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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.

Background Human papillomavirus (HPV) infections and associated diseases remain a serious burden worldwide. It is now clear that HPV serves as the etiological factor and biologic carcinogen for HPV-associated lesions and cancers. Although preventative HPV vaccines are available, these vaccines do not induce strong therapeutic effects against established HPV infections and lesions. These concerns create a critical need for the development of therapeutic strategies, such as vaccines, to treat these existing infections and diseases. Main Body Unlike preventative vaccines, therapeutic vaccines aim to generate cell-mediated immunity. HPV oncoproteins E6 and E7 are responsible for the malignant progression of HPV-associated diseases and are consistently expressed in HPV-associated diseases and cancer lesions; therefore, they serve as ideal targets for the development of therapeutic HPV vaccines. In this review we revisit therapeutic HPV vaccines that utilize this knowledge to treat HPV-associated lesions and cancers, with a focus on the findings of recent therapeutic HPV vaccine clinical trials. Conclusion Great progress has been made to develop and improve novel therapeutic HPV vaccines to treat existing HPV infections and diseases; however, there is still much work to be done. We believe that therapeutic HPV vaccines have the potential to become a widely available and successful therapy to treat HPV and HPV-associated diseases in the near future.

The interaction between immune cells and phosphatidylserine (PS) molecules exposed on the surface of apoptotic-tumor bodies, such as those induced by chemotherapies, contributes to the formation of an immunosuppressive tumor microenvironment (TME). Annexin A5 (AnxA5) binds with high affinity to PS externalized by apoptotic cells, thereby hindering their interaction with immune cells. Here, we show that AnxA5 administration rescue the immunosuppressive state of the TME induced by chemotherapy. Due to the preferential homing of AnxA5 to the TME enriched with PS+ tumor cells, we demonstrate in vivo that fusing tumor-antigen peptide to AnxA5 significantly enhances its immunogenicity and antitumor efficacy when administered after chemotherapy. Also, the therapeutic antitumor effect of an AnxA5-peptide fusion can be further enhanced by administration of other immune checkpoint inhibitors. Our findings support the administration of AnxA5 following chemotherapy as a promising immune checkpoint inhibitor for cancer treatment. AnnexinV has been shown to bind phosphatidylserine expressed by chemotherapy-induced apoptotic cells increasing their immunogeneicity. Here, the authors demonstrate in a preclinical tumor model that fusing tumor-antigen peptide to Annexin V enhances its efficacy when administered after chemotherapy and with other immune checkpoint inhibitors.

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45⁺ immune cells and the percentage of active CD8⁺ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

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.

Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3′ to a signal sequence and 5′ to the HSP70 gene of Mycobacterium tuberculosis . Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8 + T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8 + T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation. IMPORTANCE Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. For patients with HPV16 + cervical intraepithelial neoplasia grade 2/3 (CIN2/3), the precursor of cervical cancer, intramuscular vaccination with a DNA vaccine targeting HPV16 E7 and then a recombinant vaccinia virus expressing HPV16/18 E6-E7 fusion proteins (TA-HPV) was safe, and half of the patients cleared their lesions in a small study (NCT00788164). Here, we sought to improve upon this therapeutic approach by developing a new DNA vaccine that targets E6 and E7 of HPV16 and HPV18 for administration prior to a TA-HPV booster vaccination and for application against cervical cancer in combination with a PD-1-blocking antibody.

The Ras-ERK signaling pathway regulates diverse cellular processes in response to environmental stimuli and contains important therapeutic targets for cancer. Recent single cell studies revealed stochastic pulses of ERK activation, the frequency of which determines functional outcomes such as cell proliferation. Here we show that ERK pulses are initiated by localized protrusive activities. Chemically and optogenetically induced protrusions trigger ERK activation through various entry points into the feedback loop involving Ras, PI3K, the cytoskeleton, and cellular adhesion. The excitability of the protrusive signaling network drives stochastic ERK activation in unstimulated cells and oscillations upon growth factor stimulation. Importantly, protrusions allow cells to sense combined signals from substrate stiffness and the growth factor. Thus, by uncovering the basis of ERK pulse generation we demonstrate how signals involved in cell growth and differentiation are regulated by dynamic protrusions that integrate chemical and mechanical inputs from the environment. Cellular ERK activation occurs as discrete pulses but their relationship to upstream Ras signaling is still under debate. Here, the authors show that Ras signaling associated with cellular protrusions triggers pulsed ERK activation, thereby enabling cells to integrate chemical and mechanical stimuli.

Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.

Typical epidermodysplasia verruciformis (EV) is a rare, autosomal recessive disorder characterized by an unusual susceptibility to infection with specific skin-trophic types of human papillomavirus, principally betapapillomaviruses , and a propensity for developing malignant skin tumors in sun exposed regions. Its etiology reflects biallelic loss-of-function mutations in TMC6 ( EVER1 ), TMC8 ( EVER2 ) or CIB1 . A TMC6-TMC8-CIB1 protein complex in the endoplasmic reticulum is hypothesized to be a restriction factor in keratinocytes for βHPV infection. However, the complex is also present in lymphocytes and its loss may compromise cellular immune control of βHPV infection. Indeed, certain primary immunodeficiencies, iatrogenic immunosuppression and AIDS are associated with the atypical form of EV. While well controlled in immunocompetent mice, murine papillomavirus MmuPV1 was first isolated from immunodeficient mice with florid skin warts, modeling atypical EV. To examine their potential as a model of typical EV, Tmc6 -/- , Tmc8 -/- or wildtype FVB mice were challenged with MmuPV1. At day 16 post vaginal challenge with MmuPV1, the levels of viral transcripts were similar in Tmc6 -/- and Tmc8 -/- mice and wildtype FVB mice, arguing against Tmc6/8 acting as intracellular restriction factors. Thereafter, greater clearance of MmuPV1 by the wildtype that the Tmc6 -/- and Tmc8 -/- FVB mice was evident, supporting the hypothesis that typical EV reflects a subtle cellular immune deficit. Indeed, Tmc6 -/- or Tmc8 -/- mice exhibit partial CD8 T cell deficits and elevated Treg. While interferon-γ production and surface CD25 were similarly elevated in CD8 T cells upon in vitro stimulation with anti-CD3/CD28, the fraction of Tmc6 -/- or Tmc8 -/- CD8 T cells that were dividing was lower compared to wildtype. Typical EV patients exhibit normal control of most viral infections; Tmc6 -/- , Tmc8 -/- and wildtype FVB mice similarly controlled vaccinia virus after skin challenge and induced neutralizing antibodies.