Visual analysis of tyrosine kinase inhibitors in HER2 positive breast cancer / 中国药房

OBJECTIVE To analyze the research status， hotspot and development trend of tyrosine kinase inhibitors （TKIs） in the treatment of human epidermal growth factor receptor 2 （HER2） positive breast cancer. METHODS The literature related to TKIs in the treatment of HER2 positive breast cancer were searched from the Web of Science core collection database； the author， country/region， institution， subject field， journal and keywords was visualized by CiteSpace 6.1.R3 software. RESULTS A total of 732 pieces of literature were included， and the number of literature published showed an increasing trend year by year. The number of literature published in the United States was the largest （center degree 0.10）， and the number of literature published in China ranked second （center degree 0.05）. The most published and cited authors were Crown from St. Vincent’s University Hospital in Australia and Slamon from University of California， Los Angeles in the United States； the institution with the highest number of literature was the University of Texas MD Anderson Cancer Center， and the journal with the highest number of literature was the Journal of Clinical Oncology. The research mainly focused on five aspects： HER2 positive breast cancer treatment drugs， TKIs receptor， TKIs mechanism of action， HER2 positive breast cancer brain metastasis， and TKIs clinical trials. The main frontier areas and development trends were the combination of TKIs with other drugs or therapies to enhance targeting and reduce toxic side effects. CONCLUSIONS The study of TKIs in the treatment of HER2 positive breast cancer has attracted the attention of scholars at home and abroad. Chinese scholars and research teams need to strengthen cooperation and communication in the future， and cooperation with other countries should be strengthened in terms of the efficacy and safety of TKIs alone and combined with other drugs in the treatment of HER2 positive breast cancer.

Improved Neutralization of Omicron BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent BA.4/5 Vaccine

The BNT162b2 bivalent BA.4/5 COVID-19 vaccine has been authorized to mitigate COVID-19 due to current Omicron and potentially future variants. New sublineages of SARS-CoV-2 Omicron continue to emerge and have acquired additional mutations, particularly in the spike protein, that may lead to improved viral fitness and immune evasion. The present study characterized neutralization activities against new Omicron sublineages BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 after a 4th dose (following three doses of BNT162b2) of either the original monovalent BNT162b2 or the bivalent BA.4/5 booster in individuals >55 years of age. For all participants, the 4th dose of monovalent BNT162b2 vaccine induced a 3.0x, 2.9x, 2.3x, 2.1x, 1.8x, and 1.5x geometric mean neutralizing titer fold rise (GMFR) against USA/WA1-2020 (a strain isolated in January 2020), BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1, respectively; the bivalent vaccine induced 5.8x, 13.0x, 11.1x, 6.7x, 8.7x, and 4.8x GMFRs. For individuals without SARS-CoV-2 infection history, BNT162b2 monovalent induced 4.4x, 3.0x, 2.5x, 2.0x, 1.5x, and 1.3x GMFRs, respectively; the bivalent vaccine induced 9.9x, 26.4x, 22.2x, 8.4x, 12.6x, and 4.7x GMFRs. These data suggest the bivalent BA.4/5 vaccine is more immunogenic than the original BNT162b2 monovalent vaccine against circulating Omicron sublineages, including BQ.1.1 that is becoming prevalent globally.

Cross-neutralization and viral fitness of SARS-CoV-2 Omicron sublineages

The rapid evolution of SARS-CoV-2 Omicron sublineages mandates a better understanding of viral replication and cross-neutralization among these sublineages. Here we used K18-hACE2 mice and primary human airway cultures to examine the viral fitness and antigenic relationship among Omicron sublineages. In both K18-hACE2 mice and human airway cultures, Omicron sublineages exhibited a replication order of BA.5 [≥] BA.2 [≥] BA.2.12.1 > BA.1; no difference in body weight loss was observed among different sublineage-infected mice. The BA.1-, BA.2-, BA.2.12.1-, and BA.5-infected mice developed distinguisable cross-neutralizations against Omicron sublineages, but exhibited little neutralizations against the index virus (i.e., USA-WA1/2020) or the Delta variant. Surprisingly, the BA.5-infected mice developed higher neutralization activity against heterologous BA.2 and BA.2.12.1 than that against homologous BA.5; serum neutralizing titers did not always correlate with viral replication levels in infected animals. Our results revealed a distinct antigenic cartography of Omicron sublineages and support the bivalent vaccine approach.

Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1, and XBB.1 by 4 doses of parental mRNA vaccine or a BA.5-bivalent booster

The newly emerged SARS-CoV-2 Omicron BQ.1.1, XBB.1, and other sublineages have accumulated additional spike mutations that may affect vaccine effectiveness. Here we report neutralizing activities of three human serum panels collected from individuals 1-3 months after dose 4 of parental mRNA vaccine (post-dose-4), 1 month after a BA.5-bivalent-booster (BA.5-bivalent-booster), or 1 month after a BA.5-bivalent-booster with previous SARS-CoV-2 infection (BA.5-bivalent-booster-infection). Post-dose-4 sera neutralized USA-WA1/2020, BA.5, BF.7, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 SARS-CoV-2 with geometric mean titers (GMTs) of 1533, 95, 69, 62, 26, 22, and 15, respectively; BA.5-bivalent-booster sera improved the GMTs to 3620, 298, 305, 183, 98, 73, and 35; BA.5-bivalent-booster-infection sera further increased the GMTs to 5776, 1558,1223, 744, 367, 267, and 103. Thus, although BA.5-bivalent-booster elicits better neutralization than parental vaccine, it does not produce robust neutralization against the newly emerged Omicron BA.2.75.2, BQ.1.1, and XBB.1. Previous infection enhances the magnitude and breadth of BA.5-bivalent-booster-elicited neutralization.

Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro

The SARS-CoV-2 virus is the causal agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). There is an urgent need for potent, specific antiviral compounds against SARS-CoV-2. The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses, and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, non-covalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment. One-Sentence SummaryA oral non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication.

Neutralization of SARS-CoV-2 Omicron sublineages by 4 doses of mRNA vaccine

Since the initial emergence of SARS-CoV-2 Omicron BA.1, several Omicron sublineages have emerged, leading to BA.5 as the current dominant sublineage. Here we report the neutralization of different Omicron sublineages by human sera collected from individuals who had distinct mRNA vaccination and/or BA.1 infection. Four-dose-vaccine sera neutralize the original USA-WA1/2020, Omicron BA.1, BA.2, BA.212.1, BA.3, and BA.4/5 viruses with geometric mean titers (GMTs) of 1554, 357, 236, 236, 165, and 95, respectively; 2-dose-vaccine-plus-BA.1-infection sera exhibit GMTs of 2114, 1705, 730, 961, 813, and 274, respectively; and 3-dose-vaccine-plus-BA.1-infection sera show GMTs of 2962, 2038, 983, 1190, 1019, and 297, respectively. Thus, 4-dose-vaccine elicits the lowest neutralization against BA.5; 2-dose-vaccine-plus-BA.1-infection elicits significantly higher GMTs against Omicron sublineages than 4-dose-vaccine; and 3-dose-vaccine-plus-BA.1-infection elicits slightly higher GMTs (statistically insignificant) than the 2-dose-vaccine-plus-BA.1-infection. Finally, compared with BA.5, the newly emerged BA.2.75 is equally evasive of 4-dose-vaccine-elicited neutralization, but more susceptible to 3-dose-vaccine-plus-BA.1-infection-elicited neutralization.

Neutralization of Omicron sublineages and Deltacron SARS-CoV-2 by 3 doses of BNT162b2 vaccine or BA.1 infection

Distinct SARS-CoV-2 Omicron sublineages have evolved showing increased fitness and immune evasion than the original Omicron variant BA.1. Here we report the neutralization activity of sera from BNT162b2 vaccinated individuals or unimmunized Omicron BA.1-infected individuals against Omicron sublineages and "Deltacron" variant (XD). BNT162b2 post-dose 3 immune sera neutralized USA-WA1/2020, Omicron BA.1-, BA.2-, BA.2.12.1-, BA.3-, BA.4/5-, and XD-spike SARS-CoV-2s with geometric mean titers (GMTs) of 1335, 393, 298, 315, 216, 103, and 301, respectively; thus, BA.4/5 SARS-CoV-2 spike variant showed the highest propensity to evade vaccine neutralization compared to the original Omicron variants BA.1. BA.1-convalescent sera neutralized USA-WA1/2020, BA.1-, BA.2-, BA.2.12.1-, BA.3-, BA.4/5-, and Deltacron-spike SARS-CoV-2s with GMTs of 15, 430, 110, 109, 102, 25, and 284, respectively. The low neutralization titers of vaccinated sera or convalescent sera from BA. 1 infected individuals against the emerging and rapidly spreading Omicron BA.4/5 variants provide important results for consideration in the selection of an updated vaccine in the current Omicron wave.

SARS-CoV-2 Delta breakthrough infections in vaccinated patients

The continuous emergence of SARS-CoV-2 variants with increased transmission and immune evasion has caused breakthrough infections in vaccinated population. It is important to determine the threshold of neutralizing antibody titers that permit breakthrough infections. Here we tested the neutralization titers of vaccinated patients who contracted Delta variant. All 75 patients with Delta breakthrough infections exhibited neutralization titers (NT50) of less than 70. Among the breakthrough patients, 76%, 18.7%, and 5.3% of them had the NT50 ranges of <20, 20-50, and 50-69, respectively. These clinical laboratory results have implications in vaccine strategy and public health policy.

Cross neutralization of Omicron BA.1 against BA.2 and BA.3 SARS-CoV-2

The Omicron SARS-CoV-2 has three distinct sublineages, among which sublineage BA.1 is responsible for the initial Omicron surge and is now being replaced by BA.2 world-wide, whereas BA.3 is currently at a low frequency. The ongoing BA.1-to-BA.2 replacement underscores the importance to understand the cross-neutralization among the three Omicron sublineages. Here we tested the neutralization of BA.1-infected human sera against BA.2, BA.3, and USA/WA1-2020 (a strain isolated in late January 2020). The BA.1-infected sera neutralized BA.1, BA.2, BA.3, and USA/WA1-2020 SARS-CoV-2s with geometric mean titers (GMTs) of 445, 107, 102, and 16, respectively. Thus, the neutralizing GMTs against heterologous BA.2, BA.3, and USA/WA1-2020 were 4.2-, 4.4-, and 28.4-fold lower than the GMT against homologous BA.1, respectively. These findings have implications in COVID-19 vaccine strategy.

Neutralization of Omicron BA.1, BA.2, and BA.3 SARS-CoV-2 by 3 doses of BNT162b2 vaccine

The newly emerged Omicron SARS-CoV-2 has 3 distinct sublineages: BA.1, BA.2, and BA.3. BA.1 accounts for the initial surge and is being replaced by BA.2, whereas BA.3 is at a low prevalence at this time. Here we report the neutralization of BNT162b2-vaccinated sera (collected at 1 month after dose 3) against the three Omicron sublineages. To facilitate the neutralization testing, we engineered the complete BA.1, BA.2, or BA.3 spike into an mNeonGreen USA-WA1/2020 SRAS-CoV-2. All BNT162b2-vaccinated sera neutralized USA-WA1/2020, BA.1-, BA.2-, and BA.3-spike SARS-CoV-2s with titers of >20; the neutralization geometric mean titers (GMTs) against the four viruses were 1211, 336, 300, and 190, respectively. Thus, the BA.1-, BA.2-, and BA.3-spike SARS-CoV-2s were 3.6-, 4.0-, and 6.4-fold less efficiently neutralized than the USA-WA1/2020, respectively. Our data have implications in vaccine strategy and understanding the biology of Omicron sublineages.

Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth.

One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv) 2 design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.

A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions

We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcriptional regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 ({Delta}3678). The {Delta}3678 virus replicates about 7,500-fold lower than wild-type SARS-CoV-2 on primary human airway cultures, but restores its replication on interferon-deficient Vero-E6 cells that are approved for vaccine production. The {Delta}3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the {Delta}3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the {Delta}3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter {Delta}3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that {Delta}3678 SARS-CoV-2 may serve as a live-attenuated vaccine candidate and a research tool for potential biosafety level-2 use.

Neutralization of Omicron SARS-CoV-2 by 2 or 3 doses of BNT162b2 vaccine

We report the antibody neutralization against Omicron SARS-CoV-2 after 2 and 3 doses of BNT162b2 mRNA vaccine. Vaccinated individuals were serially tested for their neutralization against wild-type SARS-CoV-2 (strain USA-WA1/2020) and an engineered USA-WA1/2020 bearing the Omicron spike glycoprotein. Plaque reduction neutralization results showed that at 2 or 4 weeks post-dose-2, the neutralization geometric mean titers (GMTs) were 511 and 20 against the wild-type and Omicron-spike viruses, respectively, suggesting that two doses of BNT162b2 were not sufficient to elicit robust neutralization against Omicron; at 1 month post-dose-3, the neutralization GMTs increased to 1342 and 336, respectively, indicating that three doses of vaccine increased the magnitude and breadth of neutralization against Omicron; at 4 months post-dose-3, the neutralization GMTs decreased to 820 and 171, respectively, suggesting similar neutralization decay kinetics for both variants. The data support a three-dose vaccine strategy and provide the first glimpse of the neutralization durability against Omicron.

Illness perception and influencing factors among patients with non-alcoholic fatty liver disease / 预防医学

Objective@#To investigate the perception about illness and identify its influencing factors among patients with non-alcoholic fatty liver disease ( NAFLD ) , so as to provide insights into the management of NAFLD patients. @*Methods@#NAFLD patients admitted to Hangzhou First People's Hospital Affiliated to Medical School of Zhejiang University from January to June, 2020, were selected as the study subjects, and subjects' demographic features were collected using questionnaires, including gender, age and education level. The perception about illness, coping models and social support were assessed using the Brief Illness Perception Questionnaire (BIPQ), Medical Coping Modes Questionnaire ( MCMQ ) and Social Support Rating Scale ( SSRS ), respectively, and factors affecting the perception about illness were identified using multivariable linear regression analysis among NAFLD patients.@*Results@#The 286 respondents included 151 males ( 52.80% ) and 135 females ( 47.20% ), and had a mean age of ( 55.27±10.39 ) years. The mean illness perception score was 38.55±9.21 among the respondents. The mean SSRS score was 42.90±8.64. The mean coping mode scores of confronce, avoidance and resignation were 23.51±4.30, 17.49±2.82, and 7.12±2.05, respectively. Multivariable linear regression analysis identified education level ( high school, β'=-0.216; diploma and above, β'=-0.355 ), household monthly income per capita ( β'=-0.372 ), regular exercise ( β'=-0.310 ), coping modes ( confronce, β'=-0.326; avoidance, β'=-0.191 ) and social support level ( β'=-0.259 ) as factors affecting the perception about illness among NAFLD patients.@*Conclusion@#Negative perceptions about illness are found among NAFLD patients, and household income, education level, regular exercise and coping modes are factors affecting the illness perception among NAFLD patients.

Segmentation of meibomian glands based on deep learning / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To explore the application value of deep learning technology in automatic meibomian glands segmentation. METHODS:Infrared meibomian gland images were collected and 193 of them were picked out for establishing the database. The images were manually labeled by three clinicians. UNet++ network and automatic data expansion strategy were introduced to construct the automatic meibomian glands segmentation model. The feasibility and effectiveness of the proposed segmentation model were analyzed by precision, sensitivity, specificity, accuracy and intersection over union.RESULTS: Taking manual labeling as the gold standard, the presented method segment the glands effectively and steadily with accuracy, sensitivity and specificity of 94.31%, 82.15% and 96.13% respectively. On the average, only 0.11s was taken for glands segmentation of single image.CONCLUSIONS: In this paper, deep learning technology is introduced to realize automatic segmentation of meibomian glands, achieving high accuracy, good stability and efficiency. It would be quite useful for calculation of gland morphological parameters, the clinical diagnosis and screening of related diseases, improving the diagnostic efficiency.

TGR5 deficiency activates antitumor immunity in non-small cell lung cancer via restraining M2 macrophage polarization

The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages, and plays a critical role in regulating inflammatory response. Our previous work has shown its role in promoting the progression of non-small cell lung cancer (NSCLC), yet the mechanism remains unclear. Here, using Tgr5-knockout mice, we show that TGR5 is required for M2 polarization of tumor-associated macrophages (TAMs) and suppresses antitumor immunity in NSCLC via involving TAMs-mediated CD8+ T cell suppression. Mechanistically, we demonstrate that TGR5 promotes TAMs into protumorigenic M2-like phenotypes via activating cAMP-STAT3/STAT6 signaling. Induction of cAMP production restores M2-like phenotypes in TGR5-deficient macrophages. In NSCLC tissues from human patients, the expression of TGR5 is associated with the infiltration of TAMs. The co-expression of TGR5 and high TAMs infiltration are associated with the prognosis and overall survival of NSCLC patients. Together, this study provides molecular mechanisms for the protumor function of TGR5 in NSCLC, highlighting its potential as a target for TAMs-centric immunotherapy in NSCLC.

Incidence of extrauterine growth retardation and its risk factors in very preterm infants during hospitalization: a multicenter prospective study / 中国当代儿科杂志

OBJECTIVES@#To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China.@*METHODS@#A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined.@*RESULTS@#The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05).@*CONCLUSIONS@#It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.

Expert consensus on early childhood caries management / 国际口腔科学杂志·英文版

Early childhood caries (ECC) is a significant chronic disease of childhood and a rising public health burden worldwide. ECC may cause a higher risk of new caries lesions in both primary and permanent dentition, affecting lifelong oral health. The occurrence of ECC has been closely related to the core microbiome change in the oral cavity, which may be influenced by diet habits, oral health management, fluoride use, and dental manipulations. So, it is essential to improve parental oral health and awareness of health care, to establish a dental home at the early stage of childhood, and make an individualized caries management plan. Dental interventions according to the minimally invasive concept should be carried out to treat dental caries. This expert consensus mainly discusses the etiology of ECC, caries-risk assessment of children, prevention and treatment plan of ECC, aiming to achieve lifelong oral health.

Neutralization against Omicron SARS-CoV-2 from previous non-Omicron infection

The explosive spread of the Omicron SARS-CoV-2 variant underscores the importance of analyzing the cross-protection from previous non-Omicron infection. We developed a high-throughput neutralization assay for Omicron SARS-CoV-2 by engineering the Omicron spike gene into an mNeonGreen USA-WA1/2020 SARS-CoV-2 (isolated in January 2020). Using this assay, we determined the neutralization titers of patient sera collected at 1- or 6-months after infection with non-Omicron SARS-CoV-2. From 1- to 6-month post-infection, the neutralization titers against USA-WA1/2020 decreased from 601 to 142 (a 4.2-fold reduction), while the neutralization titers against Omicron-spike SARS-CoV-2 remained low at 38 and 32, respectively. Thus, at 1- and 6-months after non-Omicron SARS-CoV-2 infection, the neutralization titers against Omicron were 15.8- and 4.4-fold lower than those against USA-WA1/2020, respectively. The low cross-neutralization against Omicron from previous non-Omicron infection supports vaccination of formerly infected individuals to mitigate the health impact of the ongoing Omicron surge.

A modified porous silicon microparticle promotes mucosal delivery of SARS-CoV-2 antigen and induction of potent and durable systemic and mucosal T helper 1 skewed protective immunity

Development of optimal SARS-CoV-2 vaccines to induce potent, long-lasting immunity and provide cross-reactive protection against emerging variants remains a high priority. Here, we report that a modified porous silicon microparticle (mPSM)-adjuvanted SARS-CoV-2 receptor-binding domain (RBD) vaccine activated dendritic cells and generated more potent and durable SARS-CoV-2-specific systemic humoral and type 1 helper T (Th) cell-mediated immune responses than alum-formulated RBD following parenteral vaccination, and protected mice from SARS-CoV-2 and Beta variant infection. mPSM facilitated the uptake of SARS-CoV-2 RBD antigens by nasal and airway epithelial cells. Parenteral and intranasal prime and boost vaccinations with mPSM-RBD elicited potent systemic and lung resident memory T and B cells and SARS-CoV-2 specific IgA responses, and markedly diminished viral loads and inflammation in the lung following SARS-CoV-2 Delta variant infection. Our results suggest that mPSM can serve as potent adjuvant for SARS-CoV-2 subunit vaccine which is effective for systemic and mucosal vaccination.