results reveal additional protease determinants for SARS-CoV-2 infection and enhance our understanding on the biology of coronavirus entry.

The relationship between the radiation dose of pelvic-bone marrow and lymphocytic toxicity in concurrent chemoradiotherapy for cervical cancer.

OBJECTIVE: The purpose of this study is to verify the correlation between medium and low radiation doses of the pelvic-bone marrow and the incidence of lymphocytic toxicity during concurrent chemoradiotherapy for cervical cancer. MATERIALS AND METHODS: This research included 117 cervical cancer patients, who received concurrent chemoradiotherapy. Radiotherapy included external-beam radiation therapy and brachytherapy. The dosimetry parameters include the Volume receiving 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), 30 Gy (V30), 40 Gy (V40), 50 Gy (V50), and the mean dose (D mean) of the bone marrow. Lymphocytic toxicity was calculated from lowest lymphocytic count after two cycles of concurrent chemotherapy. RESULTS: During concurrent chemoradiotherapy, the incidence of lymphocytic toxicity is 94.88%. The incidence of grade 3-4 toxicity is 68.38%. Multivariate analysis findings show that the dosimetry parameters V5, V10, V20, and V30 are significantly correlated with lymphocytic toxicity. The patients are divided into small-volume subgroups and large-volume subgroups based on the cutoff values. The relative risk of both grade 1-4 and grade 3-4 lymphocytic toxicity is significantly lower in the small-volume subgroups than in the large-volume subgroups (P < 0.05). Kaplan-Meier analysis shows that the incidence of both grade 1-4 and grade 3-4 lymphocytic toxicity of the small-volume subgroups is significantly lower than that of the large-volume subgroups (P < 0.05). CONCLUSION: There is a significant correlation between a medium and low dose of pelvic-bone-marrow radiation and incidence of lymphocytic toxicity. Reducing the volume of medium and low radiation doses could effectively reduce incidence of lymphocytic toxicity.

The Epitope Basis of Embryonic Stem Cell-Induced Antitumor Immunity against Bladder Cancer.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) share many cellular and molecular features with cancer cells. Taking advantage of these similarities, stem cells are effective vaccines against cancers in animal models. However, the molecular basis is not well understood, which hinders the development of effective cancer vaccines. Here, prophylactic and therapeutic bladder cancer vaccines composed of allogeneic ESCs and CpG with or without granulocyte macrophage colony stimulating factor are tested. The ESC-based cancer vaccines are able to induce specific antitumor immunity including stimulating cytotoxic CD8+ T cells and memory CD4+ T cells, reducing myeloid-derived suppressor cells, and preventing bladder cancer growth in mouse models. Furthermore, several genes that are overexpressed in both ESCs and tumors are identified. An epitope-based vaccine designed with shared overexpressed proteins induces specific antitumor immunity and reduces bladder cancer growth. Functional epitopes underlying the action of stem cell-based vaccines against bladder cancer are identified and it is confirmed that ESC-based anticancer vaccines have great potential. A systematic approach is provided here to developing novel effective epitope-based cancer vaccines in the future.

The effect of chronoradiotherapy on cervical cancer patients: A multicenter randomized controlled study.

Objectives: To investigate the short-term efficacy and radiotoxicity 3.543of chronoradiotherapy in patients with cervical cancer. We also examined the overall symptom score and quality of life (QOL) of patients who underwent morning radiotherapy and evening radiotherapy. Methods: We conducted a multicenter randomized controlled trial to compare the effects of morning radiotherapy (9:00-11:00 AM) with evening radiotherapy (7:00-9:00 PM) in cervical cancer patients receiving radiotherapy. From November 2021 to June 2022, 114 cervical cancer patients admitted to eight cancer center hospitals in Tianjin, Chongqing, Hubei, Shanxi, Shandong, Shaanxi, Hebei, and Cangzhou were randomly divided into the morning radiotherapy group (MG; N = 61) and the evening radiotherapy group (EG; N = 53). The short-term efficacy of radiotherapy on cervical cancer patients at different time points and the occurrence of radiotoxicity were explored after patients had undergone radiotherapy. Results: The total effective response (partial remission [PR] + complete remission [CR]) rate was similar across the two groups (93.5% vs. 96.3%, p > 0.05). However, the incidence of bone marrow suppression and intestinal reaction in the two groups were significantly different (p < 0.05). The patients in the MG had significantly higher Anderson symptom scores than patients in the EG (21.64 ± 7.916 vs. 18.53 ± 4.098, p < 0.05). In terms of physical activity, functional status, and overall QOL, the MG had significantly lower scores than the EG (p < 0.05). No other measures showed a significant difference between the groups. Conclusion: The radiotherapy effect of the MG was consistent with that of the EG. The incidence of radiation enteritis and radiation diarrhea in the MG was significantly higher than that in the EG; however, bone marrow suppression and blood toxicity in the EG were more serious than in the MG. Because of the small sample size of the study, we only examined the short-term efficacy of radiotherapy. Therefore, further clinical trials are needed to verify the efficacy and side effects of chronoradiotherapy. Clinical Trial Registration: http://www.chictr.org.cn/searchproj.aspx, Registration Number: ChiCTR2100047140.

Non-Neutralizing Epitopes Shade Neutralizing Epitopes against Omicron in a Multiple Epitope-Based Vaccine.

The ongoing coronavirus disease 2019 pandemic has raised concerns about the risk of re-infection. Non-neutralizing epitopes are one of the major reasons for antibody-dependent enhancement. Past studies on the ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed an infectivity-enhancing site on the ancestral SARS-CoV-2 spike protein. However, infection enhancement associated with the SARS-CoV-2 Omicron strain remains elusive. In this study, we examined the antibodies induced by a multiple epitope-based vaccine, which showed infection enhancement for the Omicron strain but not for the ancestral SARS-CoV-2 or Delta strain. By examining the antibodies induced by single epitope-based vaccines, we identified a conserved epitope, IDf (450-469), with neutralizing activity against ancestral SARS-CoV-2, Delta, and Omicron. Although neutralizing epitopes are present in the multiple epitope-based vaccine, other immunodominant non-neutralizing epitopes such as IDg (480-499) can shade their neutralizing activity, leading to infection enhancement of Omicron. Our study provides up-to-date epitope information on SARS-CoV-2 variants to help design better vaccines or antibody-based therapeutics against future variants.

Virological features and pathogenicity of SARS-CoV-2 Omicron BA.2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 was a dominant circulating SARS-CoV-2 variant worldwide. Recent reports hint that BA.2 is similarly potent regarding antibody evasion but may be more transmissible than BA.1. The pathogenicity of BA.2 remains unclear and is of critical public health significance. Here we investigated the virological features and pathogenicity of BA.2 with in vitro and in vivo models. We show that BA.2 is less dependent on transmembrane protease serine 2 (TMPRSS2) for virus entry in comparison with BA.1 in vitro. In K18-hACE2 mice, BA.2 replicates more efficiently than BA.1 in the nasal turbinates and replicates marginally less efficiently in the lungs, leading to decreased body weight loss and improved survival. Our study indicates that BA.2 is similarly attenuated in lungs compared with BA.1 but is potentially more transmissible because of its better replication at the nasal turbinates.

Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2.

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating SARS-CoV-2 variant globally. Omicron BA.1 contains more than 30 mutations in the spike protein, which contribute to its altered virological features when compared to the ancestral SARS-CoV-2 or previous SARS-CoV-2 variants. Recent studies by us and others demonstrated that Omicron BA.1 is less dependent on transmembrane serine protease 2 (TMPRSS2), less efficient in spike cleavage, less fusogenic, and adopts an altered propensity to utilize the plasma membrane and endosomal pathways for virus entry. Ongoing studies suggest that these virological features of Omicron BA.1 are in part retained by the subsequent Omicron sublineages. However, the exact spike determinants that contribute to these altered features of Omicron remain incompletely understood. In this study, we investigated the spike determinants for the observed virological characteristics of Omicron. By screening for the individual changes on Omicron BA.1 and BA.2 spike, we identify that 69-70 deletion, E484A, and H655Y contribute to the reduced TMPRSS2 usage while 25-27 deletion, S375F, and T376A result in less efficient spike cleavage. Among the shared spike mutations of BA.1 and BA.2, S375F and H655Y reduce spike-mediated fusogenicity. Interestingly, the H655Y change consistently reduces serine protease usage while increases the use of endosomal proteases. In keeping with these findings, the H655Y substitution alone reduces plasma membrane entry and facilitates endosomal entry when compared to SARS-CoV-2 WT. Overall, our study identifies key changes in Omicron spike that contributes to our understanding on the virological determinant and pathogenicity of Omicron.

Targeting ACLY efficiently inhibits SARS-CoV-2 replication.

The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets. In this study, we dissected the metabolome derived from COVID-19 patients to identify key host factors that are required for efficient SARS-CoV-2 replication. Through a series of metabolomic analyses, in vitro, and in vivo investigations, we identified ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. ACLY should be further explored as a novel intervention target for COVID-19.

Intradermal delivery of mRNA using cryomicroneedles.

Microneedles can realize the intradermal and transdermal delivery of drugs. However, most conventional microneedles made of metal, polymer and ceramics are unsuitable for the delivery of mRNA drugs that are fragile and temperature-sensitive. This study explores the usage of cryomicroneedles (CryoMNs) for the intradermal delivery of mRNA molecules. Taking luciferase mRNA as an example, we first optimize the formulation of CryoMNs to maximize mRNA stability. Later, in the mouse model, we compare the delivery efficiency with the conventional subcutaneous injection for both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully induce specific B-cell antibody, neutralizing activity and T-cell responses. STATEMENT OF SIGNIFICANCE: mRNA vaccines are fragile and temperature-sensitive, so they are mainly delivered by intramuscular injection that often causes pain and requires clinical expertise to immunize patients. Microneedles permit convenient, fast and safe vaccination. However, existing microneedle platforms are ineffective to protect the integrity of mRNA vaccines in fabrication, storage, and administration. This work utilizes cryomicroneedles (CryoMNs) technology to intradermally deliver mRNA. In the mouse model, CryoMNs are compared with the subcutaneous injection for the delivery efficiency of both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully produce specific B-cell antibodies, T-cell responses, and neutralizing activity. This work is expected to provide a new delivery strategy for the emerging mRNA therapeutics.

Computation of Antigenicity Predicts SARS-CoV-2 Vaccine Breakthrough Variants.

It has been reported that multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta can reduce neutralization by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralization assays are typically performed to monitor potential vaccine breakthrough strains. However, experiment-based methods took several weeks whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralization titers. Based on this correlation, we obtained a computational model for the receptor-binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralization titers with high accuracy (~0.79). Our predicted results were comparable to experimental neutralization titers of variants, including Alpha, Beta, Delta, Gamma, Epsilon, Iota, Kappa, and Lambda, as well as SARS-CoV. Here, we predicted the fold of decrease of Omicron as 17.4-fold less susceptible to neutralization. We visualized all 1,521 SARS-CoV-2 lineages to indicate variants including Mu, B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs Beta, Gamma, Delta, and Omicron. Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.

Bacillus Calmette-Guérin-induced trained immunity protects against SARS-CoV-2 challenge in K18-hACE2 mice.

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.

In-Silico Analysis of Monoclonal Antibodies against SARS-CoV-2 Omicron.

Omicron was designated by the WHO as a VOC on 26 November 2021, only 4 days after its sequence was first submitted. However, the impact of Omicron on current antibodies and vaccines remains unknown and evaluations are still a few weeks away. We analysed the mutations in the Omicron variant against epitopes. In our database, 132 epitopes of the 120 antibodies are classified into five groups, namely NTD, RBD-1, RBD-2, RBD-3, and RBD-4. The Omicron mutations impact all epitopes in NTD, RBD-1, RBD-2, and RBD-3, with no antibody epitopes spared by these mutations. Only four out of 120 antibodies may confer full resistance to mutations in the Omicron spike, since all antibodies in these three groups contain one or more epitopes that are affected by these mutations. Of all antibodies under EUA, the neutralisation potential of Etesevimab, Bamlanivimab, Casirivimab, Imdevima, Cilgavimab, Tixagevimab, Sotrovimab, and Regdanvimab might be dampened to varying degrees. Our analysis suggests the impact of Omicron on current therapeutic antibodies by the Omicron spike mutations may also apply to current COVID-19 vaccines.