Efficacy Of Vaccine Candidates Research Articles

Loss of HIV candidate vaccine efficacy in male macaques by mucosal nanoparticle immunization rescued by V2-specific response

Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIVmac251 acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17+NKp44+ innate lymphoid cells (ILCs). We investigated whether increased mucosal responses to V2 benefit vaccine efficacy by delivering oral nanoparticles (NPs) that release V2-scaffolded on Typhoid Toxin B (TTB) to the large intestine. Strikingly, mucosal immunization of male macaques abrogated vaccine efficacy with control TTB or empty NPs, but vaccine efficacy of up to 47.6% was preserved with V2-TTB NPs. The deleterious effects of NPs were linked to preferential recruitment of mucosal plasmacytoid dendritic cells (pDCs), reduction of protective mucosal NKp44+ ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ+NKG2A-NKp44-ILCs, and increased levels of mucosal activated Ki67+CD4+ T cells, a potential target for virus infection. V2-TTB NP mucosal boosting rescued vaccine efficacy, likely via high avidity V2-specific antibodies mediating ADCC, and higher frequencies of mucosal NKp44+ ILCs and of ∆V1gp120 binding antibody-secreting B cells in the rectal mucosa. These findings emphasize the central role of systemic immunization and mucosal V2-specific antibodies in the protection afforded by ΔV1 envelope immunogens and encourage careful evaluation of vaccine delivery platforms to avoid inducing immune responses favorable to HIV transmission.

Intranasal Immunization with a Recombinant Adenovirus Encoding Multi-Stage Antigens of Mycobacterium tuberculosis Preferentially Elicited CD8+ T Cell Immunity and Conferred a Superior Protection in the Lungs of Mice than Bacillus Calmette-Guerin.

The development of a tuberculosis (TB) vaccine is imperative. Employing multi-stage Mycobacterium tuberculosis (Mtb) antigens as targeted antigens represents a critical strategy in establishing an effective novel TB vaccine. In this investigation, we evaluated the immunogenicity and protective efficacy of a recombinant adenovirus vaccine expressing two fusion proteins, Ag85B-ESAT6 (AE) and Rv2031c-Rv2626c (R2), derived from multi-stage antigens of Mtb via intranasal administration in mice. Intranasal delivery of Ad-AE-R2 induced both long-lasting mucosal and systemic immunities, with a preferential elicitation of CD8+ T cell immunity demonstrated by the accumulation and retention of CD8+ T cells in BALF, lung, and spleen, as well as the generation of CD8+ TRM cells in BALF and lung tissues. Compared to subcutaneous immunization with Bacillus Calmette-Guerin (BCG), Ad-AE-R2 provided superior protection against high-dose intratracheal BCG challenge, specifically within the lungs of mice. Our findings support the notion that empowering T cells within the respiratory mucosa is crucial for TB vaccine development while highlighting targeting CD8+ T cell immunity as an effective strategy for optimizing TB vaccines and emphasizing that eliciting systemic memory immunity is also vital for the successful development of a TB mucosal vaccine. Furthermore, our results demonstrate that the BCG challenge serves as a convenient and efficient method to evaluate candidate vaccine efficacy.

Serial cell culture passaging in vitro led to complete attenuation and changes in the characteristic features of a virulent porcine deltacoronavirus strain.

Porcine deltacoronavirus (PDCoV) is an important enteric coronavirus that has caused enormous economic losses in the pig industry worldwide. However, no commercial vaccine is currently available. Therefore, developing a safe and efficacious live-attenuated vaccine candidate is urgently needed. In this study, the PDCoV strain CH/XJYN/2016 was continuously passaged in LLC-PK cells until passage 240, and the virus growth kinetics in cell culture, pathogenicity in neonatal piglets, transcriptome differences after LLC-PK infection, changes in the functional characteristics of the spike (S) protein in the high- and low-passage strains, genetic variation of the virus genome, resistance to pepsin and acid, and protective effects of this strain when used as a live-attenuated vaccine were examined. The results of animal experiments demonstrated that the virulent PDCoV strain CH/XJYN/2016 was completely attenuated and not pathogenic in piglets following serial cell passage. Genome sequence analysis showed that amino acid mutations in nonstructural proteins were mainly concentrated in Nsp3, structural protein mutations were mainly concentrated in the S protein, and the N, M, and E genes were conserved. Transcriptome comparison revealed that compared with negative control cells, P10-infected LLC-PK cells had the most differentially expressed genes (DEGs), while P0 and P240 had the least number of DEGs. Analysis of trypsin dependence and related structural differences revealed that the P10 S protein interacted more strongly with trypsin and that the P120 S protein interacted more strongly with the APN receptor. Moreover, the infectivity of P240 was not affected by pepsin but was significantly decreased after exposure to low pH. Furthermore, the P240-based live-attenuated vaccine provided complete protection to piglets against the challenge of virulent PDCoV. In conclusion, we showed that a PDCoV strain was completely attenuated through serial passaging in vitro. These results provide insights into the potential molecular mechanisms of PDCoV attenuation and the development of a promising live-attenuated PDCoV vaccine.IMPORTANCEPorcine deltacoronavirus (PDCoV) is one of the most important enteropathogenic pathogens that cause diarrhea in pigs of various ages, especially in suckling piglets, and causes enormous economic losses in the global commercial pork industry. There are currently no effective measures to prevent and control PDCoV. As reported in previous porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus studies, inactivated vaccines usually elicit less robust protective immune responses than live-attenuated vaccines in native sows. Therefore, identifying potential attenuation mechanisms, gene evolution, pathogenicity differences during PDCoV passaging, and immunogenicity as live-attenuated vaccines is important for elucidating the mechanism of attenuation and developing safe and effective vaccines for virulent PDCoV strains. In this study, we demonstrated that the virulence of the PDCoV strain CH/XJYN/2016 was completely attenuated following serial cell passaging in vitro, and changes in the biological characteristics and protection efficacy of the strain were evaluated. Our results help elucidate the mechanism of PDCoV attenuation and support the development of appropriate designs for the study of live PDCoV vaccines.

Memory T cells: promising biomarkers for evaluating protection and vaccine efficacy against leishmaniasis.

Understanding the immune response to Leishmania infection and identifying biomarkers that correlate with protection are crucial for developing effective vaccines. One intriguing aspect of Leishmania infection is the persistence of parasites, even after apparent lesion healing. Various host cells, including dendritic cells, fibroblasts, and Langerhans cells, may serve as safe sites for latent infection. Memory T cells, especially tissue-resident memory T cells (TRM), play a crucial role in concomitant immunity against cutaneous Leishmania infections. These TRM cells are long-lasting and can protect against reinfection in the absence of persistent parasites. CD4+ TRM cells, in particular, have been implicated in protection against Leishmania infections. These cells are characterized by their ability to reside in the skin and rapidly respond to secondary infections by producing cytokines such as IFN-γ, which activates macrophages to kill parasites. The induction of CD4+ TRM cells has shown promise in experimental immunization, leading to protection against Leishmania challenge infections. Identifying biomarkers of protection is a critical step in vaccine development and CD4+ TRM cells hold potential as biomarkers, as their presence and functions may correlate with protection. While recent studies have shown that Leishmania-specific memory CD4+ T-cell subsets are present in individuals with a history of cutaneous leishmaniasis, further studies are needed to characterize CD4+ TRM cell populations. Overall, this review highlights the importance of memory T cells, particularly skin-resident CD4+ TRM cells, as promising targets for developing effective vaccines against leishmaniasis and as biomarkers of immune protection to assess the efficacy of candidate vaccines against human leishmaniasis.

Protection of the receptor binding domain (RBD) dimer against SARS-CoV-2 and its variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants achieved immune escape and became less virulent and easily transmissible through rapid mutation in the spike protein, thus the efficacy of vaccines on the market or in development continues to be challenged. Updating the vaccine, exploring compromise vaccination strategies, and evaluating the efficacy of candidate vaccines for the emerging variants in a timely manner are important to combat complex and volatile SARS-CoV-2. This study reports that vaccines prepared from the dimeric receptor-binding domain (RBD) recombinant protein, which can be quickly produced using a mature and stable process platform, had both good immunogenicity and protection in vivo and could completely protect rodents from lethal challenge by SARS-CoV-2 and its variants, including the emerging Omicron XBB.1.16, highlighting the value of dimeric recombinant vaccines in the post-COVID-19 era.

Newcastle disease virus (NDV) recombinant expressing Marek’s disease virus (MDV) glycoprotein B significantly protects chickens against MDV and NDV challenges

Marek’s disease (MD) is a highly contagious viral neoplastic disease of chickens caused by Marek’s disease virus (MDV), resulting in significant economic losses to the poultry industry worldwide. The commonly used live and/or vectored MDV vaccines are expensive to produce and difficult to handle due to the requirement of liquid nitrogen for manufacturing and delivering frozen infected cells that are viable. In this study, we aimed to develop a Newcastle disease virus (NDV) vectored MDV vaccine that can be lyophilized, stored, and transported at 4 °C. Four NDV LaSota (LS) vaccine strain-based recombinant viruses expressing MDV glycoproteins gB, gC, gE, or gI were generated using reverse genetics technology. The biological assessments showed that these recombinant viruses were slightly attenuated in vivo yet retained similar growth kinetics and virus titers in vitro compared to the parental LaSota virus. Vaccination of leghorn chickens (Lines 15I5x71 F1 cross) with these recombinant viruses via intranasal and intraocular routes conferred different levels of protection against virulent MDV challenge. The recombinant expressing the MDV gB protein, rLS/MDV-gB, protected vaccinated birds significantly against MDV-induced tumor formation when challenged at 14 days post-vaccination (DPV) but moderately at 5 DPV. Whereas the other three recombinants provided little protection against the MDV challenge. All four recombinants conferred complete protection against the velogenic NDV challenge. These results demonstrated that the rLS/MDV-gB virus is a safe and efficacious dual vaccine candidate that can be lyophilized and potentially mass-administered via aerosol or drinking water to large chicken populations at a meager cost.

Challenge Inoculum for Hepatitis C Virus Controlled Human Infection Model.

For any controlled human infection model (CHIM), a safe, standardized, and biologically relevant challenge inoculum is necessary. For hepatitis C virus (HCV) CHIM, we propose that human-derived high-titer inocula of several viral genotypes with extensive virologic, serologic, and molecular characterizations should be the most appropriate approach. These inocula should first be tested in human volunteers in a step-wise manner to ensure safety, reproducibility, and curability prior to using them for testing the efficacy of candidate vaccines.

Single-dose mucosal replicon-particle vaccine protects against lethal Nipah virus infection up to 3 days after vaccination.

Nipah virus (NiV) causes a highly lethal disease in humans who present with acute respiratory or neurological signs. No vaccines against NiV have been approved to date. Here, we report on the clinical impact of a novel NiV-derived nonspreading replicon particle lacking the fusion (F) protein gene (NiVΔF) as a vaccine in three small animal models of disease. A broad antibody response was detected that included immunoglobulin G (IgG) and IgA subtypes with demonstrable Fc-mediated effector function targeting multiple viral antigens. Single-dose intranasal vaccination up to 3 days before challenge prevented clinical signs and reduced virus levels in hamsters and immunocompromised mice; decreases were seen in tissues and mucosal secretions, critically decreasing potential for virus transmission. This virus replicon particle system provides a vital tool to the field and demonstrates utility as a highly efficacious and safe vaccine candidate that can be administered parenterally or mucosally to protect against lethal Nipah disease.

Characterization of cysteine proteases from poultry red mite, tropical fowl mite, and northern fowl mite to assess the feasibility of developing a broadly efficacious vaccine against multiple mite species.

Infestation with poultry red mites (PRM, Dermanyssus gallinae) causes anemia, reduced egg production, and death in serious cases, resulting in significant economic losses to the poultry industry. As a novel strategy for controlling PRMs, vaccine approaches have been focused upon and several candidate vaccine antigens against PRMs have been reported. Tropical (TFM, Ornithonyssus bursa) and northern (NFM, Ornithonyssus sylviarum) fowl mites are also hematophagous and cause poultry industry problems similar to those caused by PRM. Therefore, ideal antigens for anti-PRM vaccines are molecules that cross-react with TFMs and NFMs, producing pesticidal effects similar to those against PRMs. In this study, to investigate the potential feasibility of developing vaccines with broad efficacy across mite species, we identified and characterized cysteine proteases (CPs) of TFMs and NFMs, which were previously reported to be effective vaccine antigens of PRMs. The open reading frames of CPs from TFMs and NFMs had the same sequences, which was 73.0% similar to that of PRMs. Phylogenetic analysis revealed that the CPs of TFMs and NFMs clustered in the same clade as CPs of PRMs. To assess protein functionality, we generated recombinant peptidase domains of CPs (rCP-PDs), revealing all rCP-PDs showed CP-like activities. Importantly, the plasma obtained from chickens immunized with each rCP-PD cross-reacted with rCP-PDs of different mites. Finally, all immune plasma of rCP-PDs reduced the survival rate of PRMs, even when the plasma was collected from chickens immunized with rCP-PDs derived from TFM and NFM. Therefore, CP antigen is a promising, broadly efficacious vaccine candidate against different avian mites.

Development of HPV16 mouse and dog models for more accurate prediction of human vaccine efficacy

BackgroundAnimal models are essential to understand the physiopathology of human diseases but also to evaluate new therapies. However, for several diseases there is no appropriate animal model, which complicates the development of effective therapies. HPV infections, responsible for carcinoma cancers, are among these. So far, the lack of relevant animal models has hampered the development of therapeutic vaccines. In this study, we used a candidate therapeutic vaccine named C216, similar to the ProCervix candidate therapeutic vaccine, to validate new mouse and dog HPV preclinical models. ProCervix has shown promising results with classical subcutaneous murine TC-1 cell tumor isografts but has failed in a phase II study.ResultsWe first generated E7/HPV16 syngeneic transgenic mice in which the expression of the E7 antigen could be switched on through the use of Cre–lox recombination. Non-integrative LentiFlash® viral particles were used to locally deliver Cre mRNA, resulting in E7/HPV16 expression and GFP reporter fluorescence. The expression of E7/HPV16 was monitored by in vivo fluorescence using Cellvizio imaging and by local mRNA expression quantification. In the experimental conditions used, we observed no differences in E7 expression between C216 vaccinated and control groups. To mimic the MHC diversity of humans, E7/HPV16 transgenes were locally delivered by injection of lentiviral particles in the muscle of dogs. Vaccination with C216, tested with two different adjuvants, induced a strong immune response in dogs. However, we detected no relationship between the level of cellular response against E7/HPV16 and the elimination of E7-expressing cells, either by fluorescence or by RT-ddPCR analysis.ConclusionsIn this study, we have developed two animal models, with a genetic design that is easily transposable to different antigens, to validate the efficacy of candidate vaccines. Our results indicate that, despite being immunogenic, the C216 candidate vaccine did not induce a sufficiently strong immune response to eliminate infected cells. Our results are in line with the failure of the ProCervix vaccine that was observed at the end of the phase II clinical trial, reinforcing the relevance of appropriate animal models.

Major HIV vaccine candidates

Introduction and objective: Human immunodeficiency virus (HIV) is a virus, which is responsible for an acquired immunodeficiency syndrome (AIDS). This pathogen is widespread worldwide causing a pandemic that has been going on for decades. Researches around the world are trying to end this situation and it seems that the greatest hope lies in finding an effective vaccine. It is important due to the fact that AIDS and its consequences are responsible even nowadays for death of many people infected around the world. The aim of this study was to provide the most important information about major HIV vaccine trials and efficacy of vaccine candidates.
 Materials and methods: For the purposes of writing this article, the available literature was reviewed. The database of medical publications – Pubmed datebase and other publicaly available books, database and online sites was searched, with the use of keywords such as HIV, HIV vaccine, HIV epidemiology.
 State of knowledge: According to review studies HIV vaccine trials has been going for 4 decades. Over 250 trials has been conducted since then, but unfortunately, none of them resulted in effective vaccine. The difficulties of this task are mainly connected with the nature of HIV virus. To date, one study has shown some effectiveness, but not enough to claim success. Other studies are ongoing around the world and more are planned.
 Conclusions: Developing an effective HIV vaccine is the clue to solving the problem, which is new HIV infections. Further researches, further research funding and international cooperation are needed to end this pandemic.

Experimental Medicine for HIV Vaccine Research and Development.

The development of safe and effective HIV vaccines has been a scientific challenge for more than 40 years. Despite disappointing results from efficacy clinical trials, much has been learnt from years of research and development. In a rapidly evolving HIV prevention landscape, swift evaluation of multiple vaccine approaches eliciting cross-reactive humoral and cellular responses is needed to ensure the development of efficacious vaccine candidates. To contain increasing costs, innovative clinical research methods are required. Experimental medicine has the potential to accelerate vaccine discovery by iterating early stages of clinical testing faster and by selecting the most promising immunogen combinations for further clinical evaluation. As part of its mission to unite diverse stakeholders involved in the response to the HIV epidemic, the Global HIV Vaccine Enterprise at IAS-the International AIDS Society-hosted a series of online events between January and September 2022 to discuss the merits and challenges of experimental medicine studies to accelerate the development of safe and effective HIV vaccines. This report summarizes key questions and discussions across the series of events, which brought together scientists, policy makers, community stakeholders, advocates, bioethicists, and funders.

Glycosylated nanoparticle-based PfCSP vaccine confers long-lasting antibody responses and sterile protection in mouse malaria model

The development of an effective and durable vaccine remains a central goal in the fight against malaria. Circumsporozoite protein (CSP) is the major surface protein of sporozoites and the target of the only licensed Plasmodium falciparum (Pf) malaria vaccine, RTS,S/AS01. However, vaccine efficacy is low and short-lived, highlighting the need for a second-generation vaccine with superior efficacy and durability. Here, we report a Helicobacter pylori apoferritin-based nanoparticle immunogen that elicits strong B cell responses against PfCSP epitopes that are targeted by the most potent human monoclonal antibodies. Glycan engineering of the scaffold and fusion of an exogenous T cell epitope enhanced the anti-PfCSP B cell response eliciting strong, long-lived and protective humoral immunity in mice. Our study highlights the power of rational vaccine design to generate a highly efficacious second-generation anti-infective malaria vaccine candidate and provides the basis for its further development.

Pathological features of African horse sickness virus infection in IFNAR-/- mice.

African Horse Sickness (AHS) is a vector-borne viral disease of equids. The disease can be highly lethal with mortality rates of up to 90% in non-immune equine populations. The clinical presentation in the equine host varies, but the pathogenesis underlying this variation remains incompletely understood. Various small animal models of AHS have been developed over the years to overcome the financial, bio-safety and logistical constraints of studying the pathology of this disease in the target species. One of the most successful small animal models is based on the use of interferon-alpha gene knock-out (IFNAR-/-) mice. In order to increase our understanding of African Horse Sickness virus (AHSV) pathogenesis, we characterised the pathology lesions of AHSV infection in IFNAR-/- mice using a strain of AHSV serotype 4 (AHSV-4). We found AHSV-4 infection was correlated with lesions in various organs; necrosis in the spleen and lymphoid tissues, inflammatory infiltration in the liver and brain, and pneumonia. Significant viral antigen staining was only detected in the spleen and brain, however. Together these results confirm the value of the IFNAR-/- mouse model for the study of the immuno-biology of AHSV infections in this particular in vivo system, and its usefulness for evaluating protective efficacy of candidate vaccines in preclinical studies.

Evolution of tetraspanin antigens in the zoonotic Asian blood fluke Schistosoma japonicum

BackgroundDespite successful control efforts in China over the past 60 years, zoonotic schistosomiasis caused by Schistosoma japonicum remains a threat with transmission ongoing and the risk of localised resurgences prompting calls for a novel integrated control strategy, with an anti-schistosome vaccine as a core element. Anti-schistosome vaccine development and immunisation attempts in non-human mammalian host species, intended to interrupt transmission, and utilising various antigen targets, have yielded mixed success, with some studies highlighting variation in schistosome antigen coding genes (ACGs) as possible confounders of vaccine efficacy. Thus, robust selection of target ACGs, including assessment of their genetic diversity and antigenic variability, is paramount. Tetraspanins (TSPs), a family of tegument-surface antigens in schistosomes, interact directly with the host’s immune system and are promising vaccine candidates. Here, for the first time to our knowledge, diversity in S. japonicum TSPs (SjTSPs) and the impact of diversifying selection and sequence variation on immunogenicity in these protiens were evaluated.MethodsSjTSP sequences, representing parasite populations from seven provinces across China, were gathered by baiting published short-read NGS data and were analysed using in silico methods to measure sequence variation and selection pressures and predict the impact of selection on variation in antigen protein structure, function and antigenic propensity.ResultsHere, 27 SjTSPs were identified across three subfamilies, highlighting the diversity of TSPs in S. japonicum. Considerable variation was demonstrated for several SjTSPs between geographical regions/provinces, revealing that episodic, diversifying positive selection pressures promote amino acid variation/variability in the large extracellular loop (LEL) domain of certain SjTSPs. Accumulating polymorphisms in the LEL domain of SjTSP-2, -8 and -23 led to altered structural, functional and antibody binding characteristics, which are predicted to impact antibody recognition and possibly blunt the host’s ability to respond to infection. Such changes, therefore, appear to represent a mechanism utilised by S. japonicum to evade the host’s immune system.ConclusionWhilst the genetic and antigenic geographic variability observed amongst certain SjTSPs could present challenges to vaccine development, here we demonstrate conservation amongst SjTSP-1, -13 and -14, revealing their likely improved utility as efficacious vaccine candidates. Importantly, our data highlight that robust evaluation of vaccine target variability in natural parasite populations should be a prerequisite for anti-schistosome vaccine development.Graphical abstract

A bibliometric study on Marburg virus research with prevention and control strategies

Marburg virus (MARV) is a pathogenic zoonotic RNA virus etiologic for Marburg virus disease (MVD), a severe hemorrhagic fever. This is a rare disease, with a high fatality rate, that spreads via infected blood or body fluids or indirectly via fomites (contaminated objects and substances such as clothed, beds, personal protective equipment, or medical equipments). A few vaccines to protect against MARV are undergoing clinical trials, but there is not yet an approved vaccine against this disease. Eventually, prevention and control guidelines should be adhered to rigorously to alleviate this infection. This bibliometric analysis aimed to harness narrative evaluation, emphasizing the significance of quantitative approaches and delineating the most thought-provoking concerns for researchers using VOSviewer software (Centre for Science and Technology Studies, Leiden University, the Netherlands). “Marburg Virus” OR “MARV” AND “Diseases” search criteria were used for the analysis of articles published between 1962 and 2022. Co-occurrence analysis was carried out, which characterized different thematic clusters. From this analysis, we found that 1688 published articles, and the number of publications increased across that period annually, with a growth rate of 8.78%. It is also conspicuous that the number of publications in the United States reached its acme during this period (i.e., 714 publications, accounting for 42.29% of the total), and the United States Army Medical Research Institute of Infectious Diseases published the most literature (i.e., 146 papers). Our study found that the three pre-eminent authors of Marburg virus papers were “FELDMANN, HEINZ“ of the National Institute of Allergy and Infectious Diseases, United States, “BECKER, STEPHAN” of the Philipps University of Marburg, Germany, and “GEISBERT, THOMAS W” of the University of Texas Medical Branch, United States. In this study we found that “JOURNAL OF VIROLOGY” has published the most pertinent literature, totaling 88 articles, followed by “The journal of Infectious Diseases”, which published 76 relevant papers, and “VIRUSES”, which published 52 corresponding papers. The most cited paper on the Marburg virus was published in Nature Medicine, with 522 total citations and 29 citations/year. Studies of the changing epidemiology and evolving nature of the virus and its ecological niche are required; breakthrough and implementation of the efficacious vaccine candidate(s), prophylaxis and therapeutic alternatives and supervision strategies, unveiling awareness-raising programs, and developing apposite and timely preparedness, prevention, and proactive control strategies are of utmost importance.

Nanoparticle-Based Bivalent Swine Influenza Virus Vaccine Induces Enhanced Immunity and Effective Protection against Drifted H1N1 and H3N2 Viruses in Mice.

Swine influenza virus (SIV) circulates worldwide, posing substantial economic loss and disease burden to humans and animals. Vaccination remains the most effective way to prevent SIV infection and transmission. In this study, we evaluated the protective efficacy of a recombinant, baculovirus-insect cell system-expressed bivalent nanoparticle SIV vaccine in mice challenged with drifted swine influenza H1N1 and H3N2 viruses. After a prime-boost immunization, the bivalent nanoparticle vaccine (BNV) induced high levels of hemagglutination inhibition (HAI) antibodies, virus-neutralization (VN) antibodies, and antigen-specific IgG antibodies in mice, as well as more efficient cytokine levels. The MF59 and CPG1 adjuvant could significantly promote both humoral and cellular immunity of BNV. The MF59 adjuvant showed a balanced Th1/Th2 immune response, and the CPG1 adjuvant tended to show a Th1-favored response. The BALB/c challenge test showed that BNV could significantly reduce lung viral loads and feces viral shedding, and showed fewer lung pathological lesions than those in PBS and inactivated vaccine groups. These results suggest that this novel bivalent nanoparticle swine influenza vaccine can be used as an efficacious vaccine candidate to induce robust immunity and provide broad protection against drifted subtypes in mice. Immune efficacy in pigs needs to be further evaluated.

The Road to Elimination: Current State of Schistosomiasis Research and Progress Towards the End Game.

The new WHO Roadmap for Neglected Tropical Diseases targets the global elimination of schistosomiasis as a public health problem. To date, control strategies have focused on effective diagnostics, mass drug administration, complementary and integrative public health interventions. Non-mammalian intermediate hosts and other vertebrates promote transmission of schistosomiasis and have been utilized as experimental model systems. Experimental animal models that recapitulate schistosomiasis immunology, disease progression, and pathology observed in humans are important in testing and validation of control interventions. We discuss the pivotal value of these models in contributing to elimination of schistosomiasis. Treatment of schistosomiasis relies heavily on mass drug administration of praziquantel whose efficacy is comprised due to re-infections and experimental systems have revealed the inability to kill juvenile schistosomes. In terms of diagnosis, nonhuman primate models have demonstrated the low sensitivity of the gold standard Kato Katz smear technique. Antibody assays are valuable tools for evaluating efficacy of candidate vaccines, and sera from graded infection experiments are useful for evaluating diagnostic sensitivity of different targets. Lastly, the presence of Schistosomes can compromise the efficacy of vaccines to other infectious diseases and its elimination will benefit control programs of the other diseases. As the focus moves towards schistosomiasis elimination, it will be critical to integrate treatment, diagnostics, novel research tools such as sequencing, improved understanding of disease pathogenesis and utilization of experimental models to assist with evaluating performance of new approaches.

Impact of Dietary Protein Restriction on the Immunogenicity and Efficacy of Whole-Sporozoite Malaria Vaccination.

Malaria remains one of the world’s most prevalent infectious diseases. Several vaccination strategies currently under investigation aim at hampering the development of the Plasmodium parasite during the clinically silent liver stage of its life cycle in the mammalian host, preventing the subsequent disease-associated blood stage of infection. Immunization with radiation-attenuated sporozoites (RAS), the liver-infecting parasite forms, can induce sterile protection against malaria. However, the efficacy of vaccine candidates in malaria-naïve individuals in high-income countries is frequently higher than that found in populations where malaria is endemic. Malnutrition has been associated with immune dysfunction and with a delay or impairment of the immune response to some vaccines. Since vaccine efficacy depends on the generation of competent immune responses, and malaria-endemic regions are often associated with malnutrition, we hypothesized that an inadequate host nutritional status, specifically resulting from a reduction in dietary protein, could impact on the establishment of an efficient anti-malarial immune response. We developed a model of RAS immunization under low protein diet to investigate the impact of a reduced host protein intake on the immunogenicity and protective efficacy of this vaccine. Our analysis of the circulating and tissue-associated immune compartments revealed that a reduction in dietary protein intake during immunization resulted in a decrease in the frequency of circulating CD4+ T cells and of hepatic NK cells. Nevertheless, the profile of CD8+ T cells in the blood, liver and spleen was robust and minimally affected by the dietary protein content during RAS immunization, as assessed by supervised and in-depth unsupervised X-shift clustering analysis. Although mice immunized under low protein diet presented higher parasite liver load upon challenge than those immunized under adequate protein intake, the two groups displayed similar levels of protection from disease. Overall, our data indicate that dietary protein reduction may have minimal impact on the immunogenicity and efficacy of RAS-based malaria vaccination. Importantly, this experimental model can be extended to assess the impact of other nutrient imbalances and immunization strategies, towards the refinement of future translational interventions that improve vaccine efficacy in malnourished individuals.

Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2.HLA-DR4.Rag1KO.IL-2RγcKO.NOD) for COVID-19

ABSTRACT We report a Human Immune System (HIS)-humanized mouse model (“DRAGA”: HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103+) CD8+ and CD4+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics.