The Safety and Efficacy of a Therapeutic Vaccine for Chronic Hepatitis B: A Follow-Up Study of Phase III Clinical Trial

The objective of the present study was to assess the safety and efficacy of a therapeutic vaccine containing both HBsAg and HBcAg (NASVAC) in patients with chronic hepatitis B (CHB) three years after the end of treatment (EOT) as a follow-up of a phase III clinical trial. NASVAC was administered ten times by the nasal route and five times by subcutaneous injection. A total of 59 patients with CHB were enrolled. Adverse events were not seen in any of the patients. Out of the 59 CHB patients, 54 patients exhibited a reduction in HBV DNA, compared with their basal levels. Although all the patients had alanine transaminase (ALT) above the upper limit of normal (>42 IU/L) before the commencement of therapy, the levels of ALT were within the ULN level in 42 patients. No patient developed cirrhosis of the liver. The present study, showing the safety and efficacy of NASVAC 3 years after the EOT, is the first to report follow-up data of an immune therapeutic agent against CHB. NASVAC represents a unique drug against CHB that is safe, of finite duration, can be administered by the nasal route, is capable of reducing HBV DNA and normalizing ALT, and contains hepatic fibrosis.

NSP4 as Adjuvant for Immunogenicity and Design of Effective Therapeutic HPV16 E6/E7/L1 DNA Vaccine in Tumoric and Healthy C57BL/6 Mice

Introduction: In humans, approximately 5% of all cancers are attributable to HPV infection. Prophylactic vaccines can inhibit viral migration and persistence. However, requirement to develop therapeutic treatments prevails. To achieve this goal, we designed a therapeutic HPV DNA vaccine encoding a construct of E6/E7/L1 and used NSP4 antigen as adjuvant to assess efficiency of this construct in generating antigen-specific antitumor immune responses.Material and Methods: Sixty female C57BL/6 mice (6–8 weeks old) were purchased from Institute Pasteur of Iran. 30 of them became cancerous, but 30 of them were healthy control. To amplify E6/E7/L1-pcDNA3, NSP4-pcDNA3, expression vector of DH5α and TC-1 cell line were used to generate a tumor. Mice were immunized with HPV DNA vaccine. Cell proliferation was assessed by MTT assay. Finally, we assessed cytokine responses (IL-2, IL-4, INF- γ), in the serum of mice spleen cells.Result: Mice receiving the NSP4/E6-E7-L1 vaccine had the highest stimulatory index compared to other groups but it was not significant. Interleukin 4/12 and INF-γ production were significantly higher in E6-E7-L1 / NSP4 group and E6-E7-L1 group compared to other groups (P <0.05). Among different groups, E6/E7/L1 + NSP4 group was able to slow down the tumor growth process, but it was not significant (p>0.05). Among the cytokines mentioned, IFN-γ and IL-12 are among the cytokines that stimulate the Th1 pathway and IL-4 cytokine stimulates the Th2 pathway and B lymphocytes.Conclusion: Our data suggest that present vaccine can stimulate innate and acquired immunity response, and can be a therapeutic vaccine in the tumoric mice.

Developments in Vaccination for Herpes Simplex Virus

Herpes simplex virus (HSV) is an alpha herpes virus, with two subtypes: HSV-1 and HSV-2. HSV is one of the most prevalent sexually transmitted infections. It is the cause of severe neonatal infections and a leading cause of infectious blindness in the Western world. As of 2016, 13.2% of the global population ages 15–49 were existing with HSV-2 infection and 66.6% with HSV-1. This high prevalence of disease and the fact that resistance to current therapies is on the rise makes it imperative to develop and discover new methods of HSV prevention and management. Among the arsenal of therapies/treatments for this virus has been the development of a prophylactic or therapeutic vaccine to prevent the complications of HSV reactivation. Our current understanding of the immune responses involved in latency and reactivation provides a unique challenge to the development of vaccines. There are no approved vaccines currently available for either prophylaxis or therapy. However, there are various promising candidates in the pre-clinical and clinical phases of study. Vaccines are being developed with two broad focuses: preventative and therapeutic, some with a dual use as both immunotherapeutic and prophylactic. Within this article, we will review the current guidelines for the treatment of herpes simplex infections, our understanding of the immunological pathways involved, and novel vaccine candidates in development.

Vaccine-Based Immunotherapy for Head and Neck Cancers

In 2019, the FDA approved pembrolizumab, a monoclonal antibody targeting PD-1, for the first-line treatment of recurrent or metastatic head and neck cancers, despite only a limited number of patients benefiting from the treatment. Promising effects of therapeutic vaccination led the FDA to approve the use of the first therapeutic vaccine in prostate cancer in 2010. Research in the field of therapeutic vaccination, including possible synergistic effects with anti-PD(L)1 treatments, is evolving each year, and many vaccines are in pre-clinical and clinical studies. The aim of this review article is to discuss vaccines as a new therapeutic strategy, particularly in the field of head and neck cancers. Different vaccination technologies are discussed, as well as the results of the first clinical trials in HPV-positive, HPV-negative, and EBV-induced head and neck cancers.

Effect of Intranodally Administered Dendritic Cell-Based HIV Vaccine in Combination With Pegylated Interferon α-2a on Viral Control Following ART Discontinuation: A Phase 2A Randomized Clinical Trial

IntroductionFunctional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches.Materials and MethodsWe conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1.ResultsTwenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4–6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients’ viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (&gt;0.5log10p = 0.05). HIV-1-specific T-cell responses (IFN-ƴ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration.DiscussionResults from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants.Clinical Trial Registration(www.ClinicalTrials.gov), identifier NCT02767193

Modelling in Synthesis and Optimization of Active Vaccinal Components

Cancer is the second leading cause of mortality worldwide, behind heart diseases, accounting for 10 million deaths each year. This study focusses on adenocarcinoma, which is a target of a number of anticancer therapies presently being tested in medical and pharmaceutical studies. The innovative study for a therapeutic vaccine comprises the investigation of gold nanoparticles and their influence on the immune response for the annihilation of cancer cells. The model is intended to be realized using Quantitative-Structure Activity Relationship (QSAR) methods, explicitly artificial neural networks combined with fuzzy rules, to enhance automated properties of neural nets with human perception characteristics. Image processing techniques such as morphological transformations and watershed segmentation are used to extract and calculate certain molecular characteristics from hyperspectral images. The quantification of single-cell properties is one of the key resolutions, representing the treatment efficiency in therapy of colon and rectum cancerous conditions. This was accomplished by using manually counted cells as a reference point for comparing segmentation results. The early findings acquired are conclusive for further study; thus, the extracted features will be used in the feature optimization process first, followed by neural network building of the required model.

Design and Immunological Validation of Macaca fascicularis Papillomavirus Type 3 Based Vaccine Candidates in Outbred Mice: Basis for Future Testing of a Therapeutic Papillomavirus Vaccine in NHPs

Persistent human papillomavirus (HPV) infections are causative for cervical neoplasia and carcinomas. Despite the availability of prophylactic vaccines, morbidity and mortality induced by HPV are still too high. Thus, an efficient therapy, such as a therapeutic vaccine, is urgently required. Herein, we describe the development and validation of Macaca fascicularis papillomavirus type 3 (MfPV3) antigens delivered via nucleic-acid and adenoviral vectors in outbred mouse models. Ten artificially fused polypeptides comprising early viral regulatory proteins were designed and optionally linked to the T cell adjuvant MHC-II-associated invariant chain. Transfected HEK293 cells and A549 cells transduced with recombinant adenoviruses expressing the same panel of artificial antigens proved proper and comparable expression, respectively. Immunization of outbred CD1 and OF1 mice led to CD8+ and CD4+ T cell responses against MfPV3 antigens after DNA- and adenoviral vector delivery. Moreover, in vivo cytotoxicity of vaccine-induced CD8+ T cells was demonstrated in BALB/c mice by quantifying specific killing of transferred peptide-pulsed syngeneic target cells. The use of the invariant chain as T cell adjuvant enhanced the T cell responses regarding cytotoxicity and in vitro analysis suggested an accelerated turnover of the antigens as causative. Notably, the fusion-polypeptide elicited the same level of T-cell responses as administration of the antigens individually, suggesting no loss of immunogenicity by fusing multiple proteins in one vaccine construct. These data support further development of the vaccine candidates in a follow up efficacy study in persistently infected Macaca fascicularis monkeys to assess their potential to eliminate pre-malignant papillomavirus infections, eventually instructing the design of an analogous therapeutic HPV vaccine.