Repeated Dose Toxicity Study and Developmental and Reproductive Toxicology Studies of a Respiratory Syncytial Virus Candidate Vaccine in Rabbits and Rats

2021 ◽  
pp. 109158182098578
Author(s):  
Alan H. Stokes ◽  
Kelle Franklin ◽  
Daniel E. Fisher ◽  
Lorraine M. Posobiec ◽  
Ornella Binazon ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Young Children ◽  
Postnatal Development ◽  
Toxicity Study ◽  
Repeated Dose ◽  
Repeated Dose Toxicity ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections, and vaccines are needed to treat young children and older adults. One of GSK’s candidate vaccines for RSV contains recombinant RSVPreF3 protein maintained in the prefusion conformation. The differences in immune function of young children and older adults potentially require different vaccine approaches. For young children, anti-RSV immunity can be afforded during the first months of life by vaccinating the pregnant mother during the third trimester with unadjuvanted RSVPreF3, which results in protection of the infant due to the transplacental passage of anti-RSV maternal antibodies. For older adults with a waning immune response, the approach is to adjuvant the RSVPreF3 vaccine with AS01 to elicit a more robust immune response. The local and systemic effects of biweekly intramuscular injections of the RSVPreF3 vaccine (unadjuvanted, adjuvanted with AS01, or coadministered with a diphtheria-tetanus-acellular pertussis vaccine) was tested in a repeated dose toxicity study in rabbits. After three intramuscular doses, the only changes observed were those commonly related to a vaccine-elicited inflammatory reaction. Subsequently, the effects of unadjuvanted RSVPreF3 vaccine on female fertility, embryo-fetal, and postnatal development of offspring were evaluated in rats and rabbits. There were no effects on pregnancy, delivery, lactation, or the pre- and postnatal development of offspring. In conclusion, the RSVPreF3 vaccine was well-tolerated locally and systemically and was not associated with any adverse effects on female reproductive function or on the pre- and postnatal growth and development of offspring.

scholarly journals Contribution of Resident Memory CD8+ T Cells to Protective Immunity Against Respiratory Syncytial Virus and Their Impact on Vaccine Design

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 147 ◽  
Author(s):  
Retamal-Díaz ◽  
Covián ◽  
Pacheco ◽  
Castiglione-Matamala ◽  
Bueno ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Respiratory Syncytial Virus ◽  
Viral Infections ◽  
Memory T Cells ◽  
Effector Memory ◽  
Memory Cells ◽  
Effective Immune Response ◽  
Syncytial Virus ◽  
Tract Infections

Worldwide, human respiratory syncytial virus (RSV) is the most common etiological agent for acute lower respiratory tract infections (ALRI). RSV-ALRI is the major cause of hospital admissions in young children, and it can cause in-hospital deaths in children younger than six months old. Therefore, RSV remains one of the pathogens deemed most important for the generation of a vaccine. On the other hand, the effectiveness of a vaccine depends on the development of immunological memory against the pathogenic agent of interest. This memory is achieved by long-lived memory T cells, based on the establishment of an effective immune response to viral infections when subsequent exposures to the pathogen take place. Memory T cells can be classified into three subsets according to their expression of lymphoid homing receptors: central memory cells (TCM), effector memory cells (TEM) and resident memory T cells (TRM). The latter subset consists of cells that are permanently found in non-lymphoid tissues and are capable of recognizing antigens and mounting an effective immune response at those sites. TRM cells activate both innate and adaptive immune responses, thus establishing a robust and rapid response characterized by the production of large amounts of effector molecules. TRM cells can also recognize antigenically unrelated pathogens and trigger an innate-like alarm with the recruitment of other immune cells. It is noteworthy that this rapid and effective immune response induced by TRM cells make these cells an interesting aim in the design of vaccination strategies in order to establish TRM cell populations to prevent respiratory infectious diseases. Here, we discuss the biogenesis of TRM cells, their contribution to the resolution of respiratory viral infections and the induction of TRM cells, which should be considered for the rational design of new vaccines against RSV.

scholarly journals Immunological, Viral, Environmental, and Individual Factors Modulating Lung Immune Response to Respiratory Syncytial Virus

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Silvia Vandini ◽  
Paolo Bottau ◽  
Giacomo Faldella ◽  
Marcello Lanari
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Animal Models ◽  
Respiratory Tract Infections ◽  
Clinical Course ◽  
Respiratory Infections ◽  
Syncytial Virus ◽  
High Risk Infants ◽  
Tract Infections ◽  
Lung Response

Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high risk infants and adults. Several studies have been performed to investigate the immune response that determines the clinical course of the infection. In the present paper, we review the literature on viral, environmental, and host factors influencing virus response; the mechanisms of the immune response; and the action of nonimmunological factors. These mechanisms have often been studied in animal models and in the present review we also summarize the main findings obtained from animal models as well as the limits of each of these models. Understanding the lung response involved in the pathogenesis of these respiratory infections could be useful in improving the preventive strategies against respiratory syncytial virus.

scholarly journals Effects of Human Metapneumovirus and Respiratory Syncytial Virus Antigen Insertion in Two 3′ Proximal Genome Positions of Bovine/Human Parainfluenza Virus Type 3 on Virus Replication and Immunogenicity

2003 ◽  
Vol 77 (20) ◽  
pp. 10819-10828 ◽  
Author(s):  
Roderick S. Tang ◽  
Jeanne H. Schickli ◽  
Mia MacPhail ◽  
Fiona Fernandes ◽  
Leenas Bicha ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Young Children ◽  
Virus Type ◽  
Human Metapneumovirus ◽  
Viral Rna ◽  
Parainfluenza Virus ◽  
Viral Genes ◽  
Syncytial Virus ◽  
Type 3

ABSTRACT A live attenuated bovine parainfluenza virus type 3 (PIV3), harboring the fusion (F) and hemagglutinin-neuraminidase (HN) genes of human PIV3, was used as a virus vector to express surface glycoproteins derived from two human pathogens, human metapneumovirus (hMPV) and respiratory syncytial virus (RSV). RSV and hMPV are both paramyxoviruses that cause respiratory disease in young children, the elderly, and immunocompromised individuals. RSV has been known for decades to cause acute lower respiratory tract infections in young children, which often result in hospitalization, while hMPV has only been recently identified as a novel human respiratory pathogen. In this study, the ability of bovine/human PIV3 to express three different foreign transmembrane surface glycoproteins and to induce a protective immune response was evaluated. The RNA-dependent RNA polymerase of paramyxoviruses binds to a single site at the 3′ end of the viral RNA genome to initiate transcription of viral genes. The genome position of the viral gene determines its level of gene expression. The promoter-proximal gene is transcribed with the highest frequency, and each downstream gene is transcribed less often due to attenuation of transcription at each gene junction. This feature of paramyxoviruses was exploited using the PIV3 vector by inserting the foreign viral genes at the 3′ terminus, at position 1 or 2, of the viral RNA genome. These locations were expected to yield high levels of foreign viral protein expression stimulating a protective immune response. The immunogenicity and protection results obtained with a hamster model showed that bovine/human PIV3 can be employed to generate bivalent PIV3/RSV or PIV3/hMPV vaccine candidates that will be further evaluated for safety and efficacy in primates.

scholarly journals Downregulation of A20 Expression Increases the Immune Response and Apoptosis and Reduces Virus Production in Cells Infected by the Human Respiratory Syncytial Virus

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 100
Author(s):  
María Martín-Vicente ◽  
Rubén González-Sanz ◽  
Isabel Cuesta ◽  
Sara Monzón ◽  
Salvador Resino ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Virus Production ◽  
Antiviral Response ◽  
Human Respiratory Syncytial Virus ◽  
Negative Regulator ◽  
Infected Cells ◽  
Syncytial Virus ◽  
Tract Infections ◽  
The Impact

Human respiratory syncytial virus (HRSV) causes severe lower respiratory tract infections in infants, the elderly, and immunocompromised adults. Regulation of the immune response against HRSV is crucial to limiting virus replication and immunopathology. The A20/TNFAIP3 protein is a negative regulator of nuclear factor kappa B (NF-κB) and interferon regulatory factors 3/7 (IRF3/7), which are key transcription factors involved in the inflammatory/antiviral response of epithelial cells to virus infection. Here, we investigated the impact of A20 downregulation or knockout on HRSV growth and the induction of the immune response in those cells. Cellular infections in which the expression of A20 was silenced by siRNAs or eliminated by gene knockout showed increased inflammatory/antiviral response and reduced virus production. Similar results were obtained when the expression of A20-interacting proteins, such as TAX1BP1 and ABIN1, was silenced. Additionally, downregulation of A20, TAX1BP1, and ABIN1 increased cell apoptosis in HRSV-infected cells. These results show that the downregulation of A20 expression might contribute in the control of HRSV infections by potentiating the early innate immune response and increasing apoptosis in infected cells.

scholarly journals Disease Burden Due to Respiratory Syncytial Virus in Indian Pediatric Population: A Literature Review

2021 ◽  
Vol 15 ◽  
pp. 117955652110292
Author(s):  
Canna Ghia ◽  
Gautam Rambhad
Keyword(s):  
Respiratory Syncytial Virus ◽  
Young Children ◽  
Literature Review ◽  
Indian Pediatric ◽  
Disease Burden ◽  
Pediatric Population ◽  
Age Groups ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) is one of the leading causes of lower respiratory tract infections in young children. Globally, there is huge disease burden, high treatment cost, and health impact beyond acute episodes due to RSV which necessitate development and implementation of preventive strategies for the control of RSV infection. The disease burden due to RSV in pediatric population across India is still not clearly understood so this literature review was therefore conducted to gather data on disease burden due to RSV in Indian pediatric population. Systematic literature search was performed using PubMed and Google search with different medical subject headings from 2007 to 2020. Studies performed in Indian pediatric population were selected for review. Literature review revealed that in India, epidemiology of RSV infection is well documented in young children (0-5 years) as compared to children from other age groups. The rates of RSV detection in various studies conducted in younger children (0-5 years) vary from 2.1% to 62.4% in India which is higher as compared to children from other age groups. In India, RSV mainly peaks around rainy to early winter season, that is, during months of June through October while smaller peak was noted during December, January, and February. In 2020, higher RSV-associated disease burden was reported among children (<5 years) in low-income and lower-middle-income countries. Considering significant disease burden due to RSV in young Indian children, availability of RSV vaccine would be crucial to prevent RSV infections in children and its spread in the community.

scholarly journals Role of Respiratory Syncytial Virus in Pediatric Pneumonia

2020 ◽  
Vol 8 (12) ◽  
pp. 2048
Author(s):  
Sonia Bianchini ◽  
Ettore Silvestri ◽  
Alberto Argentiero ◽  
Valentina Fainardi ◽  
Giovanna Pisi ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Young Children ◽  
Respiratory Infections ◽  
Clinical Signs ◽  
Supportive Therapy ◽  
Respiratory Pathogens ◽  
Single Polymerase Chain Reaction ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory viral infections represent the leading cause of hospitalization in infants and young children worldwide and the second leading cause of infant mortality. Among these, Respiratory Syncytial Virus (RSV) represents the main cause of lower respiratory tract infections (LRTIs) in young children worldwide. RSV manifestation can range widely from mild upper respiratory infections to severe respiratory infections, mainly bronchiolitis and pneumonia, leading to hospitalization, serious complications (such as respiratory failure), and relevant sequalae in childhood and adulthood (wheezing, asthma, and hyperreactive airways). There are no specific clinical signs or symptoms that can distinguish RSV infection from other respiratory pathogens. New multiplex platforms offer the possibility to simultaneously identify different pathogens, including RSV, with an accuracy similar to that of single polymerase chain reaction (PCR) in the majority of cases. At present, the treatment of RSV infection relies on supportive therapy, mainly consisting of oxygen and hydration. Palivizumab is the only prophylactic method available for RSV infection. Advances in technology and scientific knowledge have led to the creation of different kinds of vaccines and drugs to treat RSV infection. Despite the good level of these studies, there are currently few registered strategies to prevent or treat RSV due to difficulties related to the unpredictable nature of the disease and to the specific target population.

Sign in / Sign up

Export Citation Format

Share Document