Vaccines — Open Access Journal

Q fever is a zoonosis of concern in many countries. Vaccination is the most effective means of prevention, and since 1989, Australia has had a licensed Q fever vaccine, Q-VAX^®. This vaccine was also used in the Netherlands in 2011 following the largest recorded Q fever outbreak globally. There is a paucity of available data regarding adverse events following immunisation (AEFI) for young adult females. Such data are important for informing future vaccination recommendations both within Australia and internationally. This study collected Q fever vaccine (Q-VAX^®) AEFI data in veterinary and animal science students at Australian universities. Students were enrolled at the time of vaccination and were emailed a link to an online AEFI survey one week later. Of the 60% (499/827) that responded, 85% were female and the median age was 18 years. Local injection site reactions (ISRs) occurred in 98% (95%; CI 96–99%) of respondents, of which 30% (95% CI 24–32%) were severe. Systemic AEFI occurred in 60% (95%; CI 55–64%) of respondents within the seven days following immunisation. Medical attention was sought by 19/499 (3.8%) respondents, of whom one sought treatment at a hospital emergency department. Females were more likely than males to experience any local ISR (odds ratio [OR] 9.3; 95% CI 2.5–33.8; p < 0.001), ISRs of greater severity (OR 2.5; 95% CI 1.5–4.2; p < 0.001), and any systemic AEFI (OR 1.9; 95% CI 1.1–3.1; p = 0.016). These safety data suggest that a high frequency of adverse events following immunisation should be expected in young adults, particularly females. However, the consequences of Q fever disease are potentially far more debilitating. Full article

The two currently available ten- and thirteen-valent pneumococcal conjugate vaccines (PCV10 and PCV13) both induce serotype-specific IgG anti-polysaccharide antibodies and are effective in preventing vaccine serotype induced invasive pneumococcal disease (IPD) as well as in reducing overall vaccine-serotype carriage and transmission and thereby inducing herd protection in the whole population. IgG levels decline after vaccination and could become too low to prevent carriage acquisition and/or pneumococcal disease. We compared the levels of 10-valent (PCV10) and 13-valent (PCV13) pneumococcal vaccine induced serum IgG antibodies at multiple time points after primary vaccinations. Data from two separate studies both performed in the Netherlands in infants vaccinated at 2, 3, and 4 months of age with either PCV10 or PCV13 were compared. Antibody levels were measured at 5, 8, and 11 months of age, during the interval between the primary immunization series and the 11-months booster dose. Serotype-specific IgG levels were determined by multiplex immunoassay. Although antibody kinetics showed significant variation between serotypes and between vaccines for the majority of the 10 shared serotypes, i.e., 1, 5, 7F, 9V, 14, 18C, and 23F, antibody concentrations were sufficiently high for both vaccines, immediately after the primary series and throughout the whole period until the booster dose. In contrast, for serotypes 4 and 19F in the PCV10 group and for serotypes 4 and 6B in the PCV13 group, IgG antibody concentrations already come within reach of the frequently used seroprotection level of 0.35 μg/mL immediately after the primary series at the five month time point and/or at eight months. This paper addresses the importance of revealing differences in serotype-specific and pneumococcal vaccine-dependent IgG antibody patterns during the interval between the primary series and the booster dose, an age period with a high IPD incidence. Trial registration: www.trialregister.nl NTR3069 and NTR2316. Full article

As evidenced from recent epidemics, both Ebola and Zika virus infection are potentially catastrophic when occurring in pregnant women. Ebola virus causes extremely high rates of mortality in both mothers and infants; Zika virus is a TORCH infection that produces a congenital malformation syndrome and pediatric neurodevelopmental abnormalities. Production of efficacious vaccines has been a public health priority for both infections. Unfortunately, during the clinical trials and subsequent deployment of a vaccine for the Ebola virus, pregnant and lactating women were, and continue to be, excluded from receiving the life-saving vaccine. The most serious consequence of Zika virus infection, congenital Zika syndrome, results from fetal infection during pregnancy. Thus, pregnant women have a major stake in the ongoing development of a vaccine for Zika virus. The exclusion of pregnant women from the development, clinical trials and administration of a potential Zika vaccine unfairly deprives them and their infants of the protection they need against this potentially catastrophic intrauterine infection. When creating policy about these issues, it is important to critically evaluate vaccine safety in pregnancy in the context of the substantial risk of infection for the pregnant woman and her fetus in the absence of immunization. Full article

Although different types of therapeutic vaccines against established cancerous lesions in various indications have been developed since the 1990s, their clinical benefit is still very limited. This observed lack of effectiveness in cancer eradication may be partially due to the often deficient immunocompetent status of cancer patients, which may facilitate tumor development by different mechanisms, including immune evasion. The most frequently used cellular vehicle in clinical trials are dendritic cells (DCs), thanks to their crucial role in initiating and directing immune responses. Viable vaccination options using DCs are available, with a positive toxicity profile. For these reasons, despite their limited therapeutic outcomes, DC vaccination is currently considered an additional immunotherapeutic option that still needs to be further explored. In this review, we propose potential actions aimed at improving DC vaccine efficacy by counteracting the detrimental mechanisms recognized to date and implicated in establishing a poor immunocompetent status in cancer patients. Full article

Herpes zoster (HZ) vaccination is approved for adults aged 50+ for the prevention of HZ, but it is underutilized. The objective of this study was to evaluate the association between out-of-pocket cost and HZ vaccine utilization. Adults aged 65 or older enrolled for at least 12 months in Medicare Advantage/Part D (MAPD) and Medicare Part D only (PDP) plans from 1 January 2007 to 30 June 2014 were selected. Abandonment was defined as a reversed claim for HZ vaccine with no other paid claim within 90 days. Out-of-pocket costs used were actual amounts recorded in the claim. Overall, the HZ vaccine abandonment rate was 7.3%. Mean out-of-pocket costs were higher for individuals who abandoned versus those who did not ($88 (±$55) versus $80 (± $49)). Logistic regression indicated individuals with out-of-pocket costs of $80–$90 were 21% more likely (OR = 1.21, 1.16–1.27 95% CI), and those with out-of-pocket costs >$90 were 90% more likely (OR = 1.90, 1.85–1.96 95% CI) to abandon than those with out-of-pocket costs <$80. The models also suggested that socioeconomic, racial, and ethnic disparities in vaccine abandonment existed. Different vaccine targeting efforts and pharmacy benefit design strategies may be needed to increase use, improve adherence, and minimize disparities. Full article

In early 2014, a relatively obscure virus, the Zika virus, made headlines worldwide following an increase in the number of congenital malformations. Since then, research on Zika virus, treatment and vaccines have progressed swiftly with various drugs being repurposed and vaccines heading into clinical trials. Nonetheless, the need for a vaccine is crucial in order to eradicate this re-emerging arthropod-borne virus which remained silent since its first discovery in 1947. In this review, we focused on how the inconspicuous virus managed to spread, the key immunological factors required for a vaccine and the various vaccine platforms that are currently being studied. Full article

The Ribonuclease A Superfamily is composed of cationic peptides that are secreted by immune cells and epithelial tissues. Although their physiological roles are unclear, several members of the vertebrate Ribonuclease A Superfamily demonstrate antimicrobial and immune modulation activities. The objective of this review is to provide an overview of the published literature on the Ribonuclease A Superfamily with an emphasis on each peptide’s regulation, antimicrobial properties, and immunomodulatory functions. As additional insights emerge regarding the mechanisms in which these ribonucleases eradicate invading pathogens and modulate immune function, these ribonucleases may have the potential to be developed as a novel class of therapeutics for some human diseases. Full article

Avian viral diseases including avian influenza, Marek’s disease and Newcastle disease are detrimental to economies around the world that depend on the poultry trade. A significant zoonotic threat is also posed by avian influenza viruses. Vaccination is an important and widely used method for controlling these poultry diseases. However, the current vaccines do not provide full protection or sterile immunity. Hence, there is a need to develop improved vaccines. The major aim of developing improved vaccines is to induce strong and specific humoral and cellular immunity in vaccinated animals. One strategy used to enhance the immunogenicity of vaccines is the selective delivery of protective antigens to antigen-presenting cells (APCs) including dendritic cells, macrophages and B cells. APCs have a central role in the initiation and maintenance of immune responses through their ability to capture, process and present antigens to T and B cells. Vaccine technology that selectively targets APCs has been achieved by coupling antigens to monoclonal antibodies or ligands that are targeted by APCs. The aim of this review is to discuss existing strategies of selective delivery of antigens to APCs for effective vaccine development in poultry. Full article

Influenza H7N9 virus is a potentially pandemic subtype to which most people are immunologically naïve. To be better prepared for the potential occurrence of an H7N9 pandemic, in 2017 the World Health Organization recommended developing candidate vaccine viruses from two new H7N9 viruses, A/Guangdong/17SF003/2016 (A/GD) and A/Hong Kong/125/2017 (A/HK). This report describes the development of live attenuated influenza vaccine (LAIV) candidates against A/GD and A/HK viruses and study of their safety and immunogenicity in the ferret model in order to choose the most promising one for a phase I clinical trial. The A/HK-based vaccine candidate (A/17/HK) was developed by classical reassortment in eggs. The A/GD-based vaccine candidate (A/17/GD) was generated by reverse genetics. Ferrets were vaccinated with two doses of LAIV or phosphate-buffered saline. Both H7N9 LAIVs tested were safe for ferrets, as shown by absence of clinical signs, and by virological and histological data; they were immunogenic after a single vaccination. These results provide a compelling argument for further testing of these vaccines in volunteers. Since the A/HK virus represents the cluster that has caused the majority of human cases, and because the A/HK-based LAIV candidate was developed by classical reassortment, this is the preferred candidate for a phase I clinical trial. Full article

Flaviviruses include many medically important viruses, such as Dengue virus (DENV), Japanese encephalitis (JEV), tick-borne encephalitis (TBEV), West Nile (WNV), yellow fever (YFV), and Zika viruses (ZIKV). Currently, there are licensed human vaccines for DENV, JEV, TBEV and YFV, but not for WNV or ZIKV. Memory T cells play a central role in adaptive immunity and are important for host protection during flavivirus infection. In this review, we discuss recent findings from animal models and clinical trials and provide new insights into the role of memory T cells in host protective immunity upon vaccination with the licensed flavivirus vaccines. Full article

Melittin, the major active peptide of honeybee venom (BV), has potential for use in adjuvant immunotherapy. The immune system response to different stimuli depends on the secretion of different metabolites from macrophages. One potent stimulus is lipopolysaccharide (LPS), a component isolated from gram-negative bacteria, which induces the secretion of pro-inflammatory cytokines in macrophage cell cultures. This secretion is amplified when LPS is combined with melittin. In the present study, pure melittin was isolated from whole BV by flash chromatography to obtain pure melittin. The ability of melittin to enhance the release of tumour necrosis factor-α (TNF-α), Interleukin (IL-1β, IL-6, and IL-10) cytokines from a macrophage cell line (THP-1) was then assessed. The response to melittin and LPS, applied alone or in combination, was characterised by metabolic profiling, and the metabolomics results were used to evaluate the potential of melittin as an immune adjuvant therapy. The addition of melittin enhanced the release of inflammatory cytokines induced by LPS. Effective chromatographic separation of metabolites was obtained by liquid chromatography-mass spectrometry (LC-MS) using a ZIC-pHILIC column and an ACE C4 column. The levels of 108 polar and non-polar metabolites were significantly changed (p ˂ 0.05) following cell activation by the combination of LPS and melittin when compared to untreated control cells. Overall, the findings of this study suggested that melittin might have a potential application as a vaccine adjuvant. Full article

To evaluate the humoral immune response to mixed Equine Influenza vaccination, a common practice in the field, an experimental study was carried out on 42 unvaccinated thoroughbred weanling foals divided into six groups of seven. Three groups were vaccinated using a non-mixed protocol (Equilis^® Prequenza-Te, Proteqflu-Te^® or Calvenza-03^®) and three other groups were vaccinated using a mix of the three vaccines mentioned previously. Each weanling underwent a primary EI vaccination schedule composed of two primary immunisations (V1 and V2) four weeks apart followed by a third boost immunisation (V3) six months later. Antibody responses were monitored until one-year post-V3 by single radial haemolysis (SRH). The results showed similar antibody responses for all groups using mixed EI vaccination and the group exclusively vaccinated with Equilis^® Prequenza-TE, which were significantly higher than the other two groups vaccinated with Proteqflu-TE^® and Calvenza-03^®. All weanlings (100%) failed to seroconvert after V1 and 21% (9/42) still had low or no SRH antibody titres two weeks post-V2. All weanlings had seroconverted and exceeded the clinical protection threshold one month after V3. The poor response to vaccination was primarily observed in groups exclusively vaccinated with Proteqflu-Te^® and Calvenza-03^®. A large window of susceptibility (3–4.5-month duration) usually called immunity gap was observed after V2 and prior to V3 for all groups. The SRH antibody level was maintained above the clinical protection threshold for three months post-V3 for the groups exclusively vaccinated with Proteqflu-Te^® and Calvenza-03^®, and six months to one year for groups using mixed EI vaccination or exclusively vaccinated with Equilis^® Prequenza-Te. This study demonstrates for the first time that the mix of EI vaccines during the primary vaccination schedule has no detrimental impact on the correlate of protection against EIV infection. Full article

From the perspective of vaccine development, it is imperative to accurately diagnose target infections in order to exclude subjects with prior exposure from evaluations of vaccine effectiveness, to track incident infection during the course of a clinical trial and to differentiate immune reactions due to natural infections from responses that are vaccine related. When vaccine development is accelerated to a rapid pace in response to emerging infectious disease threats, the challenges to develop such diagnostic tools is even greater. This was observed through the recent expansion of Zika virus infections into the Western Hemisphere in 2014–2017. When initial Zika vaccine clinical trials were being designed and launched in response to the outbreak, there were no standardized sets of viral and immunological assays, and no approved diagnostic tests for Zika virus infection. The diagnosis of Zika virus infection is still an area of active research and development on many fronts. Here we review emerging infectious disease vaccine clinical assay development and trial execution with a special focus on the state of Zika virus clinical assays and diagnostics. Full article

Exosomes are extracellular vesicles ranging from 30 to 150 nm in diameter that contain molecular constituents of their host cells. They are released from different types of cells ranging from immune to tumor cells and play an important role in intercellular communication. Exosomes can be manipulated by altering their host cells and can be loaded with products of interest such as specific drugs, proteins, DNA and RNA species. Due to their small size and the unique composition of their lipid bilayer, exosomes are capable of reaching different cell types where they alter the pathophysiological conditions of the recipient cells. There is growing evidence that exosomes are used as vehicles that can modulate the immune system and play an important role in cancer progression. The cross communication between the tumors and the cells of the immune system has gained attention in various immunotherapeutic approaches for several cancer types. In this review, we discuss the exosome biogenesis, their role in inter-cellular communication, and their capacity to modulate the immune system as a part of future cancer immunotherapeutic approaches and their potential to serve as biomarkers of therapy response. Full article

The first human influenza virus was isolated more than 85 years ago, and several vaccine candidates were developed and tested soon after. Yet, controlling infections mediated by this respiratory pathogen continues to present a formidable challenge. Development of an effective influenza vaccine has been undermined by the dynamic nature of influenza viruses: these viruses have the unique capacity to escape pre-existing immunity. In this perspective, I highlight pre-existing immunity as a different, but related, hurdle that may actually lessen the effectiveness of influenza vaccine-induced immune responses. Specifically, I discuss the impact of pre-existing immunity on the generation of de novo B cell responses to influenza vaccination. As the influenza virus changes its major antigenic determinants, it creates new ones in the process. Our immune system adapts by targeting the new determinants. However, pre-existing antibodies and memory B cells interfere with the generation of de novo responses against these newly formed epitopes, rendering vaccines less effective. Overcoming such interference is essential for the development of more effective influenza vaccines. Full article

Ulcerative colitis (UC) is characterized by aberrant regulation of tight junctions (TJ), signal transducer and activator of transcription 3 (STAT3), and interleukin (IL)-8/18, which lead to intestinal barrier defects. Catestatin (CST), an enterochromaffin-derived peptide, regulates immune communication and STAT-3 in the inflamed intestine. Here, we investigated the effects of CST during the development of inflammation using human biopsies from patients with active UC, human colonic epithelial cells (Caco2), and an experimental model of UC (dextran sulfate sodium [DSS]-colitis). In UC patients, the protein and mRNA level of CST was significantly decreased. Colonic expression of CST showed a strong positive linear relationship with TJ proteins and STAT3, and a strong negative correlation with IL-8 and IL-18. Intra-rectal administration of CST reduced the severity of experimental colitis, IL-18 colonic levels, maintained TJ proteins and enhanced the phosphorylation of STAT3. CST administration increased proliferation, viability, migration, TJ proteins, and p-STAT3 levels, and reduced IL-8 & IL-18 in LPS- & DSS-induced Caco2 cell epithelial injury, and the presence of STAT-3 inhibitor abolished the beneficial effect of CST. In inflammatory conditions, we conclude that CST could regulate intestinal mucosal dynamic via a potential STAT3-dependent pathway that needs to be further defined. Targeting CST in intestinal epithelial cells (IECs) should be a promising therapeutic approach such as when intestinal epithelial cell homeostasis is compromised in UC patients. Full article

Influenza virus M2 protein has a highly conserved ectodomain (M2e) as a cross-protective antigenic target. We investigated the antigenic and immunogenic properties of tandem repeat M2e (5xM2e) proteins and virus-like particles (5xM2e VLP) to better understand how VLP and protein platform vaccines induce innate and protective adaptive immune responses. Despite the high antigenic properties of 5xM2e proteins, the 5xM2e VLP was superior to 5xM2e proteins in inducing IgG2a isotype antibodies, T cell responses, plasma cells and germinal center B cells as well as in conferring cross protection. Mice primed with 5xM2e VLP were found to be highly responsive to 5xM2e protein boost, overcoming the low immunogenicity and protective efficacy of 5xM2e proteins. Immunogenic differences between VLPs and proteins in priming immune responses might be due to an intrinsic ability of 5xM2e VLP to stimulate dendritic cells secreting T helper type 1 (Th1) cytokines. We also found that 5xM2e VLP was effective in inducing inflammatory cytokines and chemokines, and in recruiting macrophages, monocytes, neutrophils, and CD11b⁺ dendritic cells at the injection site. Therefore, this study provides evidence that 5xM2e VLP is an effective vaccine platform, inducing cross-protection by stimulating innate and adaptive immune responses. Full article

Dendritic cell (DC) vaccines show promising effects in cancer immunotherapy. However, their efficacy is affected by a number of factors, including (1) the quality of the DC vaccine and (2) tumor immune evasion. The recently characterized BDCA1+CD14+ immunosuppressive cells combine both aspects; their presence in DC vaccines may directly hamper vaccine efficacy, whereas, in patients, BDCA1+CD14+ cells may suppress the induced immune response in an antigen-specific manner systemically and at the tumor site. We hypothesize that BDCA1+CD14+ cells are present in a broad spectrum of cancers and demand further investigation to reveal treatment opportunities and/or improvement for DC vaccines. In this review, we summarize the findings on BDCA1+CD14+ cells in solid cancers. In addition, we evaluate the presence of BDCA1+CD14+ cells in leukemic cancers. Preliminary results suggest that the presence of BDCA1+CD14+ cells correlates with clinical features of acute and chronic myeloid leukemia. Future research focusing on the differentiation from monocytes towards BDCA1+CD14+ cells could reveal more about their cell biology and clinical significance. Targeting these cells in cancer patients may improve the outcome of cancer immunotherapy. Full article