Influenza and memory T cells : how to awake the force

Annual influenza vaccination is an effective way to prevent human influenza. Current vaccines are mainly focused on eliciting a strain-matched humoral immune response, requiring yearly updates, and do not provide protection for all vaccinated individuals. The past few years, the importance of cellular immunity, and especially memory T cells, in long-lived protection against influenza virus has become clear. To overcome the shortcomings of current influenza vaccines, eliciting both humoral and cellular immunity is imperative. Today, several new vaccines such as infection-permissive and recombinant T cell inducing vaccines, are being developed and show promising results. These vaccines will allow us to stay several steps ahead of the constantly evolving influenza virus

Progress in Vaccine Development for HCV Infection

Hepatitis C virus (HCV) is a blood-transmitted disease that spreads among 3% of the world’s population causing seriously increasing mortality rates. The HCV prevalence in Egypt in October 2008 was 14.7% and declined to 6.3% in the survey carried out in October 2015. Nowadays, the new direct-acting antivirals (DAAs) show amazing results especially with regard to HCV genotype 1, but there is still a great necessity to produce a vaccine to avoid this viral infection. Additionally, neutralizing anti-HCV antibodies could be utilized in combination with DAAs empowering their effect. A powerful candidate HCV vaccine should create comprehensively cross-receptive T cells CD4 and CD8 and effectively neutralizing antibodies to successfully clear the virus. The current clinical trials for HCV vaccines comprise synthetic peptides, DNA-based vaccines, or recombinant protein vaccines. Several preclinical vaccine studies are under research including cell culture-derived HCV (HCVcc), HCV-like particles, and recombinant adenoviral vaccines. This mini-review will discuss the prevalence of HCV worldwide and in Egypt. We will present the recent progress in basic research and preclinical and clinical studies for HCV vaccine. Finally, it will present the phenomena of spontaneous clearance of HCV without treatment as a model for study of HCV vaccine development

Apolipoprotein E mediates evasion from hepatitis C virus−neutralizing antibodies

Background & Aims Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined. Methods We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell culture−derived HCV−producing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell culture−derived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein E2 and HCV virions by immunoprecipitation. Results Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein E2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies. Conclusions In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines

Which Vaccination Strategies and Immune Responses are More Effective Against HIV Infections?

Vaccination is one of the most successful approaches for controlling various viral diseases. Novel approaches will be needed to develop highly effective vaccines to prevent infectious diseases such as HIV. There are many aspects of HIV-1 biology that make the development of an HIV vaccine difficult, including viral diversity, effective type of immune response, and suitable experimental model for preclinical trials. In spite of these challenges, recent published results showed that a vaccine regimen could reduce HIV infection rates by 31% in Thailand. This vaccine named as RV144 is composed of a recombinant canarypox vector expressing three HIV-1 proteins as a prime and two different recombinant HIV-1 gp120 envelope glycoproteins with alum adjuvant as a boost. In addition, a subunit vaccine constructed from the viral envelope protein could be efficiently developed using new techniques available through genetic engineering. The current HIV-1 vaccine development focuses on antibody-based approaches. It was shown that immunization with the viral envelope glycoprotein, gp120, should generate neutralizing antibodies that would prevent infection, thereby yielding protective immunity. However, HIV could develop many pathways to escape from antibodies that bind to the different parts of the viral envelope molecules. Thus, the generation of neutralizing antibodies is very difficult after viral infection or immunization protocols. Indeed, the viral envelope molecules (Env) possess glycosylated residues that cover surface epitopes for binding and neutralizing antibodies, even if the antibodies are produced. Furthermore, the trimeric structures of envelope molecules show rapid conformational changes due to the interaction with viral cell surface receptors, CCR5/CXCR4 and CD4; thus the transition state is very poor to be recognized by the immune system. Currently, studies focus on generating stable trimeric envelope molecules (gp120/gp41) as immunogens that can induce neutralizing antibodies that can compete for binding to the cell surface receptors. Altogether, it is clear that the design of a vaccine to elicit HIV-neutralizing antibodies is not straightforward, and it causes major challenges in structural biology and immunology, several other studies strongly suggest cytotoxic T-lymphocyte (CTL)-based immune responses against HIV infections. Indeed, CD8+ T cells play a major role in controlling viral replication during primary HIV infections and in maintaining a stable viral load during the chronic phase. In this line, live-attenuated vaccines could elicit more potent and durable pathogen-specific immune responses than inactivated or subunit vaccines. Generally, DNA vaccines are poorly immunogenic alone, and viral vector vaccines are ineffective due to vector-specific immune responses if used repeatedly; hence, the two approaches have often been tested in combination as prime-boost vaccination strategies. Indeed, the prime-boost vaccination has been considered as an efficient strategy against HIV infections. In this chapter, we will represent challenges to determine the best vaccine strategies against HIV infections

Using the nonhuman primate model of HCMV to guide vaccine development.

The natural history of human cytomegalovirus (HCMV) is inextricably associated with mucosal surfaces. The vast preponderance of primary infections occur following mucosal exposure to infectious virions, and the high seroprevalence of HCMV throughout the world is due to long-term excretion of HCMV in bodily fluids from multiple mucosal sites. Accumulating evidence presents a model where the earliest virus-host interactions following infection dictate the long-term pattern of infection, alter innate immune responses that skew adaptive responses to enable persistence within an immune host, and are essential for reinfection of a host with prior immunity. HCMV has evolved a complex repertoire of viral functions fine-tuned to manipulate the immune environment both locally at the sites of infection and systemically within an infected host. Collectively, viral immune modulation represents a significant impediment for an HCMV vaccine. As HCMV can disseminate beyond mucosal surfaces to reinfect immune hosts, it may not matter whether prior immunity results from prior infection or immunization. A better understanding of the earliest virus-hosts interactions at mucosal surfaces may identify elements of the viral proteome that are especially susceptible to vaccine-mediated disruption and prevent challenge virus from disseminating to distal sites, particularly the maternal-fetal interface

Breast Cancer Vaccines: New insights into Immunomodulatory and Nano-therapeutic Approaches

Breast cancer (BC) is known to be a highly heterogeneous disease that is clinically subdivided into four primary molecular subtypes, each having distinct morphology and clinical implications. These subtypes are principally defined by hormone receptors and other proteins involved (or not involved) in BC development. BC therapeutic vaccines [including peptide-based vaccines, protein-based vaccines, nucleic acid-based vaccines (DNA/RNA vaccines), bacterial/viral-based vaccines, and different immune cell-based vaccines] have emerged as an appealing class of cancer immunotherapeutics when used alone or combined with other immunotherapies. Employing the immune system to eliminate BC cells is a novel therapeutic modality. The benefit of active immunotherapies is that they develop protection against neoplastic tissue and readjust the immune system to an anti-tumor monitoring state. Such immunovaccines have not yet shown effectiveness for BC treatment in clinical trials. In recent years, nanomedicines have opened new windows to increase the effectiveness of vaccinations to treat BC. In this context, some nanoplatforms have been designed to efficiently deliver molecular, cellular, or subcellular vaccines to BC cells, increasing the efficacy and persistence of anti-tumor immunity while minimizing undesirable side effects. Immunostimulatory nano-adjuvants, liposomal-based vaccines, polymeric vaccines, virus-like particles, lipid/calcium/phosphate nanoparticles, chitosan-derived nanostructures, porous silicon microparticles, and selenium nanoparticles are among the newly designed nanostructures that have been used to facilitate antigen internalization and presentation by antigen-presenting cells, increase antigen stability, enhance vaccine antigenicity and remedial effectivity, promote antigen escape from the endosome, improve cytotoxic T lymphocyte responses, and produce humoral immune responses in BC cells. Here, we summarized the existing subtypes of BC and shed light on immunomodulatory and nano-therapeutic strategies for BC vaccination. Finally, we reviewed ongoing clinical trials on BC vaccination and highlighted near-term opportunities for moving forward

In the era of rapid mRNA-based vaccines: why is there no effective hepatitis C virus vaccine yet?

Hepatitis C virus (HCV) is responsible for no less than 71 million people chronically infected and is one of the most frequent indications for liver transplantation worldwide. Despite direct-acting antiviral therapies fuel optimism in controlling HCV infections, there are several obstacles regarding treatment accessibility and reinfection continues to remain a possibility. Indeed, the majority of new HCV infections in developed countries occur in people who inject drugs and are more plausible to get reinfected. To achieve global epidemic control of this virus the development of an effective prophylactic or therapeutic vaccine becomes a must. The coronavirus disease 19 (COVID-19) pandemic led to auspicious vaccine development against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which has renewed interest on fighting HCV epidemic with vaccination. The aim of this review is to highlight the current situation of HCV vaccine candidates designed to prevent and/or to reduce HCV infectious cases and their complications. We will emphasize on some of the crossroads encountered during vaccine development against this insidious virus, together with some key aspects of HCV immunology which have, so far, hampered the progress in this area. The main focus will be on nucleic acid-based as well as recombinant viral vector-based vaccine candidates as the most novel vaccine approaches, some of which have been recently and successfully employed for SARS-CoV-2 vaccines. Finally, some ideas will be presented on which methods to explore for the design of live-attenuated vaccines against HCV

CD8+ T-cell responses in vaccination: Reconsidering targets and function in the context of chronic antigen stimulation

Cytotoxic CD8 T cells play important roles in eliminating infected and transformed cells. Owing to their potential for therapeutic applications, significant efforts are dedicated toward developing CD8 T cell-based vaccines. Thus far, CD8 T-cell vaccination strategies have had limited success therapeutically in contrast to those targeting antibody-based immunity. However, if the current challenges and gaps in the understanding of T-cell biology are overcome, the full potential of rational CD8 T-cell vaccine design might be realized. Here, we review recent progress in this direction, focusing on target selection and maintenance of function in the settings of chronic infections and cancers