Human Vaccine Research Articles

Analysis and Optimal Control Measures of a Typhoid Fever Mathematical Model for Two Socio-Economic Populations

Typhoid fever is an infectious disease that affects humanity worldwide; it is particularly dangerous in areas with communities of a lower socio-economic status, where many individuals are exposed to a dirty environment and unclean food. A mathematical model is formulated to analyze the impact of control measures such as vaccination of susceptible humans, treatment of infected humans and sanitation in different socio-economic communities. The model assumed that the population comprises of two socio-economic classes. The essential dynamical system analysis of our model was appropriately carried out. The impact of the control measures was analyzed, and the optimal control theory was applied on the control model to explore the impact of the different control measures. Numerical simulation of the models and the optimal controls were carried out and the obtained results indicate that the overall combination of the control measures eradicates typhoid fever in the population, but the controls are more optimal in higher socio-economic status communities.

Development of a novel squalene/α-tocopherol-based self-emulsified nanoemulsion incorporating Leishmania peptides for induction of antigen-specific immune responses

Vaccination has emerged as the most effective strategy to confront infectious diseases, among which is leishmaniasis, that threat public health. Despite laborious efforts there is still no vaccine for humans to confront leishmaniasis. Multi-epitope protein/peptide vaccines present a number of advantages, however their use along with appropriate adjuvants that may also act as antigen carriers is considered essential to overcome subunit vaccines’ low immunogenicity. In the present study, a stable self-emulsified nanoemulsion was developed and double-adjuvanted with squalene and α-tocopherol. The prepared nanoemulsion droplets exhibited low cytotoxicity in a certain range of concentrations, while they were efficiently taken up by macrophages and dendritic cells in vitro as well as in vivo in secondary lymphoid organs. To further characterize nanoformulation’s potent antigen delivery capability, three multi-epitope Leishmania peptides were incorporated into the nanoemulsion. Peptide encapsulation resulted in dendritic cells’ functional differentiation characterized by elevated levels of maturation markers and intracellular cytokine production. Intramuscular administration of the nanoemulsion incorporating Leishmania peptides induced antigen-specific spleen cell proliferation as well as elicitation of CD4+ central memory cells, supporting the potential of the developed nanoformulation to successfully act also as an antigen delivery vehicle and thus encouraging further preclinical studies on its vaccine candidate potency.

Antibody-Mediated Suppression Regulates the Humoral Immune Response to Influenza Vaccination in Humans.

Preexisting immunity, including memory B cells and preexisting antibodies, can modulate antibody responses to influenza in vivo to antigenically related antigens. We investigated whether preexisting hemagglutination inhibition (HAI) antibodies targeting the K163 epitope on the hemagglutinin (K163 antibodies) could affect antibody responses following vaccination with A/California/07/2009-like A(H1N1)pdm09 influenza viruses in humans. Pre- and postvaccination sera collected from 300 adults (birth years, 1961-1998) in 6 seasons (2010-2016) were analyzed by HAI assays with 2 reverse genetics viruses and A(H1N1) viruses circulated from 1977 to 2018. Antibody adsorption assays were used to verify the preexisting K163 antibody-mediated suppression effect. Preexisting K163 antibody titers ≥80 affected HAI antibody responses following influenza vaccination containing A/California/07/2009-like antigens. At high K163 antibody concentrations (HAI antibody titers ≥160), all HAI antibody responses were suppressed. However, at moderate K163 antibody concentrations (HAI antibody titer, 80), only K163 epitope-specific antibody responses were suppressed, and novel HAI antibody responses targeting the non-K163 epitopes were induced by vaccination. Novel antibodies targeting non-K163 epitopes cross-reacted with newly emerging A(H1N1)pdm09 strains with a K163Q mutation rather than historic 1977-2007 A(H1N1) viruses. K163 antibody-mediated suppression shapes antibody responses to A(H1N1)pdm09 vaccination. Understanding how preexisting antibodies suppress and redirect vaccine-induced antibody responses is of great importance to improve vaccine effectiveness.

Bridging responses to a human telomerase reverse transcriptase-based peptide cancer vaccine candidate in a mechanism-based model

Therapeutic cancer vaccines are novel immuno-therapeutics, aiming to improve clinical outcomes with other immunotherapies. However, obstacles to their successful clinical development remain, which model-informed drug development approaches may address. UV1 is a telomerase based therapeutic cancer vaccine candidate being investigated in phase I clinical trials for multiple indications. We developed a mechanism-based model structure, using a nonlinear mixed‐effects modeling techniques, based on longitudinal tumor sizes (sum of the longest diameters, SLD), UV1-specific immunological assessment (stimulation index, SI) and overall survival (OS) data obtained from a UV1 phase I trial including non-small cell lung cancer (NSCLC) patients and a phase I/IIa trial including malignant melanoma (MM) patients. The final structure comprised a mechanistic tumor growth dynamics (TGD) model, a model describing the probability of observing a UV1-specific immune response (SI ≥ 3) and a time-to-event model for OS. The mechanistic TGD model accounted for the interplay between the vaccine peptides, immune system and tumor. The model-predicted UV1-specific effector CD4+ T cells induced tumor shrinkage with half-lives of 103 and 154 days in NSCLC and MM patients, respectively. The probability of observing a UV1-specific immune response was mainly driven by the model-predicted UV1-specific effector and memory CD4+ T cells. A high baseline SLD and a high relative increase from nadir were identified as main predictors for a reduced OS in NSCLC and MM patients, respectively. Our model predictions highlighted that additional maintenance doses, i.e. UV1 administration for longer periods, may result in more sustained tumor size shrinkage.

Immunization with different recombinant West Nile virus envelope proteins induces varying levels of serological cross-reactivity and protection from infection.

West Nile Virus (WNV) is a zoonotic flavivirus transmitted by mosquitoes. Especially in the elderly or in immunocompromised individuals an infection with WNV can lead to severe neurological symptoms. To date, no human vaccine against WNV is available. The Envelope (E) protein, located at the surface of flaviviruses, is involved in the invasion into host cells and is the major target for neutralizing antibodies and therefore central to vaccine development. Due to their close genetic and structural relationship, flaviviruses share highly conserved epitopes, such as the fusion loop domain (FL) in the E protein, that are recognized by cross-reactive antibodies. These antibodies can lead to enhancement of infection with heterologous flaviviruses, which is a major concern for potential vaccines in areas with co-circulation of different flaviviruses, e.g. Dengue or Zika viruses. To reduce the potential of inducing cross-reactive antibodies, we performed an immunization study in mice using WNV E proteins with either wild type sequence or a mutated FL, and WNV E domain III which does not contain the FL at all. Our data show that all antigens induce high levels of WNV-binding antibodies. However, the level of protection against WNV varied, with the wildtype E protein inducing full, the other antigens only partial protection. On the other hand, serological cross-reactivity to heterologous flaviviruses was significantly reduced after immunization with the mutated E protein or domain III as compared to the wild type version. These results have indications for choosing antigens with the optimal specificity and efficacy in WNV vaccine development.

Development of a multi-epitope vaccine candidate for leishmanial parasites applying immunoinformatics and in vitro approaches.

Leishmaniasis is a neglected tropical disease, and its severity necessitates the development of a potent and efficient vaccine for the disease; however, no human vaccine has yet been approved for clinical use. This study aims to design and evaluate a multi-epitope vaccine against the leishmanial parasite by utilizing helper T-lymphocyte (HTL), cytotoxic T-lymphocyte (CTL), and linear B-lymphocyte (LBL) epitopes from membrane-bound acid phosphatase of Leishmania donovani (LdMAcP). The designed multi-epitope vaccine (LdMAPV) was highly antigenic, non-allergenic, and non-toxic, with suitable physicochemical properties. The three-dimensional structure of LdMAPV was modeled and validated, succeeded by molecular docking and molecular dynamics simulation (MDS) studies that confirmed the high binding affinity and stable interactions between human toll-like receptors and LdMAPV. In silico disulfide engineering provided improved stability to LdMAPV, whereas immune simulation displayed the induction of both immune responses, i.e., antibody and cell-mediated immune responses, with a rise in cytokines. Furthermore, LdMAPV sequence was codon optimized and cloned into the pET-28a vector, followed by its expression in a bacterial host. The recombinant protein was purified using affinity chromatography and subjected to determine its effect on cytotoxicity, cytokines, and nitric oxide generation by mammalian macrophages. Altogether, this report provides a multi-epitope vaccine candidate from a leishmanial protein participating in parasitic virulence that has shown its potency to be a promising vaccine candidate against leishmanial parasites.

Digital Personal Health Coaching Platform for Promoting Human Papillomavirus Infection Vaccinations and Cancer Prevention: Knowledge Graph-Based Recommendation System.

Health promotion can empower populations to gain more control over their well-being by using digital interventions that focus on preventing the root causes of diseases. Digital platforms for personalized health coaching can improve health literacy and information-seeking behavior, leading to better health outcomes. Personal health records have been designed to enhance patients' self-management of a disease or condition. Existing personal health records have been mostly designed and deployed as a supplementary service that acts as views into electronic health records. We aim to overcome some of the limitations of electronic health records. This study aims to design and develop a personal health library (PHL) that generates personalized recommendations for human papillomavirus (HPV) vaccine promotion and cancer prevention. We have designed a proof-of-concept prototype of the Digital Personal Health Librarian, which leverages machine learning; natural language processing; and several innovative technological infrastructures, including the Semantic Web, social linked data, web application programming interfaces, and hypermedia-based discovery, to generate a personal health knowledge graph. We have designed and implemented a proof-of-the-concept prototype to showcase and demonstrate how the PHL can be used to store an individual's health data, for example, a personal health knowledge graph. This is integrated with web-scale knowledge to support HPV vaccine promotion and prevent HPV-associated cancers among adolescents and their caregivers. We also demonstrated how the Digital Personal Health Librarian uses the PHL to provide evidence-based insights and knowledge-driven explanations that are personalized and inform health decision-making. Digital platforms such as the PHL can be instrumental in improving precision health promotion and education strategies that address population-specific needs (ie, health literacy, digital competency, and language barriers) and empower individuals by facilitating knowledge acquisition to make healthy choices.

Identification of Host Factors for Rift Valley Fever Phlebovirus.

Rift Valley fever phlebovirus (RVFV) is a zoonotic pathogen that causes Rift Valley fever (RVF) in livestock and humans. Currently, there is no licensed human vaccine or antiviral drug to control RVF. Although multiple species of animals and humans are vulnerable to RVFV infection, host factors affecting susceptibility are not well understood. To identify the host factors or genes essential for RVFV replication, we conducted CRISPR-Cas9 knockout screening in human A549 cells. We then validated the putative genes using siRNA-mediated knock-downs and CRISPR-Cas9-mediated knock-out studies. The role of a candidate gene in the virus replication cycle was assessed by measuring intracellular viral RNA accumulation, and the virus titers were analyzed using plaque assay or TCID50 assay. We identified approximately 900 genes with potential involvement in RVFV infection and replication. Further evaluation of the effect of six genes on viral replication using siRNA-mediated knock-downs revealed that silencing two genes (WDR7 and LRP1) significantly impaired RVFV replication. For further analysis, we focused on the WDR7 gene since the role of the LRP1 gene in RVFV replication was previously described in detail. WDR7 knockout A549 cell lines were generated and used to dissect the effect of WRD7 on a bunyavirus, RVFV, and an orthobunyavirus, La Crosse encephalitis virus (LACV). We observed significant effects of WDR7 knockout cells on both intracellular RVFV RNA levels and viral titers. At the intracellular RNA level, WRD7 affected RVFV replication at a later phase of its replication cycle (24 h) when compared with the LACV replication, which was affected in an earlier replication phase (12 h). In summary, we identified WDR7 as an essential host factor for the replication of two different viruses, RVFV and LACV, both of which belong to the Bunyavirales order. Future studies will investigate the mechanistic role through which WDR7 facilitates phlebovirus replication.

CONVERGENCE STRATEGY OF DIGITAL LIVESTOCK PRODUCTION AND ANIMAL BIOMODELS FOR HUMAN WELLNESS IN FUTURE: A REVIEW

As human lifespan increase, interest in human health and the digital livestock system is also increasing. Therefore, it is necessary to converge the digital livestock system and animal biomodels. In the fourth industrial revolution, animal biomodels and the digital livestock system as algorithms in agriculture are emerging rapid evolution by converging enovation technologies in fields of bio-healthcare, biomedical research, and life science. Animal biomodels have been used as important foundational tools to transit screening processes and clinical trials for useful substances and potential drugs in human and animal life science. Animal biomodels for studying human and animal diseases have enabled medical innovation and derived numerous outcomes such as vaccines. It is very important to choose appropriate animal biomodels in clinical studies. When selecting experimental animals for human and animal diseases, some parameters should be kept in mind. Convergence of the digital livestock system with animal biomodel can help us greatly solve human and animal health diseases and welfare issues. It enables prevention of human diseases and vaccine development for emerging infectious diseases by applying appropriate animal biomodels, thus contributing to the development of bio-healthcare industry. Animal biomodels are in vivo models for determining mechanisms of life phenomena and diseases progression. They can also be used to evaluate the safety, effectiveness, new cosmetic materials, and action mechanisms of functional materials and foods. Animal experiments using animal biomodels must be based on ethical considerations. Animal biomodels can be produced through drugs, diet, surgical procedures, spontaneous mutation, crossbreeding, biotechnology such as transformation and genetic manipulation, and so on. In this paper, preemptive response strategies for the development of livestock and biomedical industry of the future are reviewed through understanding the importance of animal biomodels and the digital livestock system as agriculture algorithms. Animal models for studying mechanisms of diseases in human, livestock, and birds, in ovo technology for poultry, preparation theories, animal bioethics, and practical cases are also explained. Keywords: Digital livestock system, biomodels, clinical trial, animal bioehtics, agriculture algorithms

Immunoperoxidase and neutralization/RT-PCR to estimate the efficiency of the human rotavirus VP8 structural protein candidate subunit vaccine.

Immunoperoxidase and neutralization/RT-PCR to estimate the efficiency of the human rotavirus VP8 structural protein candidate subunit vaccine.

Reconstituted dry powder formulations of ZnO-adjuvanted ovalbumin induce equivalent antigen specific antibodies but lower T cell responses than ovalbumin adjuvanted with Alhydrogel® or cationic adjuvant formulation 01 (CAF®01)

Most licensed human vaccines are based on liquid dosage forms but have poor storage stability and require continuous and expensive cold-chain storage. In contrast, the use of solid vaccine dosage forms produced by for example spray drying, extends shelf life and eliminates the need for a cold chain. Zinc oxide (ZnO)-based nanoparticles display immunomodulatory properties, but their adjuvant effect as a dry powder formulation is unknown. Here, we show that reconstituted dry powder formulations of ZnO particles containing the model antigen ovalbumin (OVA) induce antigen-specific CD8+ T-cell and humoral responses. By systematically varying the ratio between ZnO and mannitol during spray drying, we manufactured dry powder formulations of OVA-containing ZnO particles that displayed: (i) a spherical or wrinkled surface morphology, (ii) an aerodynamic diameter and particle size distribution optimal for deep lung deposition, and (iii) aerosolization properties suitable for lung delivery. Reconstituted dry powder formulations of ZnO particles were well-tolerated by Calu-3 lung epithelial cells. Furthermore, almost equivalent OVA-specific serum antibody responses were stimulated by reconstituted ZnO particles, OVA adjuvanted with Alhydrogel®, and OVA adjuvanted with the cationic adjuvant formulation 01 (CAF®01). However, reconstituted dry powder ZnO particles and OVA adjuvanted with Alhydrogel® induced significantly lower OVA-specific CD8+CD44+ T-cell responses in the spleen than OVA adjuvanted with CAF®01. Similarly, reconstituted dry powder ZnO particles activated significantly lower percentages of follicular helper T cells and germinal center B cells in the draining lymph nodes than OVA adjuvanted with CAF®01. Overall, our results show that reconstituted dry powder formulations of ZnO nanoparticles can induce antigen-specific antibodies and can be used in vaccines to enhance antigen-specific humoral immune responses against subunit protein antigens.

Safety and immunogenicity of three dose levels of an investigational, highly purified Vero cell rabies vaccine: A randomized, controlled, observer-blinded, Phase II study with a simulated post-exposure regimen in healthy adults

ABSTRACT A serum-free, highly purified rabies vaccine produced in Vero cells is under development. The initial formulation, PVRV-NG, was evaluated in five Phase II studies and subsequently reformulated (PVRV-NG2). This multicenter, observer-blinded Phase II study investigated the safety and immune response of three different doses (antigen content) of PVRV-NG2 versus a licensed human diploid cell rabies vaccine (HDCV; Imovax rabies®). Healthy adults (N = 320) were randomized to receive PVRV-NG2 (low, medium, or high dose), PVRV-NG, or HDCV (2:2:2:1:1 ratio), according to a five-dose Essen simulated post-exposure regimen (Days [D] 0, 3, 7, 14, and 28). All participants received human rabies immunoglobulin intramuscularly on D0. Immunogenicity was assessed at D0, 14, 28, 42, and 6 months after the final injection using the rapid fluorescent focus inhibition test. Seroconversion rates were calculated as the percentage of participants achieving rabies virus neutralizing antibody titers ≥0.5 IU/mL. All analyses were descriptive. At each timepoint, geometric mean titers (GMTs) increased with antigen content (measured using an enzyme-linked immunosorbent assay). High-dose PVRV-NG2 GMTs were the highest at all timepoints, medium-dose PVRV-NG2 GMTs were similar to those with HDCV, and low-dose PVRV-NG2 GMTs were similar to PVRV-NG. The safety profile of PVRV-NG2 was comparable to PVRV-NG; however, fewer injection site reactions were reported with PVRV-NG2 or PVRV-NG (range 36.7–47.5%) than with HDCV (61.5%). This study demonstrated a dose–effect of antigen content at all timepoints. As post-exposure prophylaxis, the safety and immunogenicity profiles of the high-dose PVRV-NG2 group compared favorably with HDCV. Clinicaltrials.gov number: NCT03145766.

Clade 2.3.4.4 H5 chimeric cold-adapted attenuated influenza vaccines induced cross-reactive protection in mice and ferrets.

Clade 2.3.4.4 H5Nx avian influenza viruses (AIVs) have circulated globally and caused substantial economic loss. Increasing numbers of humans have been infected with Clade 2.3.4.4 H5N6 AIVs in recent years. Only a few human influenza vaccines have been licensed to date. However, the licensed live attenuated influenza virus vaccine exhibited the potential of being recombinant with the wild-type influenza A virus (IAV). Therefore, we developed a chimeric cold-adapted attenuated influenza vaccine based on the Clade 2.3.4.4 H5 AIVs. These H5 vaccines demonstrate the advantage of being non-recombinant with circulated IAVs in the future influenza vaccine study. The findings of our current study reveal that these H5 vaccines can induce cross-reactive protective efficacy in mice and ferrets. Our H5 vaccines may provide a novel option for developing human-infected Clade 2.3.4.4 H5 AIV vaccines.

Assessing vaccine hesitancy and support for vaccination requirements for pets and potential Spillovers from humans

BackgroundGrowing vaccination hesitancy is well-document among humans. However, we know very little about vaccination hesitancy for pets as well as whether the two phenomena are interconnected. Moreover, support for pet vaccination requirements also remain underassessed. MethodsWe fielded a large, national survey (N = 3,958) on August 18 and August 19, 2023, to assess U.S. public opinion about the vaccination status of dogs (rabies, canine parvovirus, canine distemper, canine influenza, and Lyme disease) and cats (rabies, feline panleukopenia (parvo), feline herpesvirus-1, feline chlamydia, and feline Bordetella) in the United States. We also queried respondents about their support for vaccination requirements for the 10 diseases. ResultsWe find that the vast majority of cats and dogs are vaccinated. However, a substantial minority of pets is not, particularly for cats and for non-core vaccines. We find that attitudinal measures of human and pet vaccine hesitancy are closely related to each other. Moreover, they are strong predictors of vaccine behavior. Measures of vaccine hesitancy are also strong predictors of support for vaccination mandates. Common measures used to assess human vaccine hesitancy showed inconsistent effects. However, pet vaccinations appear to be less politically polarizing. ConclusionThe high correlation between pet and human measures raises the stake for public health efforts to improve attitudes about vaccines and vaccination rates across the board. Strong support for vaccination requirements should encourage policymakers to explore policy change. Moreover, veterinarians and their associations should consider expanding the number of core vaccinations.

The international trade in human vaccines before COVID‐19

AbstractThe recent COVID‐19 pandemic has highlighted the importance of global access to human vaccines. There is, however, no empirical work on either the unequal distribution of international trade or on its determinants. Applying a gravity model to the UN Comtrade database between 2000 and 2019, we explain the patterns of bilateral trade across 116 countries. Using the Poisson Pseudo‐Maximum Likelihood methodology, our results show that inequalities in international vaccine trade have steadily increased. In general, supply and demand drivers play a role in explaining the flow of human vaccines. The impact of these drivers varies depending on the income level of the importing country. High‐income countries intensify their flows with demand factors such as GDP per capita, or supply factors such as the location of big pharmaceutical companies. Conversely, low‐income countries receive more vaccines according to their population. Our results show that a poor country that houses a big pharmaceutical company acts as an exporting platform to developing and poor countries. Middle‐income countries present features similar to rich countries both by producing more and also by exporting more. The imbalance endangers the global fight against the current COVID‐19 pandemic.

Genome-wide epitope mapping across multiple host species reveals significant diversity in antibody responses to Coxiella burnetii vaccination and infection.

Coxiella burnetii is an important zoonotic bacterial pathogen of global importance, causing the disease Q fever in a wide range of animal hosts. Ruminant livestock, in particular sheep and goats, are considered the main reservoir of human infection. Vaccination is a key control measure, and two commercial vaccines based on formalin-inactivated C. burnetii bacterins are currently available for use in livestock and humans. However, their deployment is limited due to significant reactogenicity in individuals previously sensitized to C. burnetii antigens. Furthermore, these vaccines interfere with available serodiagnostic tests which are also based on C. burnetii bacterin antigens. Defined subunit antigen vaccines offer significant advantages, as they can be engineered to reduce reactogenicity and co-designed with serodiagnostic tests to allow discrimination between vaccinated and infected individuals. This study aimed to investigate the diversity of antibody responses to C. burnetii vaccination and/or infection in cattle, goats, humans, and sheep through genome-wide linear epitope mapping to identify candidate vaccine and diagnostic antigens within the predicted bacterial proteome. Using high-density peptide microarrays, we analyzed the seroreactivity in 156 serum samples from vaccinated and infected individuals to peptides derived from 2,092 open-reading frames in the C. burnetii genome. We found significant diversity in the antibody responses within and between species and across different types of C. burnetii exposure. Through the implementation of three different vaccine candidate selection methods, we identified 493 candidate protein antigens for protein subunit vaccine design or serodiagnostic evaluation, of which 65 have been previously described. This is the first study to investigate multi-species seroreactivity against the entire C. burnetii proteome presented as overlapping linear peptides and provides the basis for the selection of antigen targets for next-generation Q fever vaccines and diagnostic tests.

Calls for human challenge vaccine trials.

Calls for human challenge vaccine trials.

Bifidobacterium infantis supplementation versus placebo in early life to improve immunity in infants exposed to HIV: a protocol for a randomized trial

IntroductionInfants who are born from mothers with HIV (infants who are HIV exposed but uninfected; iHEU) are at higher risk of morbidity and display multiple immune alterations compared to infants who are HIV-unexposed (iHU). Easily implementable strategies to improve immunity of iHEU, and possibly subsequent clinical health outcomes, are needed. iHEU have altered gut microbiome composition and bifidobacterial depletion, and relative abundance of Bifidobacterium infantis has been associated with immune ontogeny, including humoral and cellular vaccine responses. Therefore, we will assess microbiological and immunological phenotypes and clinical outcomes in a randomized, double-blinded trial of B. infantis Rosell®-33 versus placebo given during the first month of life in South African iHEU.MethodsThis is a parallel, randomised, controlled trial. Two-hundred breastfed iHEU will be enrolled from the Khayelitsha Site B Midwife Obstetric Unit in Cape Town, South Africa and 1:1 randomised to receive 8 × 109 CFU B. infantis Rosell®-33 daily or placebo for the first 4 weeks of life, starting on day 1–3 of life. Infants will be followed over 36 weeks with extensive collection of meta-data and samples. Primary outcomes include gut microbiome composition and diversity, intestinal inflammation and microbial translocation and cellular vaccine responses. Additional outcomes include biological (e.g. gut metabolome and T cell phenotypes) and clinical (e.g. growth and morbidity) outcome measures.DiscussionThe results of this trial will provide evidence whether B. infantis supplementation during early life could improve health outcomes for iHEU.Ethics and disseminationApproval for this study has been obtained from the ethics committees at the University of Cape Town (HREC Ref 697/2022) and Seattle Children’s Research Institute (STUDY00003679).Trial registrationPan African Clinical Trials Registry Identifier: PACTR202301748714019. Clinical.trials.gov: NCT05923333.Protocol Version: Version 1.8, dated 18 July 2023.

Q fever - immune responses and novel vaccine strategies.

Q fever is a zoonotic disease caused by the bacterium Coxiella burnetii. It is an occupational risk for employees of animal industriesand is associated with contact with wildlifeand domestic animals. AlthoughQ fever infection may be asymptomatic, chronic sequelae such as endocarditis occur in 5% of symptomatic individuals. Disease outcomes may be predicted through measurement of immune correlates. Vaccination is the most efficient method to prevent Q fever. Currently, Q-VAX is the only licenced human vaccine. Q-VAX is highly effective; however, individuals previously exposed to C. burnetii are at risk of adverse reactions. This review examines the immunological responses of acute and chronic Q fever and the efforts to provide a safer and cost-effective Q fever vaccine.

Identification of Critical Amino Acids of Coxsackievirus A10 Associated with Cell Tropism and Viral RNA Release during Uncoating.

Coxsackievirus A10 (CV-A10) is a prevailing causative agent of hand-foot-mouth disease, necessitating the isolation and adaptation of appropriate strains in cells allowed for human vaccine development. In this study, amino acid sequences of CV-A10 strains with different cell tropism on RD and Vero cells were compared. Various amino acids on the structural and non-structural proteins related to cell tropism were identified. The reverse genetic systems of several CV-A10 strains with RD+/Vero- and RD+/Vero+ cell tropism were developed, and a set of CV-A10 recombinants were produced. The binding, entry, uncoating, and proliferation steps in the life cycle of these viruses were evaluated. P1 replacement of CV-A10 strains with different cell tropism revealed the pivotal role of the structural proteins in cell tropism. Further, seven amino acid substitutions in VP2 and VP1 were introduced to further investigate their roles played in cell tropism. These mutations cooperated in the growth of CV-A10 in Vero cells. Particularly, the valine to isoleucine mutation at the position VP1-236 (V1236I) was found to significantly restrict viral uncoating in Vero cells. Co-immunoprecipitation assays showed that the release of viral RNA from the KREMEN1 receptor-binding virions was restricted in r0195-V1236I compared with the parental strain r0195 (a RD+/Vero+ strain). Overall, this study highlights the dominant effect of structural proteins in CV-A10 adaption in Vero cells and the importance of V1236 in viral uncoating, providing a foundation for the mechanism study of CV-A10 cell tropism, and facilitating the development of vaccine candidates.