Common respiratory virus infections in cystic fibrosis : from immunity to vaccine

Cystic fibrosis is the most common lethal monogenetic disease in Caucasians. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator protein which is responsible for appropriate ion and water transport across epithelial cell membranes. The main clinical problems in cystic fibrosis are lung disease, pancreatic insufficiency and cystic fibrosisrelated diabetes. Respiratory virus infections predispose individuals with cystic fibrosis to bacterial infections and chronic colonization of the airway which exacerbate lung disease. The mechanisms behind this are poorly understood but the immune system is evidently involved. In this thesis, we studied common cold-causing enteroviruses, the Coxsackieviruses, in cystic fibrosis. In Paper I, we showed that a part of adaptive immune response towards Coxsackieviruses, namely production of neutralizing antibodies, is impaired in an experimental mouse model for cystic fibrosis (carrying the delF508 mutation). In Paper II, we elaborated on this finding and studied whether the delF508 mice could be protected from Coxsackievirus infection by vaccination and showed that vaccination was safe and efficient. We found that the production of virus-neutralizing antibodies upon vaccination in the delF508 mice was initially weak but improved upon a booster dose. We studied the frequency of Coxsackievirus infections in individuals with cystic fibrosis and found that they are common in this patient group. We conclude that common respiratory virus infections in cystic fibrosis can be successfully prevented by vaccination, which could potentially contribute to better lung function. Disease mortality is increased six-fold in individuals with cystic fibrosis-related diabetes, the pathogenesis of which is largely unknown. An autopsy study, where pancreatic tissue from cystic fibrosis patients was used as control, discovered presence of enterovirus in islets of cystic fibrosis patients with diabetes. In Paper III, we studied pancreas autopsy material from another cohort of cystic fibrosis patients with diabetes and found that 80% were positive for enterovirus in the islets compared to 40% in non-diabetic controls without cystic fibrosis. We also searched for serological evidence of a link between previous enterovirus infections and the development of cystic fibrosis-related diabetes but found no such relationship. A low-grade infection which does not induce antibody response, or a long-term persistent infection might be an explanation to this. We conclude that the role for enteroviruses in development of cystic fibrosis-related diabetes should not be excluded. In conclusion, this thesis contributes to the field of cystic fibrosis by revealing a potential immune defect in response to viral infections. It also demonstrates that common respiratory virus infections can potentially be targets for preventive treatments in cystic fibrosis. In addition, the potential role of enterovirus involvement in the pathogenesis of cystic fibrosisrelated diabetes has been presented, motivating for further studies

Pichia pastoris (Komagataella phaffii) as a Cost-Effective Tool for Vaccine Production for Low- and Middle-Income Countries (LMICs)

Vaccination is of paramount importance to global health. With the advent of the more recent pandemics, the urgency to expand the range has become even more evident. However, the potential limited availability and affordability of vaccines to resource low‐ and middle‐income countries has created a need for solutions that will ensure cost‐effective vaccine production methods for these countries. Pichia pastoris (P. pastoris) (also known as Komagataella phaffii) is one of the most promising candidates for expression of heterologous proteins in vaccines development. It combines the speed and ease of highly efficient prokaryotic platforms with some key capabilities of mammalian systems, potentially reducing manufacturing costs. This review will examine the latest developments in P. pastoris from cell engineering and design to industrial production systems with focus on vaccine development and with reference to specific key case studies

Pediatric sepsis: Important considerations for diagnosing and managing severe infections in infants, children, and adolescents

Sepsis is the leading cause of death in children worldwide. Although the diagnosis and management of sepsis in infants and children is largely influenced by studies done in adults, there are important considerations relevant for pediatrics. This article highlights pediatric-specific issues related to the definition of sepsis and its epidemiology and management. We review how the capacity of the immune system to respond to infection develops over early life. We also bring attention to primary immune deficiencies that should be considered in children recurrently infected with specific types of organisms. The management of pediatric sepsis must be tailored to the child’s age and immune capacity, and to the site, severity, and source of the infection. It is important for clinicians to be aware of infection-related syndromes that primarily affect children. Although children in developed countries are more likely to survive severe infections than adults, many survivors have chronic health impairments

Pneumonia of Viral Etiologies

Pneumonia is a common illness that continues to cause significant morbidity and mortality in both adults and children. Bacteria such as Streptococcus pneumonia, Staphylococcus aureus and Haemophilus influenzae are generally considered as the main pathogens in community-acquired pneumonia and Legionella species, Chlamydia pneumoniae and Mycoplasma pneumonia in atypical pneumonias. In contrast the proportion of pneumonias due to viruses has been both difficult to detect and quantify with any precision. However, with the advent of powerful molecular techniques and rapidly developing technologies a greater number of viruses are being implicated as pathogens and co-pathogens in pneumonia. In the case of adults, the most commonly detected viruses are influenza virus, RSV and parainfluenza. Other viruses that have recently received considerable attention, are H5N1 influenza virus and coronaviruses. Infectious causes of pneumonia in immunocompromised patients include measles, HSV, CMV, HHV-6 and Influenza viruses. Pneumonias caused by other viruses are more rarely reported and include outbreaks of rhinovirus, adenovirus (particularly serotype 14 in military institutions), coronavirus, and metapneumovirus. A range of promising therapeutic targets have been identified and numerous innovative therapeutic treatments demonstrated to improve lung injury due to viral infections

Recombinant vaccines in 2022 : a perspective from the cell factory

The last big outbreaks of Ebola fever in Africa, the thousands of avian influenza outbreaks across Europe, Asia, North America and Africa, the emergence of monkeypox virus in Europe and specially the COVID-19 pandemics have globally stressed the need for efficient, cost-effective vaccines against infectious diseases. Ideally, they should be based on transversal technologies of wide applicability. In this context, and pushed by the above-mentioned epidemiological needs, new and highly sophisticated DNA-or RNA-based vaccination strategies have been recently developed and applied at large-scale. Being very promising and effective, they still need to be assessed regarding the level of conferred long-term protection. Despite these fast-developing approaches, subunit vaccines, based on recombinant proteins obtained by conventional genetic engineering, still show a wide spectrum of interesting potentialities and an important margin for further development. In the 80's, the first vaccination attempts with recombinant vaccines consisted in single structural proteins from viral pathogens, administered as soluble plain versions. In contrast, more complex formulations of recombinant antigens with particular geometries are progressively generated and explored in an attempt to mimic the multifaceted set of stimuli offered to the immune system by replicating pathogens. The diversity of recombinant antimicrobial vaccines and vaccine prototypes is revised here considering the cell factory types, through relevant examples of prototypes under development as well as already approved products

Is Higher Viral Load in the Upper Respiratory Tract Associated With Severe Pneumonia? Findings From the PERCH Study.

Background. The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of causality of pneumonia, we compared viral load in the URT of children with World Health Organization–defined severe and very severe pneumonia and age-matched community controls. Methods. In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine optimal discriminatory viral load cutoffs. Viral load density distributions were plotted. Results. The mean viral load was higher in cases than controls for 7 viruses. However, there was substantial overlap in viral load distribution of cases and controls for all viruses. ROC curves to determine the optimal viral load cutoff produced an area under the curve of \u3c0.80 for all viruses, suggesting poor to fair discrimination between cases and controls. Fatal and very severe pneumonia cases did not have higher viral load than less severe cases for most viruses. Conclusions. Although we found higher viral loads among pneumonia cases than controls for some viruses, the utility in using viral load of URT specimens to define viral pneumonia was equivocal. Our analysis was limited by lack of a gold standard for viral pneumonia

Development of vaccine formulations : past, present and future

The current situation, heavily influenced by the ongoing pandemic, puts vaccines back into the spotlight. However, the conventional and traditional vaccines present disadvantages, particularly related to immunogenicity, stability, and storage of the final product. Often, such products require the maintenance of a “cold chain,” impacting the costs, the availability, and the distribution of vaccines. Here, after a recall of the mode of action of vaccines and the types of vaccines currently available, we analyze the past, present, and future of vaccine formulation. The past focuses on conventional formulations, the present discusses the use of nanoparticles for vaccine delivery and as adjuvants, while the future presents microneedle patches as alternative formulation and administration route. Finally, we compare the advantages and disadvantages of injectable solutions, nanovaccines, and microneedles in terms of efficacy, stability, and patient-friendly design.Peer reviewe

Expert Rev Vaccines

Introduction:Noroviruses are the leading cause of foodborne illness worldwide, account for approximately one-fifth of acute gastroenteritis (AGE) cases globally, and cause a substantial economic burden. Candidate norovirus vaccines are in development, but there is currently no licensed vaccine.Areas covered:Noroviruses cause approximately 684 million cases and 212,000 deaths per year across all age groups, though burden estimates vary by study and region. Challenges to vaccine research include substantial and rapidly evolving genetic diversity, short-term and homotypic immunity to infection, and the absence of a single, well-established correlate of protection. Nonetheless, several norovirus vaccine candidates are currently in development, utilizing virus-like particles (VLPs), P particles, and recombinant adenoviruses. Of these, a bivalent GI.1/GII.4 VLP-based intramuscular vaccine (Phase IIb) and GI.1 oral vaccine (Phase I) are in clinical trials.Expert Commentary:A norovirus vaccine should target high-risk populations, including the young and the elderly, and protect them against the most common circulating norovirus strains. A norovirus vaccine would be a powerful tool in the prevention and control of norovirus while lessening the burden of AGE worldwide. However, more robust burden and cost estimates are needed to justify investments in and guide norovirus vaccine development.20182019-09-01T00:00:00ZCC999999/Intramural CDC HHS/United States30092671PMC6410563754

Expert Rev Vaccines

Introduction:In the last two decades, the evidence related to using vaccine patches with multiple short projections ( 64 1 mm) to deliver vaccines through the skin increased significantly and demonstrated their potential as an innovative delivery platform.Areas covered:We review the vaccine patch literature published in English as of March 1, 2019, as well as available information from key stakeholders related to vaccine patches as a platform. We identify key research topics related to basic and translational science on skin physical properties and immunobiology, patch development, and vaccine manufacturing.Expert opinion:Currently, vaccine patch developers continue to address some basic science and other platform issues in the context of developing a potential vaccine patch presentation for an existing or new vaccine. Additional clinical data and manufacturing experience could shift the balance toward incentivizing existing vaccine manufactures to further explore the use vaccine patches to deliver their products. Incentives for innovation of vaccine patches differ for developed and developing countries, which will necessitate different strategies (e.g., public-private partnerships, push or pull mechanisms) to support the basic and applied research needed to ensure a strong evidence base and to overcome translational barriers for vaccine patches as a delivery platform.U2R GH001913/GH/CGH CDC HHSUnited States/2021-01-19T00:00:00Z32182145PMC78143981205