Immunotherapeutic approaches for HPV-caused cervical cancer.

Cervical cancer, the fourth most frequent women cancer worldwide, is mostly (about 99%) associated with human papillomavirus (HPV). Despite availability of three effective prophylactic vaccines for more than one decade and some other preventive measures, it is still the fourth cause of cancer death among women globally. Thus, development of therapeutic vaccines seems essential, which has been vastly studied using different vaccine platforms. Even with very wide efforts during the past years, no therapeutic vaccine has been approved yet, which might be partly due to the complex events and interactions taken place in the tumor microenvironment. On the other hand, immunotherapy has opened its way into the management plans of some cancers. The recent approval of pembrolizumab for the treatment of metastatic/recurrent cervical cancer brings new hopes to the management of this disease, while some other immunotherapeutic approaches are also under investigation either alone or in combination with vaccines. Here, following a summary about HPV and its pathogenesis, cervical cancer therapeutic vaccines would be reviewed. Cell-based vaccines as well as immunomodulation and other modalities used along with vaccines would be also discussed.

Designing a therapeutic and prophylactic candidate vaccine against human papillomavirus through vaccinomics approaches.

OBJECTIVE: Human papillomavirus (HPV) is the main cause of cervical cancer, the 4th prominent cause of death in women globally. Previous vaccine development projects have led to several approved prophylactic vaccines available commercially, all of which are made using major capsid-based (L1). Administration of minor capsid protein (L2) gave rise to the second generation investigational prophylactic HPV vaccines, none of which are approved yet due to low immunogenicity provided by the L2 capsid protein. On the other hand, post-translation proteins, E6 and E7, have been utilized to develop experimental therapeutic vaccines. Here, in silico designing of a therapeutic and prophylactic vaccine against HPV16 is performed. METHODS: In this study, several immunoinformatic and computational tools were administered to identify and design a vaccine construct with dual prophylactic and therapeutic applications consisting of several epitope regions on L2, E6, and E7 proteins of HPV16. RESULTS: Immunodominant epitope regions (aa 12-23 and 78-78 of L2 protein, aa 11-27 of E6 protein, and aa 70-89 of E7 protein) were employed, which offered adequate immunogenicity to induce immune responses. Resuscitation-promoting factors (RpfB and RpfE) of Mycobacterium tuberculosis were integrated in two separate constructs as TLR4 agonists to act as vaccine adjuvants. Following physiochemical and structural evaluations carried out by various bioinformatics tools, the designed constructs were modeled and validated, resulting in two 3D structures. Molecular docking and molecular dynamic simulations suggested stable ligand-receptor interactions between the designed construct and TLR4. CONCLUSION: Ultimately, this study led to suggest the designed construct as a potential vaccine candidate with both prophylactic and therapeutic applications against HPV by promoting Th1, Th2, CTL, and B cell immune responses, which should be further confirmed in experimental studies.

Administration of COVID-19 vaccines in immunocompromised patients.

Since the beginning of vaccination programs against COVID-19 in different countries, several populations such as patients with specific immunological conditions have been considered as the priorities for immunization. In this regard, patients with autoimmune diseases or those receiving immunosuppressive agents and anti-cancer therapies, need special attention. However, no confirmed data is presently available regarding COVID-19 vaccines in these populations due to exclusion from the conducted clinical trials. Given the probable suppression or over-activation of the immune system in such patients, reaching a consensus for their vaccination is critical, besides gathering data and conducting trials, which could probably clarify this matter in the future. In this review, besides a brief on the available COVID-19 vaccines, considerations and available knowledge about administering similar vaccines in patients with cancer, hematopoietic stem cell transplantation, solid organ transplantation, multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatologic and dermatologic autoimmune disorders are summarized to help in decision making. As discussed, live-attenuated viruses, which should be avoided in these groups, are not employed in the present COVID-19 vaccines. Thus, the main concern regarding efficacy could be met using a potent COVID-19 vaccine. Moreover, the vaccination timing for maximum efficacy could be decided according to the patient's condition, indicated medications, and the guides provided here. Post-vaccination monitoring is also advised to ensure an adequate immune response. Further studies in this area are urgently warranted.

Deep survey for designing a vaccine against SARS-CoV-2 and its new mutations.

The ongoing global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has prompted worldwide vaccine development. Several vaccines have been authorized by WHO, FDA, or MOH of different countries. However, issues such as need for cold chain, price, and most importantly access problems have limited vaccine usage in some nations especially developing countries. Moreover, the vast global demand justifies further attempts for vaccine development. Multi-epitope polypeptide vaccines enjoy several key features including safety and lower production and transfer costs and could be designed by in silico tools. Spike protein (S), membrane protein (M), and nucleocapsid protein (N), the three major structural proteins of SARS-CoV-2, are ideal candidates for epitope selection. ORF3a (open reading frame3a), a transmembrane protein with pro-apoptotic functions, could be another proper target. Thus, a novel multi-epitope vaccine against SARS-CoV-2 was designed using these four proteins and LL37, a TLR3 agonist adjuvant, through different immunoinformatics and bioinformatics tools. The proposed multi-epitope vaccine is expected to induce robust humoral and cellular immune responses against SARS-CoV-2 with a population coverage of 76.92 % due to containing different immunodominant epitopes and LL37 adjuvant. Selecting epitopes derived from one functional and three structural proteins suggests the protective ability of the vaccine irrespective of probable virus mutations. The computationally observed proper interaction of LL37 with TLR3 implies its ability to induce immune responses effectively. Besides, it showed acceptable structural and physicochemical properties. The in-silico cloning results predicted its high efficiency production in Escherichia coli. Future experimental studies could further confirm its immunological efficacy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11756-021-00866-y.

Interferon-inducer antivirals: Potential candidates to combat COVID-19.

Coronavirus disease 2019 (COVID-19) is an infective disease generated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the pandemic urgency and lack of an effective cure for this disease, drug repurposing could open the way for finding a solution. Lots of investigations are ongoing to test the compounds already identified as antivirals. On the other hand, induction of type I interferons are found to play an important role in the generation of immune responses against SARS-CoV-2. Therefore, it was opined that the antivirals capable of triggering the interferons and their signaling pathway, could rationally be beneficial for treating COVID-19. On this basis, using a database of antivirals, called drugvirus, some antiviral agents were derived, followed by searches on their relevance to interferon induction. The examined list included drugs from different categories such as antibiotics, immunosuppressants, anti-cancers, non-steroidal anti-inflammatory drugs (NSAID), calcium channel blocker compounds, and some others. The results as briefed here, could help in finding potential drug candidates for COVID-19 treatment. However, their advantages and risks should be taken into account through precise studies, considering a systemic approach. Even though the adverse effects of some of these drugs may overweight their benefits, considering their mechanisms and structures may give a clue for designing novel drugs in the future. Furthermore, the antiviral effect and IFN-modifying mechanisms possessed by some of these drugs might lead to a synergistic effect against SARS-CoV-2, which deserve to be evaluated in further investigations.

Using surrogate markers in primary electronic patient record systems to confirm or refute the diagnosis of diabetes.

BACKGROUND: UK primary care records are computerised and these records are used for both research and quality improvement. However, there is disparity in the prevalence of diabetes found in epidemiological studies compared with that reported through the UK's national quality improvement scheme. OBJECTIVE: To investigate how non-diagnostic computer data could be used to identify, confirm or refute prevalent cases of people with diabetes. METHOD: We carried out a literature review to identify the most accurate non-diagnostic markers. For each type of diabetes we focused on four broad areas; demographic details, biochemical markers, clinical features and therapeutic strategies. Sample markers were tested by calculating their positive predictive value (PPV) and sensitivity (Sn) and their ability to differentiate between types of diabetes. RESULTS: Biochemical markers were useful in identifying cases of diabetes but not in differentiating between types of diabetes as the same plasma glucose criterion is used to diagnose Type 1, Type 2, and 'other' types of diabetes; the lack of a 'fasting' qualifier blunts the use of this marker. Auto-immune markers were the most accurate in identifying Type 1 diabetes but are not recorded frequently in primary care. Clinical features of diabetes and therapeutic strategies were of some use--however, without time sequence data are difficult to interpret. Raised plasma glucose (PG), and glycated haemoglobin (HbA1c), had useful PPV but low Sn. When PG was more than 7.0 and less than 11.1 mmol/l, PPV equalled 77.8% and Sn 48%; and when PG was 11.1, PPV equalled 92% and Sn 17%. For an HbA1c of more than 6.5%, PPV was 89% and Sn 73.3%, and for an HbA1c of more than 8, PPV was 92% and Sn 26%. A person with a combination of aged under 30 years and prescribed insulin has an 84% PPV of Type 1 diabetes; if they also have a BMI <30 kg/m2 the PPV increases to 88%. A person age over 45 years and with a BMI >30 kg/m2 has a 5.3% PPV of Type 2 diabetes; if they are also hypertensive the PPV is 30%; Asian ethnicity increases PPV to 44%. CONCLUSION: Non-diagnostic data has the potential to confirm or refute the diagnosis of diabetes and identify its type.