Vaccines, Volume 9, Issue 5 (May 2021) – 126 articles

The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking. Full article

Glaesserella (Haemophilus) parasuis, an early colonizer of the nasal cavity in piglets, is a highly heterogeneous species, comprising both commensal and virulent strains. Virulent G. parasuis strains can cause fibrinous polyserositis called Glässer’s disease. Colostrum is a source of passive immunity for young piglets. When vaccinating sows, protective antibodies are transferred to their offspring through the colostrum. Here, sow vaccination was performed with a protein fragment, F4, from the outer membrane trimeric autotransporters VtaAs exclusively found in virulent G. parasuis. Piglets were allowed to suckle for 3 weeks, following which a challenge with two virulent strains of G. parasuis was performed. A group of nonvaccinated sows and their piglets were included as a control. Antibodies against F4 were confirmed using ELISA in the vaccinated sows and their offspring before the G. parasuis challenge. Compared to the control group, F4-vaccination also resulted in an increased level of serum TGF-β both in vaccinated sows and in their offspring at early time points of life. After the challenge, a lower body temperature and a higher weight were observed in the group of piglets from vaccinated sows. One piglet from the non-vaccinated group succumbed to the infection, but no other significant differences in clinical signs were noticed. At necropsy, performed 2 weeks after the virulent challenge, the level of surfactant protein D (SP-D) in bronchoalveolar lavage was higher in the piglets from vaccinated sows. Vaccination did not inhibit the nasal colonization of the piglets by the challenge strains. Full article

Dendritic cell (DC) vaccines for cancer immunotherapy have been actively developed to improve clinical efficacy. In our previous report, monocyte−derived DCs induced by interleukin (IL)−4 with a low−adherence dish (low−adherent IL-4−DCs: la−IL-4−DCs) improved the yield and viability, as well as relatively prolonged survival in vitro, compared to IL-4−DCs developed using an adherent culture protocol. However, la−IL-4−DCs exhibit remarkable cluster formation and display heterogeneous immature phenotypes. Therefore, cluster formation in la−IL-4−DCs needs to be optimized for the clinical development of DC vaccines. In this study, we examined the effects of cluster control in the generation of mature IL-4−DCs, using cell culture vessels and measuring spheroid formation, survival, cytokine secretion, and gene expression of IL-4−DCs. Mature IL-4−DCs in cell culture vessels (cluster−controlled IL-4−DCs: cc−IL-4−DCs) displayed increased levels of CD80, CD86, and CD40 compared with that of la−IL-4−DCs. cc−IL-4−DCs induced antigen−specific cytotoxic T lymphocytes (CTLs) with a human leukocyte antigen (HLA)−restricted melanoma antigen recognized by T cells 1 (MART−1) peptide. Additionally, cc−IL-4−DCs produced higher levels of IFN−γ, possessing the CTL induction. Furthermore, DNA microarrays revealed the upregulation of BCL2A1, a pro−survival gene. According to these findings, the cc−IL-4−DCs are useful for generating homogeneous and functional IL-4−DCs that would be expected to promote long−lasting effects in DC vaccines. Full article

Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials. Full article

For decades, vaccinations have been used to limit infectious bronchitis (IB) in both the broiler and layer industries. Depending on the geographical area, live attenuated vaccines are used either alone or in combination with inactivated vaccines to control infectious bronchitis virus (IBV) infections. It has been shown that administering inactivated vaccines preceded by priming with live attenuated vaccines in pullets protects laying hens against IB. However, the immunological basis of this protective response has not been adequately investigated. The objective of the study was to compare two vaccination strategies adapted by the Canadian poultry industry in terms of their ability to systemically induce an adequate immune response in IBV-impacted tissues in laying hens. The first vaccination strategy (only live attenuated IB vaccines) and second vaccination strategy (live attenuated and inactivated IB vaccines) were applied. Serum anti-IBV antibodies were measured at two time points, i.e., 3 weeks and 10 weeks post last vaccination. The recruitment of T cell subsets (i.e., CD4+ and CD8+ T cells), and the interferon (IFN)-γ mRNA expression were measured at 10 weeks post last vaccination. We observed that vaccination strategy 2 induced significantly higher serum anti-IBV antibody responses that were capable of neutralizing an IBV Mass variant associated with a flock history of shell-less egg production better than a Delmarva (DMV)1639 variant, as well as a significantly higher IFN-γ mRNA expression in the lungs, kidneys, and oviduct. We also observed that both vaccination strategies recruited CD4+ T cells as well as CD8+ T cells to the examined tissues at various extents. Our findings indicate that vaccination strategy 2 induces better systemic and local host responses in laying hens. Full article

Despite not being full-time health care workers, annual flu vaccination is nevertheless an important consideration for medical students. This study examined the reasons for refusing flu vaccination among medical students, a group characterized by low vaccination coverage, despite the fact that the flu vaccine is arguably the most effective way of preventing serious flu complications. A cross-sectional survey was performed of 1313 students at the Medical University of Lodz. The findings indicate that the main sites of vaccination were primary care centers, and main source of information about influenza vaccination (about 90% of cases) was the general practitioner (GP). The most common motivations for vaccination were a recommendation by the family doctor or the belief that it was an important factor for protection against influenza. Most students reported various adverse effects after vaccination, usually mild pain at the site of vaccination, malaise, or fever. The main reasons for rejecting influenza vaccination were the apparent low risk of disease, the need for annual vaccination, the need to pay for it, lack of time or opportunity, lack of vaccination promotion, negative attitudes toward the flu vaccine, or the belief that there are other methods of preventing flu. To increase long-term vaccine acceptance and increase the vaccination rate among medical students and qualified health care workers, there is a need to adapt the health system and to initiate ongoing promotion programs at university to raise consciousness, promote vaccinations, and develop clinical skills for immunization. Full article

Influenza could circulate in parallel with COVID-19. In the context of COVID-19, some studies observed inverse associations between influenza vaccination and SARS-CoV-2 infection and clinical outcomes, while others did not. We conducted a meta-analysis to assess the association between influenza vaccination and SARS-CoV-2 infection and clinical outcomes, aiming to provide evidence for COVID-19 prevention and vaccination promotion. We searched four databases from inception to 10 March, 2021. Random effects and fixed effects models were used to pool odds ratios (ORs) and adjusted estimates with 95% confidence intervals (CIs). We used funnel plots to evaluate the publication bias, I2 statistics to evaluate the heterogeneity, and conducted subgroup analyses. Sixteen observational studies involving 290,327 participants were included. Influenza vaccination was associated with a lower risk of SARS-CoV-2 infection (pooled adjusted OR: 0.86, 95%CI: 0.81–0.91), while not significantly associated with adverse outcomes (intensive care: adjusted OR 0.63, 95%CI: 0.22–1.81; hospitalization: adjusted OR 0.74, 95%CI: 0.51–1.06; mortality: adjusted OR 0.89, 95%CI: 0.73–1.09). Our findings suggest that influenza vaccination is associated with a lower risk of SARS-CoV-2 infection. It is crucial for policy makers to implement strategies on influenza vaccination, for it may also have benefits for COVID-19 prevention. Full article

This study aimed to compare the differences in motivation to receive a COVID-19 vaccination between frontline physicians and nurses and the Taiwanese public. The associations of threat and coping appraisals, as described in Protection Motivation Theory (PMT), with motivation to receive COVID-19 vaccination were compared between these groups, too. We recruited 279 frontline physicians and nurses and 768 members of the public by a Facebook advertisement. Participants’ motivation to receive COVID-19 vaccination, perceived severity of and vulnerability to COVID-19, self-efficacy and response efficacy of COVID-19 vaccination, response cost of COVID-19 vaccination, and knowledge about the mechanism of COVID-19 vaccination in light of PMT were determined. The results demonstrated that frontline health workers had higher motivation to receive COVID-19 vaccination than the public. Response efficacy and knowledge of COVID-19 vaccination were positively associated with motivation to receive COVID-19 vaccination in both frontline health workers and the public, whereas perceived vulnerability, perceived severity, and response cost of COVID-19 vaccination were positively associated with motivation in the public but not in frontline physicians and nurses. The factors related to motivation to receive COVID-19 vaccination should be considered when designing programs to increase motivation to receive COVID-19 vaccination among frontline health workers and the public. Full article

Cancer is the second leading cause of death worldwide. Today, the critical role of the immune system in tumor control is undisputed. Checkpoint antibody immunotherapy augments existing antitumor T cell activity with durable clinical responses in many tumor entities. Despite the presence of tumor-associated antigens and neoantigens, many patients have an insufficient repertoires of antitumor T cells. Autologous tumor vaccinations aim at alleviating this defect, but clinical success is modest. Loading tumor material into autologous dendritic cells followed by their laboratory expansion and therapeutic vaccination is promising, both conceptually and clinically. However, this process is laborious, time-consuming, costly, and hence less likely to solve the global cancer crisis. Therefore, it is proposed to re-focus on personalized anticancer vaccinations to enhance the immunogenicity of autologous therapeutic tumor vaccines. Recent work re-established the idea of using the alarming agents of the immune system, oxidative modifications, as an intrinsic adjuvant to broaden the antitumor T cell receptor repertoire in cancer patients. The key novelty is the use of gas plasma, a multi-reactive oxygen and nitrogen species-generating technology, for diversifying oxidative protein modifications in a, so far, unparalleled manner. This significant innovation has been successfully used in proof-of-concept studies and awaits broader recognition and implementation to explore its chances and limitations of providing affordable personalized anticancer vaccines in the future. Such multidisciplinary advance is timely, as the current COVID-19 crisis is inexorably reflecting the utmost importance of innovative and effective vaccinations in modern times. Full article

Peptide vaccines incorporating B- and T-cell epitopes have shown promise in the context of various cancers and infections. These vaccines are relatively simple to manufacture, but more immunogenic formulations are considered a priority. We developed tetrabranched derivatives for this purpose based on a novel peptide welding technology (PWT). PWTs provide molecular scaffolds for the efficient synthesis of ultrapure peptide dendrimers, which allow the delivery of multiple ligands within a single macromolecular structure. Peptide vaccines incorporating T-cell epitopes derived from melanoma and B-cell epitopes derived from human immunodeficiency virus, synthesized using this approach, elicited primary immune responses in vitro and in vivo. Subcutaneous administration of the B-cell epitope-based vaccines also elicited more potent humoral responses than subcutaneous administration of the corresponding peptides alone. Highly immunogenic peptide epitope-based vaccines can therefore be generated quickly and easily using a novel PWT. Full article

Background: Malignant pleural mesothelioma (MPM) is a fatal neoplasm with, if untreated, poor survival of approximately nine months from diagnosis. Until recently, phase II–III immunotherapy trials did not show any significant benefit. The lack of immunotherapy efficacy can be explained by the fact that mesothelioma is a tumor with an “immune desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of DCs, which were ex-vivo cultured, exposed to (tumor-associated) antigens, and subsequently activated, this “immune desert” phenotype might be turned into an “inflamed” phenotype. Three phase I/II studies have been performed and published using activated DCs, which support this concept. We here report on the long-term survival of patients treated with DCs in three phase I/II studies. Methods: Survival data of the phase I/II trials using DC therapy in MPM patients were obtained and subsequently analyzed. In the first two trials, DCs were loaded with autologous tumor lysate. In the third trial, DCs were loaded with allogeneic mesothelioma tumor cell line lysate. Results: In the three studies combined, 29 patients with MPM were treated with DC vaccination between 2006 and 2015. At data cut-off, the median OS was 27 months (95% CI: 21–47 months). OS at 2 years was 55.2% (95% CI: 39.7–76.6%), and OS at 5 years was 20.7% (95% CI: 10.1–42.2%). Conclusions: The long-term survival of DC therapy in MPM in these three trials is promising, which is the basis for the randomized phase II/III DENIM study. This DENIM study is currently enrolling, and the results of which have to be awaited for definite conclusions. Full article

The novel coronavirus, SARS-CoV-2, which causes COVID-19, has resulted in a pandemic with millions of deaths. To eradicate SARS-CoV-2 and prevent further infections, many vaccine candidates have been developed. These vaccines include not only traditional subunit vaccines and attenuated or inactivated viral vaccines but also nucleic acid and viral vector vaccines. In contrast to the diversity in the platform technology, the delivery of vaccines is limited to intramuscular vaccination. Although intramuscular vaccination is safe and effective, mucosal vaccination could improve the local immune responses that block the spread of pathogens. However, a lack of understanding of mucosal immunity combined with the urgent need for a COVID-19 vaccine has resulted in only intramuscular vaccinations. In this review, we summarize the history of vaccines, current progress in COVID-19 vaccine technology, and the status of intranasal COVID-19 vaccines. Future research should determine the most effective route for vaccine delivery based on the platform and determine the mechanisms that underlie the efficacy of different delivery routes. Full article

Cytomegalovirus (CMV) is the most common cause of congenital infection and non-genetic sensorineural hearing loss in childhood. Up to 2% of neonates, with the highest percentages found in developing countries, are congenitally infected with CMV. At birth, most of these infants are asymptomatic. However, approximately 10% have signs and symptoms of the disease, and 40–60% of symptomatic neonates will later develop permanent neurologic sequelae. To reduce congenital CMV (cCMV) infection, a vaccine able to prevent primary infection is essential. In this narrative review, actual ongoing research about the development of a CMV vaccine is discussed. The progressive increase in knowledge on the ways in which the host’s immune system and CMV relate has made it possible to clarify that the development of a vaccine that is certainly capable of reducing the risk of cCMV infection, and preventing both primary and nonprimary infections is extremely difficult. Many of the ways in which the virus evades the immune system and causes cCMV infection are not yet fully understood, especially in cases of nonprimary infection. Moreover, the schedule that should be recommended and that subjects must be vaccinated to obtain the greatest effect have not been precisely defined. Further studies are needed before the problem of cCMV infection and its related challenges can be totally solved. Full article

Healthcare professionals are considered to be at high risk of exposure and spread of SARS-CoV-2, and have therefore been considered a priority group in COVID-19 vaccination campaign strategies. However, it must be assumed that the immune response is influenced by numerous factors, including sex and gender. The analysis of these factors is an impact element for stratifying the population and targeting the vaccination strategy. Therefore, a large cohort of healthcare workers participating in the Italian vaccination campaign against SARS-CoV-2 has been studied to establish the impact of sex and gender on vaccination coverage using the Gender Impact Assessment approach. This study shows a significant difference in the antibody titers among different age and sex groups, with a clear decreasing trend in antibody titers in the older age groups. Overall, the serological values were significantly higher in females; the reported side effects are more frequent in females than in males. Therefore, disaggregated data point out how the evaluation of gender factors could be essential in COVID-19 vaccination strategies. On this biomedical and social basis, suggestions are provided to improve the SARS-CoV-2 vaccination campaign in healthcare professionals. Still, they could be adapted to other categories and contexts. Full article

Some African countries are still reluctant to introduce the hepatitis B vaccine birth dose (HepB-BD) into their expanded program of immunization (EPI), partly because of logistical, economic, and cost information constraints. To assist decision-makers in these countries, we assessed the economic and financial costs of HepB-BD introduction in Senegal in 2016. We performed a micro-costing study in a representative sample of Senegal’s EPI sites at all levels in 2018. Information on EPI and HepB-BD activity-related inputs and costs was collected using standardized questionnaires and semi-structured interviews. Using inverse probability weighting, we computed weighted average costs associated with HepB-BD introduction for each EPI level, country-level aggregated costs and estimated costs per newborn. Economic and financial costs from a government perspective were estimated in US dollars for 2015, 2016 and 2017. Total economic costs were USD 143,364 in 2015, USD 759,406 in 2016 and USD 867,311 in 2017, while financial costs were USD 127,745, USD 82,519 and USD 29,853, respectively. When annualizing pre-introduction and initial training costs, the economic (financial) cost per vaccinated newborn was USD 2.10 (USD 0.30) in 2016 and USD 1.90 (USD 0.20) in 2017. Our estimates provide valuable information to implement HepB-BD in Sub-Saharan African countries that have not yet integrated this vaccine. Full article

Background: Persistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, conceived in 2020, that evoke protective spike antibody responses are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. Methods: Using a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 × 10⁸ TCID₅₀ units of SARS-CoV-2, followed by assessment of clinical symptoms and viral load, chest radiographs, and sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis. Results: Vaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques. Conclusions: We demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in nonhuman primates. Full article

Tuberculosis vaccines capable of reducing disease worldwide have proven difficult to develop. BCG is effective in limiting childhood disease, but adult TB is still a major public health issue. Development of new vaccines requires identification of antigens that are both spatially and temporally available throughout infection, and immune responses to which reduce bacterial burden without increasing pathologic outcomes. Subunit vaccines containing antigen require adjuvants to drive appropriate long-lived responses. We generated a triple-antigen fusion containing the virulence-associated EsxN (Rv1793), the PPE42 (Rv2608), and the latency associated Rv2628 to investigate the balance between bacterial reduction and weight loss in an animal model of aerosol infection. We found that in both a low pattern recognition receptor (PRR) engaging adjuvant and a high PRR-engaging adjuvant (MPL/TDM/DDA) the triple-antigen fusion could reduce the bacterial burden, but also induced weight loss in the mice upon aerosol infection. The weight loss was associated with an imbalance between TNFα and IL-17 transcription in the lung upon challenge. These data indicate the need to assess both protective and pathogenic responses when investigating subunit vaccine activity. Full article

Zoonotic transmission of orthohantaviruses from rodent reservoirs to humans has been the cause of severe fatalities. Human infections are reported worldwide, but vaccines have been approved only in China and Korea. Orthohantavirus vaccine development has been pursued with no sense of urgency due to the relative paucity of cases in countries outside China and Korea. However, the orthohantaviruses continuously evolve in hosts and thus the current vaccine may not work as well against some variants. Therefore, a more effective vaccine should be prepared against the orthohantaviruses. In this review, we discuss the issues caused by the orthohantavirus vaccine. Given the pros and cons of the orthohantavirus vaccine, we suggest strategies for the development of better vaccines in terms of pandemic preparedness. Full article

Due to their increased transmissibility, three variants of high concern have emerged in the United Kingdom (also known as B.1.1.7 lineage or VOC-202012/01), South Africa (B.1.351 lineage), and Brazil (P1 lineage) with multiple substitutions in the spike protein. Since neutralizing antibodies elicited by vaccination are likely considered as correlates of protection for SARS-CoV-2 infection, it is important to analyze whether vaccinees with mRNA BNT162b2 are equally protected against these emerging SARS-CoV-2 variants. To this aim, we enrolled healthy subjects one month after complete vaccination with Comirnaty and evaluated the neutralizing response against the native Wuhan strain and the emerging B.1.1.7, B.1.351 and P1 lineages, by using the microneutralization assay, currently considered the gold standard test for the evaluation and detection of functional neutralizing antibodies. The most remarkable finding of this study was the significantly lower neutralizing antibody titer against B.1.351 lineage, compared to the wild-type virus. No significant differences were observed with the other two lineages. These findings provide evidence that vaccinated subjects may not be equally protected against all SARS-CoV-2 lineages. Full article

Introduction: New York City is one of the areas most affected by the COVID-19 pandemic in the United States. Healthcare workers are among those at high risk of contracting the virus, and a vital source of information and trust in vaccines to the community. Methods: This study was conducted about attitudes towards COVID-19 vaccination among healthcare workers at a public hospital in New York City during the beginning of COVID-19 vaccination. 428 hospital employees responded. Results: Several factors were significantly associated with vaccine attitudes, including demographics such as gender (p = 0.002), age (p = 0.005), race (p < 0.001) and home location (p < 0.001), role within the hospital (p < 0.001), knowledge about the virus (p < 0.001) and confidence in and expectations about personal protective equipment and behaviors (p < 0.001). Structural equation modeling revealed that the most predictive factors were prior vaccine attitudes and concern with the speed of testing and approval of the vaccines (p < 0.001). Multivariate analysis reinforced these, while also identifying perceived personal risk as significant (p = 0.033). Conclusions: Several modifiable factors that reflect confidence in science, scientific knowledge, personal risk perception, experience and medical authority are correlated with vaccine attitudes, indicating that a holistic educational approach to improve trust in science is likely to be effective in long-term reduction in vaccine hesitancy. Full article

Vaccination is fast becoming a key intervention against the ongoing COVID-19 pandemic. We conducted cross-sectional online surveys to investigate COVID-19 vaccine acceptance across nine Low- and Middle-Income Countries (LMICs; N = 10,183), assuming vaccine effectiveness at 90% and 95%. The prevalence of vaccine acceptance increased from 76.4% (90% effectiveness) to 88.8% (95% effectiveness). Considering a 90% effective vaccine, Malaysia, Thailand, Bangladesh, and five African countries (Democratic Republic of Congo, Benin, Uganda, Malawi, and Mali) had lower acceptance odds compared to Brazil. Individuals who perceived taking the vaccine as important to protect themselves had the highest acceptance odds (aOR 2.49) at 95% effectiveness.Vaccine acceptance was also positively associated with COVID-19 knowledge, worry/fear regarding COVID-19, higher income, younger age, and testing negative for COVID-19. However, chronic disease and female gender reduced the odds for vaccine acceptance. The main reasons underpinning vaccine refusal were fear of side effects (41.2%) and lack of confidence in vaccine effectiveness (15.1%). Further research is needed to identify country-specific reasons for vaccine hesitancy in order to develop mitigation strategies that would ensure high and equitable vaccination coverage across LMICs. Full article

Eradicating HIV-1 in infected individuals will not be possible without addressing the persistence of the virus in its multiple reservoirs. In this context, the molecular characterization of HIV-1 persistence is key for the development of rationalized therapeutic interventions. HIV-1 gene expression relies on the redundant and cooperative recruitment of cellular epigenetic machineries to cis-regulatory proviral regions. Furthermore, the complex repertoire of HIV-1 repression mechanisms varies depending on the nature of the viral reservoir, although, so far, few studies have addressed the specific regulatory mechanisms of HIV-1 persistence in other reservoirs than the well-studied latently infected CD4⁺ T cells. Here, we present an exhaustive and updated picture of the heterochromatinization of the HIV-1 promoter in its different reservoirs. We highlight the complexity, heterogeneity and dynamics of the epigenetic mechanisms of HIV-1 persistence, while discussing the importance of further understanding HIV-1 gene regulation for the rational design of novel HIV-1 cure strategies. Full article

Viruses have developed incredibly creative ways of making a virtue out of necessity, including taking full advantage of their small genomes. Indeed, viruses often encode multiple proteins within the same genomic region by using two or more reading frames in both orientations through a process called overprinting. Complex retroviruses provide compelling examples of that. The human immunodeficiency virus type 1 (HIV-1) genome expresses sixteen proteins from nine genes that are encoded in the three positive-sense reading frames. In addition, the genome of some HIV-1 strains contains a tenth gene in one of the negative-sense reading frames. The so-called Antisense Protein (ASP) gene overlaps the HIV-1 Rev Response Element (RRE) and the envelope glycoprotein gene, and encodes a highly hydrophobic protein of ~190 amino acids. Despite being identified over thirty years ago, relatively few studies have investigated the role that ASP may play in the virus lifecycle, and its expression in vivo is still questioned. Here we review the current knowledge about ASP, and we discuss some of the many unanswered questions. Full article

(1) Background: COVID-19 vaccination campaigns offer the best hope of controlling the pandemic. However, the fast production of COVID-19 vaccines has caused concern among the general public regarding their safety and efficacy. In particular, patients with chronic illnesses, such as celiac disease (CD), may be more fearful. Information on vaccine hesitancy plays a pivotal role in the development of an efficient vaccination campaign. In our study, we aimed to evaluate COVID-19 vaccine hesitancy among Italian CD patients. (2) Methods: an anonymous questionnaire was sent to CD patients followed at our tertiary referral center for CD in Milan, Italy. Patients were defined as willing, hesitant and refusing. We evaluated the reasons for hesitancy/refusal and the possible determinants, calculating crude and adjusted odds ratios [AdjORs] with 95% confidence intervals [CIs]. (3) Results: the questionnaire was sent to 346 patients with a response rate of 29.8%. Twenty-six (25.2%) of the 103 respondents were hesitant, with a total refusal rate of 4.8%. The main reason was fear of adverse events related to vaccination (68.2%). Among hesitant patients, 23% declared that their opinion was influenced by their CD. The determinants positively influencing willingness to be vaccinated against COVID-19 were adherence to a GFD, perception of good knowledge about COVID-19 and its vaccines, and a positive attitude to previous vaccines (AdjOR 12.71, 95% CI 1.82–88.58, AdjOR 6.50, 95% CI 1.44–29.22, AdjOR 0.70, 95% CI 0.11–4.34, respectively). (4) Conclusions: CD patients should be vaccinated against COVID-19 and a specific campaign to address the determinants of hesitancy should be developed. Full article

Detailed knowledge about hepatitis B virus (HBV) vaccination coverage and timeliness for sub-Saharan Africa is scarce. We used data from a community-based cross-sectional survey conducted in 2018–2019 in the area of Niakhar, Senegal, to estimate coverage, timeliness, and factors associated with non-adherence to the World Health Organisation-recommended vaccination schedules in children born in 2016 (year of the birth dose (BD) introduction in Senegal) and 2017–2018. Vaccination status was assessed from vaccination cards, surveillance data, and healthcare post vaccination records. Among 241 children with available data, for 2016 and 2017–2018, respectively, 31.0% and 66.8% received the BD within 24 h of birth (BD schedule), and 24.3% and 53.7% received the BD plus at least two pentavalent vaccine doses within the recommended timeframes (three-dose schedule). In logistic regression models, home birth, dry season birth, and birth in 2016 were all associated with non-adherence to the recommended BD and three-dose schedules. Living over three kilometres from the nearest healthcare post, being the firstborn, and living in an agriculturally poorer household were only associated with non-adherence to the three-dose schedule. The substantial proportion of children not vaccinated according to recommended schedules highlights the importance of considering vaccination timeliness when evaluating vaccination programme effectiveness. Outreach vaccination activities and incentives to bring children born at home to healthcare facilities within 24 h of birth, must be strengthened to improve timely HBV vaccination. Full article

Effective treatment of established tumors requires rational multicombination immunotherapy strategies designed to target all functions of the patient immune system and tumor immune microenvironment. While these combinations build on the foundation of successful immune checkpoint blockade antibodies, it is increasingly apparent that successful immunotherapy will also require a cancer vaccine backbone to engage the immune system, thereby ensuring that additional immuno-oncology agents will engage a tumor-specific immune response. This review summarizes ongoing clinical trials built upon the backbone of cancer vaccines and focusing on those clinical trials that utilize multicombination (3+) immuno-oncology agents. We examine combining cancer vaccines with multiple checkpoint blockade antibodies, novel multifunctional molecules, adoptive cell therapy and immune system agonists. These combinations and those yet to enter the clinic represent the future of cancer immunotherapy. With a cancer vaccine backbone, we are confident that current and coming generations of rationally designed multicombination immunotherapy can result in effective therapy of established tumors. Full article

African swine fever (ASF) is today′s number one threat for the global swine industry. Neither commercial vaccine nor treatment is available against ASF and, thus far, only live attenuated viruses (LAV) have provided robust protection against lethal ASF virus (ASFV) challenge infections. Identification of ASFV proteins inducing protective immune responses is one of the major challenges to develop safer and efficient subunit vaccines. Immunopeptidomic studies recently performed in our laboratory allowed identifying ASFV antigens recognized by ASFV-specific CD8⁺ T-cells. Here, we used data from the SLAI-peptide repertoire presented by a single set of ASFV-infected porcine alveolar macrophages to generate a complex DNA vaccine composed by 15 plasmids encoding the individual peptide-bearing ORFs. DNA vaccine priming improved the protection afforded by a suboptimal dose of the BA71ΔCD2 LAV given as booster vaccination, against Georgia2007/1 lethal challenge. Interestingly, M448R was the only protein promiscuously recognized by the induced ASFV-specific T-cells. Furthermore, priming pigs with DNA plasmids encoding M488R and MGF505-7R, a CD8⁺ T-cell antigen previously described, confirmed these two proteins as T-cell antigens with protective potential. These studies might be useful to pave the road for designing safe and more efficient vaccine formulations in the future. Full article

Our aim was to determine whether polyphosphazene (PCEP), Curdlan (β-glucan, a dectin-1 agonist), and Leptin could act as adjuvants to promote a Th17-type adaptive immune response in mice. Mice were vaccinated via the intramuscular route then boosted three weeks later with Ovalbumin plus: PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, or saline. Mice vaccinated with OVA+PCEP and OVA+Curdlan+Leptin showed significantly higher frequency of antigen-specific CD4+ T cells secreting IL-17 relative to OVA-vaccinated mice. No formulation increased the frequency of CD4+ T cells secreting IL-4 or IFNγ. Since activation of innate immunity precedes the development of adaptive immunity, we wished to establish whether induction of Th17-type immunity could be predicted from in vitro experiments and/or from the local cytokine environment after immunization with adjuvants alone. Elevated IL-6 and TGFβ with reduced secretion of IL-12 is a cytokine milieu known to promote differentiation of Th17-type immunity. We injected the immunostimulants or saline buffer into murine thigh muscles and measured acute local cytokine production. PCEP induced significant production of IL-6 and reduced IL-12 production in muscle but it did not lead to elevated TGFβ production. Curdlan+Leptin injected into muscle induced significant production of TGFβ and IL-17 but not IL-6 or IL-12. We also stimulated splenocytes with media or PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, PCEP+Leptin, and PCEP+Curdlan+Leptin and measured cytokine production. PCEP stimulation of splenocytes failed to induce significant production of IL-6, IL-12, TGFβ, or IL-17 and therefore ex vivo splenocyte stimulation failed to predict the increased frequency of Th17-type T cells in response to the vaccine. Curdlan-stimulated splenocytes produced Th1-type, inducing cytokine, IL-12. Curdlan+/-PCEP stimulated TGF-β production and Curdlan+Leptin+/- PCEP induced secretion of IL-17. We conclude that PCEP as well as Curdlan+Leptin are Th17-type vaccine adjuvants in mice but that cytokines produced in response to these adjuvants in muscle after injection or in ex vivo cultured splenocytes did not predict their role as a Th17-type adjuvant. Together, these data suggest that the cytokine environments induced by these immunostimulants did not predict induction of an antigen-specific Th17-type adaptive immune response. This is the first report of these adjuvants inducing a Th17-type adaptive immune response. Full article

We propose a system that helps decision makers during a pandemic find, in real time, the mass vaccination strategies that best utilize limited medical resources to achieve fast containments and population protection. Our general-purpose framework integrates into a single computational platform a multi-purpose compartmental disease propagation model, a human behavior network, a resource logistics model, and a stochastic queueing model for vaccination operations. We apply the modeling framework to the current COVID-19 pandemic and derive an optimal trigger for switching from a prioritized vaccination strategy to a non-prioritized strategy so as to minimize the overall attack rate and mortality rate. When vaccine supply is limited, such a mixed vaccination strategy is broadly effective. Our analysis suggests that delays in vaccine supply and inefficiencies in vaccination delivery can substantially impede the containment effort. Employing an optimal mixed strategy can significantly reduce the attack and mortality rates. The more infectious the virus, the earlier it helps to open the vaccine to the public. As vaccine efficacy decreases, the attack and mortality rates rapidly increase by multiples; this highlights the importance of early vaccination to reduce spreading as quickly as possible to lower the chances for further mutations to evolve and to reduce the excessive healthcare burden. To maximize the protective effect of available vaccines, of equal importance are determining the optimal mixed strategy and implementing effective on-the-ground dispensing. The optimal mixed strategy is quite robust against variations in model parameters and can be implemented readily in practice. Studies with our holistic modeling framework strongly support the urgent need for early vaccination in combating the COVID-19 pandemic. Our framework permits rapid custom modeling in practice. Additionally, it is generalizable for different types of infectious disease outbreaks, whereby a user may determine for a given type the effects of different interventions including the optimal switch trigger. Full article