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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new type of coronavirus that causes the Coronavirus Disease 2019 (COVID-19), which has been the most challenging pandemic in this century. Considering its high mortality and rapid spread, an effective vaccine is urgently needed to control this pandemic. As a result, the academia, industry, and government sectors are working tightly together to develop and test a variety of vaccines at an unprecedented pace. In this review, we outline the essential coronavirus biological characteristics that are important for vaccine design. In addition, we summarize key takeaways from previous vaccination studies of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), highlighting the pros and cons of each immunization strategy. Finally, based on these prior vaccination experiences, we discuss recent progress and potential challenges of COVID-19 vaccine development.

Coronavirus Disease 2019 (COVID-19) has been the most severe public health challenge in this century. Two years after its emergence, the rapid development and deployment of effective COVID-19 vaccines have successfully controlled this pandemic and greatly reduced the risk of severe illness and death associated with COVID-19. However, due to its ability to rapidly evolve, the SARS-CoV-2 virus may never be eradicated, and there are many important new topics to work on if we need to live with this virus for a long time. To this end, we hope to provide essential knowledge for researchers who work on the improvement of future COVID-19 vaccines. In this review, we provided an up-to-date summary for current COVID-19 vaccines, discussed the biological basis and clinical impact of SARS-CoV-2 variants and subvariants, and analyzed the effectiveness of various vaccine booster regimens against different SARS-CoV-2 strains. Additionally, we reviewed potential mechanisms of vaccine-induced severe adverse events, summarized current studies regarding immune correlates of protection, and finally, discussed the development of next-generation vaccines.

Key Points Cervical cancer is the second largest cause of cancer deaths in women worldwide. Persistent infection with human papillomavirus (HPV) is necessary but not sufficient to cause cervical cancer, and preventing HPV infection can prevent the disease. Cervical cancer is currently prevented by Pap smears and/or HPV testing and ablation of high-grade squamous intraepithelial lesions (HSILs). However, the US Food and Drug Administration approved a preventive HPV vaccine on 8 June 2006 for the immunization of women between 9–26 years of age. HPV virus-like particle (VLP) vaccines based on the major capsid antigen L1 show very high protective efficacy and good safety profiles so far, and therefore have the potential to globally affect cervical cancer. However, guidelines on when to vaccinate and whether a boost is necessary depend on the duration of protection, which remains to be determined. Protection with the L1 VLP vaccine shows strong HPV type restriction, therefore highly valent vaccines are required for broad protection. Minor capsid antigen L2-based vaccines might have potential for broad coverage with a monovalent vaccine. There is little evidence that HPV VLP vaccines have therapeutic activity in patients, and the continued development of therapeutic vaccines is warranted. The influence of herd immunity through the vaccination of men is likely to be beneficial, but it will have a relatively modest effect on cervical cancer rates compared with the broad vaccination of women. However, trials to evaluate the HPV vaccine in men are ongoing, as men do contract genital warts and HPV-related cancers at other sites in addition to transmitting HPV to women. Societal response is developing and will have an effect on the introduction of HPV vaccines. Cervical cancer normally occurs in developing countries that lack the resources for screening. The development of alternative HPV vaccines that are low cost and heat stable will be important for the worldwide introduction of the vaccine. Approaches to needle-free vaccination are also being tested. Immunodeficient patients suffer more severe HPV disease and have greater susceptibility to HPV-related cancer. It is important to determine whether these patients will respond less well to HPV vaccines. The FDA recently approved a human papillomavirus preventive vaccine for cervical cancer, the second largest cause of cancer deaths in women. How will the introduction of this vaccine affect cervical cancer incidence and what are the outstanding issues? Cancer of the uterine cervix is the second largest cause of cancer deaths in women, and its toll is greatest in populations that lack screening programmes to detect precursor lesions. Persistent infection with 'high risk' genotypes of human papillomavirus (HPV) is necessary, although not sufficient, to cause cervical carcinoma. Therefore, HPV vaccination provides an opportunity to profoundly affect cervical cancer incidence worldwide. A recently licensed HPV subunit vaccine protects women from a high proportion of precursor lesions of cervical carcinoma and most genital warts. Here we examine the ramifications and remaining questions that surround preventive HPV vaccines.

Over the past few decades, global metapopulation epidemic simulations built with worldwide air-transportation data have been the main tool for studying how epidemics spread from the origin to other parts of the world (e.g., for pandemic influenza, SARS, and Ebola). However, it remains unclear how disease epidemiology and the air-transportation network structure determine epidemic arrivals for different populations around the globe. Here, we fill this knowledge gap by developing and validating an analytical framework that requires only basic analytics from stochastic processes. We apply this framework retrospectively to the 2009 influenza pandemic and 2014 Ebola epidemic to show that key epidemic parameters could be robustly estimated in real-time from public data on local and global spread at very low computational cost. Our framework not only elucidates the dynamics underlying global spread of epidemics but also advances our capability in nowcasting and forecasting epidemics. Understanding global epidemics spread is crucial for preparedness and response. Here the authors introduce an analytical framework to study epidemic spread on air transport networks, and demonstrate its power to estimate key epidemic parameters by application to the recent influenza pandemic and Ebola outbreak.

Interleukin 2 (IL-2) plays a fundamental role in both immune activation and tolerance and has revolutionized the field of cancer immunotherapy since its discovery. The ability of IL-2 to mediate tumor regression in preclinical and clinical settings led to FDA approval for its use in the treatment of metastatic renal cell carcinoma and metastatic melanoma in the 1990s. Although modest success is observed in the clinic, cancer patients receiving IL-2 therapy experience a wide array of side effects ranging from flu-like symptoms to life-threatening conditions such as vascular leak syndrome. Over the past three decades, efforts have focused on circumventing IL-2-related toxicities by engineering methods to localize IL-2 to the tumor or secondary lymphoid tissue, preferentially activate CD8+ T cells and NK cells, and alter pharmacokinetic properties to increase bioavailability. This review summarizes the various IL-2-based strategies that have emerged, with a focus on chimeric fusion methods.

Paxillin (PXN) is required for receptor tyrosine kinase-mediated ERK activation, and the activation of the Raf/MEK/ERK cascade has been linked with Bcl-2 expression. We hypothesized that phosphorylation of PXN by the EGFR/Src pathway might contribute to cisplatin resistance via increased Bcl-2 expression. We show that cisplatin resistance was dependent on PXN expression, as evidenced by PXN overexpression in TL-13 and TL-10 cells and PXN knockdown in H23 and CL1-5 cells. Specific inhibitors of signaling pathways indicated that the phosphorylation of PXN at Y118 and Y31 via the Src pathway was responsible for cisplatin resistance. We further demonstrated that ERK activation was also dependent on this PXN phosphorylation. Bcl-2 transcription was upregulated by phosphorylated PXN-mediated ERK activation via increased binding of phosphorylated CREB to the Bcl-2 promoter. A subsequent increase in Bcl-2 levels by a PXN/ERK axis was responsible for the resistance to cisplatin. Animal models further confirmed the findings of in vitro cells indicating that xenograft tumors induced by TL-13-overexpressing cells were successfully suppressed by cisplatin combined with Src or ERK inhibitor compared with treatment of cisplatin, Src inhibitor or ERK inhibitor alone. A positive correlation of phosphorylated PXN with phosphorylated ERK and Bcl-2 was observed in lung tumors from NSCLC patients. Patients with tumors positive for PXN, phosphorylated PXN, phosphorylated ERK and Bcl-2 more commonly showed a poorer response to cisplatin-based chemotherapy than did patients with negative tumors. Collectively, PXN phosphorylation might contribute to cisplatin resistance via activating ERK-mediated Bcl-2 transcription. Therefore, we suggest that Src or ERK inhibitor might be helpful to improve the sensitivity for cisplatin-based chemotherapy in NSCLC patients with PXN-positive tumors.

Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens.

Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.

Chiral molecules with opposite handedness exhibit distinct physical, chemical, or biological properties. They pose challenges as well as opportunities in understanding the phase behavior of soft matter, designing enantioselective catalysts, and manufacturing single-handed pharmaceuticals. Microscopic particles, arranged in a chiral configuration, could also exhibit unusual optical, electric, or magnetic responses. Here we report a simple method to assemble achiral building blocks, i.e., the asymmetric colloidal dimers, into a family of chiral clusters. Under alternating current electric fields, two to four lying dimers associate closely with a central standing dimer and form both right- and left-handed clusters on a conducting substrate. The cluster configuration is primarily determined by the induced dipolar interactions between constituent dimers. Our theoretical model reveals that in-plane dipolar repulsion between petals in the cluster favors the achiral configuration, whereas out-of-plane attraction between the central dimer and surrounding petals favors a chiral arrangement. It is the competition between these two interactions that dictates the final configuration. The theoretical chirality phase diagram is found to be in excellent agreement with experimental observations. We further demonstrate that the broken symmetry in chiral clusters induces an unbalanced electrohydrodynamic flow surrounding them. As a result, they rotate in opposite directions according to their handedness. Both the assembly and propulsion mechanisms revealed here can be potentially applied to other types of asymmetric particles. Such kinds of chiral colloids will be useful for fabricating metamaterials, making model systems for both chiral molecules and active matter, or building propellers for microscale transport. Significance Although colloids have been used as molecular analogues for understanding how simple building blocks can assemble into functional materials, they are mostly spherical with isotropic properties. We are still far from truly accessing the diversity of structures desired for either fundamental understanding or technological application. Here, we report the electric-field–directed assembly of asymmetric colloids into clusters that exhibit a ubiquitous type of symmetry in nature: the chirality. We further demonstrate that the chirality induces unbalanced hydrodynamic flow, which causes rotational propulsion of chiral clusters that are fully dictated by their handedness. Both the assembly and propulsion mechanisms discovered can be universal and applied to other types of asymmetric particles. They are also useful in modeling active matter and making microengines.