Human Respiratory Syncytial Virus Vaccine Research Articles

Current Status of Surveillance Systems for Human Respiratory Syncytial Virus

To conduct timely surveillance of the seasonal characteristics and disease burden of Human Respiratory Syncytial Virus (HRSV) in various geographical regions of China, and further develop more precise and effective prevention and intervention strategies, there is an urgent need for China to establish a nationwide, effective, and stable HRSV surveillance system. Through combining the current status of domestic and international HRSV surveillance systems and the existing surveillance framework in China, this study proposed an HRSV surveillance type applicable to China based on different surveillance purposes, and considering the feasibility of implementation. This article aimed to provide solid scientific and technical support to monitor the dynamic changes of HRSV epidemic timely, carry out a risk assessment and early warning, and further understand the disease burden of HRSV in China. It also helps to improve the diagnosis, prevention, and control of the HRSV diseases research and development, use, and evaluation of HRSV vaccines and drugs in China.

Immunization with a mucosal, post-fusion F/G protein-based polyanhydride nanovaccine protects neonatal calves against BRSV infection.

Human respiratory syncytial virus (HRSV) is a leading cause of death in young children and there are no FDA approved vaccines. Bovine RSV (BRSV) is antigenically similar to HRSV, and the neonatal calf model is useful for evaluation of HRSV vaccines. Here, we determined the efficacy of a polyanhydride-based nanovaccine encapsulating the BRSV post-fusion F and G glycoproteins and CpG, delivered prime-boost via heterologous (intranasal/subcutaneous) or homologous (intranasal/intranasal) immunization in the calf model. We compared the performance of the nanovaccine regimens to a modified-live BRSV vaccine, and to non-vaccinated calves. Calves receiving nanovaccine via either prime-boost regimen exhibited clinical and virological protection compared to non-vaccinated calves. The heterologous nanovaccine regimen induced both virus-specific cellular immunity and mucosal IgA, and induced similar clinical, virological and pathological protection as the commercial modified-live vaccine. Principal component analysis identified BRSV-specific humoral and cellular responses as important correlates of protection. The BRSV-F/G CpG nanovaccine is a promising candidate vaccine to reduce RSV disease burden in humans and animals.

Circulation pattern and genetic variation of human respiratory syncytial virus in China during 2008-2021.

To better understand the circulation pattern and genetic characterization of human respiratory syncytial virus (HRSV) in China during 2008-2021, a total of 3967 HVR2 sequences were obtained from 20 provinces in China for phylogenetic analysis and sequence variation analysis. The results showed that the HRSV subtype presented the prevalence pattern of "ABBAABAABAAABB."Further genotyping identified sevengenotypes for HRSVA and ninegenotypes for HRSVB. Multiple genotypes of HRSV were cocirculating during 2008-2015, while ON1 and BA9 became the only predominant genotypes for HRSVA and HRSVB, respectively, since 2015. A genotype switch from NA1 to ON1 for HRSVA occurred in approximately 2014, while genotype BA9 of HRSVB had been the predominant genotype for at least 14 years. ON1 strains could be divided into four lineages with no temporal or geographical distribution tendency. In contrast, BA9 strains could be divided into three lineages with noticeable temporal clustering. Sequence variation analysis showed that two ON1 sequences in 2017 had 10 nucleotide deletion and compensatory extension at the C-terminal;15BA9 sequences during 2019-2021 had novel insertions between K225 and E226, along with 6 identical amino acid variant sites. This study further enriched the genetic data of HRSV circulating in China and provided an important basis for the development of HRSV vaccines and drugs as well as the formulation of prevention and control strategies.

Identifying Cross-Utilization of RSV Vaccine Inventions across the Human and Veterinary Field.

The respiratory syncytial virus (RSV) has two main variants with similar impact, a human and a bovine variant. The human respiratory syncytial virus (HRSV) is the most frequent cause of acute respiratory disease (pneumonia) in children, leading to hospitalization and causing premature death. In Europe, lower respiratory tract infections caused by HRSV are responsible for 42-45 percent of hospital admissions in children under two. Likewise, the bovine respiratory syncytial virus (BRSV) is a significant cause of acute viral broncho-pneumonia in calves. To date no licensed HRSV vaccine has been developed, despite the high burden of the disease. In contrast, BRSV vaccines have been on the market since the 1970s, but there is still an articulated unmet need for improved BRSV vaccines with greater efficacy. HRSV/BRSV vaccine development was chosen as a case to assess whether collaboration and knowledge-sharing between human and veterinary fields is taking place, benefiting the development of new vaccines in both fields. The genetic relatedness, comparable pathogeneses, and similar severity of the diseases suggests much can be gained by sharing knowledge and experiences between the human and veterinary fields. We analyzed patent data, as most of pharmaceutical inventions, such as the development of vaccines, are protected by patents. Our results show only little cross-utilization of inventions and no collaborations, as in shared IP as an exchange of knowledge. This suggests that, despite the similarities in the genetics and antigenicity of HRSV and BRSV, each fields follows its own process in developing new vaccines.

Intranasal immunization with HRSV prefusion F protein and CpG adjuvant elicits robust protective effects in mice

Human respiratory syncytial virus (HRSV) is a leading cause of lower respiratory tract infections in elderly individuals and young children/infants and can cause bronchiolitis and even death. There is no licensed HRSV vaccine. An ideal vaccine should induce high titers of neutralizing antibodies and a Th1-biased immune response. In this study, we used EXPI293 cells to express the fusion (F) protein with a prefusion conformation (PrF) and compared the safety and efficacy of intranasal immunization with PrF in combination with two mucosal adjuvants (CpG ODN and liposomes) in mice. After two intranasal administrations, mice in the PrF + CpG group produced high titers of neutralizing antibodies (4961) and a Th1-biased immune response compared with the PrF + Lipo group. The lung viral load of mice in the PrF + CpG group was significantly reduced (3.5 log) compared with that in the adjuvant control group, and the survival rate was 100 %, while the survival rate of mice in the PrF + Lipo group was only 67 %. At the same time, this immunization strategy reduced the pathological damage to the lungs in mice. In conclusion, the combination of PrF and CpG adjuvant is immunogenic, elicits a Th1 type immune response, and completely protects mice from a lethal HRSV challenge. It is worthy of further evaluation as an HRSV vaccine in clinical trials.Clinical trial registration.This study was not related to human participation or experimentation.

Comparison of the efficacy and safety of different immunization routes induced by human respiratory syncytial virus F protein with CpG adjuvant in mice

Human respiratory syncytial virus (HRSV) is a leading cause worldwide of severe respiratory illness in infants and the elderly. The ideal HRSV vaccine should induce a systemic immune response, especially mucosal immunity. In this study, mice were immunized twice with F protein combined with CpG adjuvant to compare the safety and efficacy of 4 immunization routes, including intranasal primed/intramuscular boosted immunization (CpG + F/in+im), intramuscular primed/intranasal boosted immunization (CpG + F/im+in), intramuscular primed/intramuscular boosted immunization (CpG + F/im + im) and intranasal primed/intranasal boosted immunization (CpG + F/in+in). Compared with the control group (CpG/in+im, CpG/im+in, CpG/im + im and CpG/in+in), all 4 immunization routes induced a high titer of neutralizing antibodies and a strong cellular immune response. Mice in the CpG + F/in+in group induced the highest antibody neutralization titer, and IgA antibody in bronchoalveolar lavage fluid (BALF) was the highest. The copy of HRSVs in the lung decreased by approximately 3 log10. As seen from the IgG1/IgG2a and IFN-γ/IL-4-secreting lymphocyte ratios, compared with the mice in the CpG + F/im + im group, mice in the CpG + F/in+in group induced Th1-baised humoral and cellular immune responses and significantly reduced lung pathological injury. In conclusion, among the 4 immunization routes, the safety and efficacy induced by the mice in the CpG + F/in+in group were the best. We can conclude that intranasal immunization is superior to intramuscular immunization using F protein with CpG adjuvant as vaccine candidates.

Establishment and application of a lethal model of an HRSV-long variant strain in BALB/c mice.

Human respiratory syncytial virus (HRSV) is a major cause of lower respiratory tract infection in infants. The lack of ideal animal models is one of the major obstacles in evaluateing the efficacy of HRSV vaccines. In this study, HRSV-50 was obtained from Hep-2 cells at the 50th passage of the original Long strain (ATCC VR-26). BALB/c mice (6 weeks) were challenged with different titers of HRSV-50. Shockingly, all mice died after 4 days of challenge (6 × 106 PFU/mouse). Whole-genome sequencing revealed 7 amino acid mutations compared with the original Long strain. To verify whether the lethal model can be used to effectively evaluate the efficacy of HRSV candidate vaccines, we studied the protective effect of FRBD protein (Pre-F of HRSV and S receptor binding domain of SARS-CoV-2) with Adju-phos or MA103 adjuvant. All mice in the PBS group died after the HRSV-50 challenge, whereas Adju-phos provided partial protection. These results suggest that we have successfully established a lethal model of HRSV in BALB/c mice.

Attention should be paid to the detection and surveillance of human respiratory syncytial virus

Human respiratory syncytial virus (HRSV) is the main pathogen of severe lower respiratory tract infection in infants and young children. It seriously endangers children's health. In recent years, great breakthroughs have been made in the research and development of HRSV vaccines and antibody-based biological products. The research and development and use strategies are inseparable from the monitoring of HRSV prevalence and virus variation characteristics. The World Health Organization (WHO) pays great attentions to the surveillance of HRSV epidemiology and virus variation characteristics, but China lacks national level and multi-center HRSV surveillance data, the surveillance case definitions used by various laboratories are inconsistent, and the detection and surveillance methods of HRSV are not unified. Results from different laboratories are difficult to be compared and analyzed. Therefore, it is urgent to establish a nation-wide HRSV surveillance network in China, and to persistently monitor the epidemic characteristics and virus variation characteristics of HRSV by using standardized HRSV detection methods and surveillance guideline, so as to provide basic scientific data for the research and development, use and evaluation of monoclonal antibodies and vaccines.

Unravelling the requirement for host cell chloride channels during HRSV infection

Ion channels are a diverse class of transmembrane proteins that selectively allow ions across membranes, influencing a multitude of cellular processes. Modulation of these channels by viruses is emerging as an important host-pathogen interaction that regulates critical stages of the virus multiplication cycle including entry, replication and egress. Human respiratory syncytial virus (HRSV) causes severe respiratory tract infections globally and is one of the most lethal respiratory pathogens for infants in developing countries, with frequent development of bronchiolitis. Furthermore, it is the most significant cause of hospitalisation of infants in the UK. Evidence also indicates that severe childhood HRSV infection contributes towards the increased incidence of adult asthma. No HRSV vaccine is available, and currently the only treatment is immunoprophylaxis which is prohibitively expensive and only moderately effective; thus new treatment options are required. Utilising GFP-expressing HRSV in combination with an extensive panel of channel specific pharmacological inhibitors, we have identified an important role of cellular chloride (Cl-) channels during HRSV infection. Interestingly, pharmacological inhibition of specific Cl- channel families has ruled out involvement of the CFTR and instead highlighted a critical requirement for calcium-activated Cl- channels (CaCCs). Time of addition studies using CaCC blockers have indicated that these channels play a post-entry role during HRSV infection. Using genetic knockdown techniques we have isolated a single channel of interest and are now further investigating its role in facilitating HRSV multiplication, as well as assessing the importance of Cl- channels in replication cycles of other negative sense RNA viruses.

Duplex real-time RT-PCR assay for detection and subgroup-specific identification of human respiratory syncytial virus

Human respiratory syncytial virus (HRSV) is a leading cause of acute respiratory illness in young children worldwide. Reliable detection and identification of HRSV subgroup A and B infections are essential for accurate disease burden estimates in anticipation of licensure of novel HRSV vaccines and immunotherapies. To ensure continued reliability, molecular assays must remain current with evolving virus strains. We have developed a HRSV subgroup-specific real-time RT-PCR (rRT-PCR) assay for detection and subgroup identification using primers and subgroup-specific probes targeting a conserved region of the nucleoprotein gene combined in a single duplex reaction using all genome sequence data currently available in GenBank. The assay was validated for analytical sensitivity, specificity, reproducibility, and clinical performance with a geographically diverse collection of viral isolates and respiratory specimens in direct comparison with an established pan-HRSV rRT-PCR reference test. The assay was sensitive, reproducibly detecting as few as 5–10 copies/reaction of target RNA. The assay was specific, showing no amplification with a panel of 16 other common respiratory pathogens or predicted by in silico primer/probe analysis. The duplex rRT-PCR assay based on the most current available genome sequence data permits rapid, sensitive and specific detection and subgroup identification of HRSV.

Immunoproteomic Lessons for Human Respiratory Syncytial Virus Vaccine Design.

Accurate antiviral humoral and cellular immune responses require prior recognition of antigenic peptides presented by human leukocyte antigen (HLA) class I and II molecules on the surface of antigen-presenting cells. Both the helper and the cytotoxic immune responses are critical for the control and the clearance of human respiratory syncytial virus (HRSV) infection, which is a significant cause of morbidity and mortality in infected pediatric, immunocompromised and elderly populations. In this article we review the immunoproteomics studies which have defined the general antigen processing and presentation rules that determine both the immunoprevalence and the immunodominance of the cellular immune response to HRSV. Mass spectrometry and functional analyses have shown that the HLA class I and II cellular immune responses against HRSV are mainly focused on three viral proteins: fusion, matrix, and nucleoprotein. Thus, these studies have important implications for vaccine development against this virus, since a vaccine construct including these three relevant HRSV proteins could efficiently stimulate the major components of the adaptive immune system: humoral, helper, and cytotoxic effector immune responses.

Investigating the requirement for host cell chloride ion channels during human respiratory syncytial virus infection

Ion channels are a diverse class of transmembrane proteins, which selectively allow ions across cellular membranes, influencing a multitude of cellular processes. Modulation of these channels by viruses is emerging as an important host-pathogen interaction, and has been demonstrated to regulate critical stages of the virus multiplication cycle including entry, replication and egress. Human respiratory syncytial virus (HRSV) causes severe respiratory tract infections (RTIs) globally and is one of the most lethal respiratory pathogens for infants in developing countries, with many cases leading to severe lower respiratory tract infections, and the development of bronchiolitis. Evidence also suggests that childhood HRSV infection contributes towards the increased incidence of adult asthma. There is no HRSV vaccine, and the only treatment is immunoprophylaxis that is prohibitively expensive and only moderately effective; thus new treatment options are required. In this study, by infecting human lung epithelial cells with HRSV in the presence of various broad-range channel modulators, Cl- channels were identified to play an important role during HRSV infection. Time of addition assays using these broad-acting Cl- channel blockers identified the stages within the HRSV lifecycle that were dependant on Cl- channel activity, and the use of family-specific Cl- channel blocking drugs identified a small sub-family of Cl-channels which, when inhibited, resulted in significantly reduced HRSV multiplication. We are now identifying the specific Cl- channel(s) facilitating the multiplication of HRSV using genetic means, and well as assessing the importance of Cl- channels in replication cycles of other negative sense RNA viruses.

The significance of human respiratory syncytial virus (HRSV) in children from Ghana with acute lower respiratory tract infection: A molecular epidemiological analysis, 2006 and 2013-2014.

BackgroundAcute lower respiratory tract infection (ALRI) is a leading cause of childhood morbidity and mortality in developing countries. Globally, human respiratory syncytial virus (HRSV) is the most common pathogen of ALRI in infants and children. However, age-stratified HRSV disease burden data are largely absent from Africa, which is a key gap in informing an evidence-based recommendation for the introduction of an HRSV vaccine by the WHO.MethodsThis study investigated the presence of HRSV in respiratory specimens from 552 children <5 years old with ALRI from Accra, Ghana in 2006 and 2013–2014 by real-time PCR. Of HRSV-positive samples the second hypervariable region of the viral G protein gene was sequenced and analyzed for phylogeny, characteristic amino acid substitutions, and potential glycosylation patterns. Further, HRSV infections have been characterized by age, symptoms and timely occurrence.ResultsHRSV was observed in 23% (127/552) of the children with ALRI, with the highest incidence in infants younger than one year (33%, 97/295, p = 0.013). Within the observed seasonal circulation time of HRSV from June (mid-wet season) to December (beginning of the dry season) the incidence of ALRI due to HRSV was as high as 46% (125/273). HRSV disease was significantly associated with (broncho-) pneumonia, bronchiolitis, LRTI, and difficulty in breathing. Phylogenetic characterization of HRSV strains from Ghana identified the circulation of the currently worldwide prevailing genotypes ON1 and BA9, and shows evidence of an independent molecular evolution of ON1 and BA9 strains in Ghana resulting in potentially new subgenotypes within ON1 and BA9, provisionally named ON1.5, ON1.6, and BA9-IV.ConclusionThis study addresses important knowledge gaps in the forefront of introducing the HRSV vaccine by providing information on the molecular evolution and incidence of HRSV in Accra (Ghana, Africa).

Structure and Function of the Human Respiratory Syncytial Virus M2-1 Protein.

Human respiratory syncytial virus (HRSV) is a non-segmented negative stranded RNA virus and is recognized as the most important viral agent of lower respiratory tract infection worldwide, responsible for up to 199,000 deaths each year. The only FDA-approved regime to prevent HRSV-mediated disease is pre-exposure administration of a humanized HRSV-specific monoclonal antibody, which although being effective, is not in widespread usage due to its cost. No HRSV vaccine exists and so there remains a strong need for alternative and complementary anti-HRSV therapies. The HRSV M2-1 protein is a transcription factor and represents an attractive target for the development of antiviral compounds, based on its essential role in the viral replication cycle. To this end, a detailed analysis of M2-1 structure and functions will aid in identifying rational targets for structure-based antiviral drug design that can be developed in future translational research. Here we present an overview of the current understanding of the structure and function of HRSV M2-1, drawing on additional information derived from its structural homologues from other related viruses.

Novel recombinant DNA vaccine candidates for human respiratory syncytial virus: Preclinical evaluation of immunogenicity and protection efficiency

ABSTRACTThe development of safe and potent vaccines for human respiratory syncytial virus (HRSV) is still a challenge for researchers worldwide. DNA-based immunization is currently a promising approach that has been used to generate human vaccines for different age groups. In this study, novel HRSV DNA vaccine candidates were generated and preclinically tested in BALB/c mice. Three different versions of the codon-optimized HRSV fusion (F) gene were individually cloned into the pPOE vector. The new recombinant vectors either express full-length (pPOE-F), secretory (pPOE-TF), or M282–90 linked (pPOE-FM2) forms of the F protein. Distinctive expression of the F protein was identified in HEp-2 cells transfected with the different recombinant vectors using ELISA and immunofluorescence. Mice immunization verified the potential for recombinant vectors to elicit significant levels of neutralizing antibodies and CD8+ T-cell lymphocytes. pPOE-TF showed higher levels of gene expression in cell culture and better induction of the humoral and cellular immune responses. Following virus challenge, mice that had been immunized with the recombinant vectors were able to control virus replication and displayed lower inflammation compared with mice immunized with empty pPOE vector or formalin-inactivated HRSV vaccine. Moreover, pulmonary cytokine profiles of mice immunized with the 3 recombinant vectors were similar to those of the mock infected group. In conclusion, recombinant pPOE vectors are promising HRSV vaccine candidates in terms of their safety, immunogenicity and protective efficiency. These data encourage further evaluation in phase I clinical trials.

Expression and antigenicity of recombinant human respiratory syncytial virus glycoproteins having different affinity tags

Human respiratory syncytial virus (HRSV) is a main cause of lower respiratory tract infections in infants and the elderly. Glycoprotein (G) is major antigen on the viral surface, and plays a key role for virus entry. Therefore, purification of the glycoprotein of HRSV is critical for the development of HRSV vaccine and serological diagnosis. In this study, we report the design and characterization of glycoprotein engineered rationally to enhance the protein solubility and to facilitate efficient purification. We permuted HRSV glycoproteins with two tags: (i) an immunoglobulin (Ig) M signal peptide and a protein A B domain tag to render HRSV glycoprotein secret into the culture media and (ii) a foldon and 6 × histidine tag with or without transmembrane domain. Three recombinant baculoviruses were constructed: (i) transmembrane-truncated HRSV glycoprotein (amino acid positions 66–298) inserted with the N-terminal IgM signal peptide and protein A B domain (MG-GΔTM), (ii) truncated HRSV glycoprotein (amino acid positions 66–298) fused with a C-terminal foldon and 6 × histidine tag (GΔTM-FH), and (iii) full-length HRSV glycoprotein (amino acid positions 1–298) fused with a C-terminal foldon and 6 × histidine tag (G-FH). Highly soluble recombinant MG-GΔTM protein was clearly purified using one-step affinity chromatography with IgG-sepharose resin, whereas the recombinant G-FH protein and truncated GΔTM-FH were purified partially using nickel-resin. Although, the antigenicity of GΔTM-FH was stronger than highly mannose-rich MG-GΔTM protein, MG-GΔTM induced neutralizing antibodies efficiently in the mice to protect from infectious HRSV.

Human Respiratory Syncytial Virus: Role of Innate Immunity in Clearance and Disease Progression.

Human respiratory syncytial virus (HRSV) infections have worldwide records. The virus is responsible for bronchiolitis, pneumonia, and asthma in humans of different age groups. Premature infants, young children, and immunocompromised individuals are prone to severe HRSV infection that may lead to death. Based on worldwide estimations, millions of cases were reported in both developed and developing countries. In fact, HRSV symptoms develop mainly as a result of host immune response. Due to inability to establish long lasting adaptive immunity, HRSV infection is recurrent and hence impairs vaccine development. Once HRSV attached to the airway epithelia, interaction with the host innate immune components starts. HRSV interaction with pulmonary innate defenses is crucial in determining the disease outcome. Infection of alveolar epithelial cells triggers a cascade of events that lead to recruitment and activation of leukocyte populations. HRSV clearance is mediated by a number of innate leukocytes, including macrophages, natural killer cells, eosinophils, dendritic cells, and neutrophils. Regulation of these cells is mediated by cytokines, chemokines, and other immune mediators. Although the innate immune system helps to clear HRSV infection, it participates in disease progression such as bronchiolitis and asthma. Resolving the mechanisms by which HRSV induces pathogenesis, different possible interactions between the virus and immune components, and immune cells interplay are essential for developing new effective vaccines. Therefore, the current review focuses on how the pulmonary innate defenses mediate HRSV clearance and to what extent they participate in disease progression. In addition, immune responses associated with HRSV vaccines will be discussed.

Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein.

Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcγRI and FcγRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe-specific antibodies. HRSV-infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe-based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T-cell responses could be complemented with a SHe-based antigen to further improve immune protection.

CD8+ T cell immunity against human respiratory syncytial virus

Human respiratory syncytial virus (HRSV) was first discovered in the 1950s, but despite decades of research, a licensed vaccine against it is not available. Epidemiological studies indicate that antibodies directed against the fusion protein (F) partially correlate with protection. In addition, an F-specific monoclonal antibody is licensed as a prophylactic treatment in children who are at high risk of developing complications following HRSV infection. Therefore, most HRSV-oriented vaccination strategies focus on inducing a humoral immune response against F. In the quest for the development of a safe HRSV vaccine, the induction of a T cell immune response has received a lot less attention. T cell immunity directed against HRSV has not been associated unequivocally with protection against HRSV and CD4+ T helper cell responses may even worsen disease due to HRSV. However, many studies support a protective role for CD8+ T cells in clearance of HRSV from the lungs. In this review we highlight the clinical and experimental evidence in favor of a CD8+ T lymphocyte-based vaccination strategy to protect against HRSV. First, we describe how T cell responses and T cell memory are induced in the lungs upon respiratory viral infection. HRSV has evolved mechanisms that hamper CD8+ T cell priming and effector functions. We appraise the information on HRSV-specific CD8+ T cell immunity gained from laboratory mouse studies, taking into account the advantages and limitations of this animal model and, where possible, the accordance with clinical evidence. Finally, we focus on recent efforts to develop T cell based vaccines against HRSV.

Impaired immune response to vaccination against infection with human respiratory syncytial virus at advanced age.

Elderly humans are prone to severe infection with human respiratory syncytial virus (HRSV). The aging of today's human population warrants the development of protective vaccination strategies aimed specifically at the elderly. This may require special approaches due to deteriorating immune function. To design and test vaccination strategies tailored to the elderly population, we need to understand the host response to HRSV vaccination and infection at old age. Moreover, the preclinical need for testing of candidate vaccines requires translational models resembling susceptibility to the (unadapted) human pathogen. Here, we explored the effects of aging on immunity and protection induced by a model HRSV vaccine candidate in a translational aging model in cotton rats (Sigmodon hispidus) and examined possibilities to optimize vaccination concepts for the elderly. We immunized young and aged cotton rats with a live-attenuated recombinant HRSV vaccine candidate and analyzed the induced immune response to and protection against challenge with HRSV. In old cotton rats, HRSV infection persisted longer, and vaccination induced less protection against infection. Aged animals developed lower levels of vaccine-induced IgG, virus-neutralizing serum antibodies, and IgA in lungs. Moreover, booster responses to HRSV challenge were impaired in animals vaccinated at an older age. However, increased dose and reduced attenuation of vaccine improved protection even in old animals. This study shows that cotton rats provide a model for studying the effects of aging on the immune response to the human respiratory pathogen HRSV and possibilities to optimize vaccine concepts for the elderly. HRSV infection poses a risk for severe disease in the elderly. The aging of the population warrants increased efforts to prevent disease at old age, whereas HRSV vaccines are only in the developmental phase. The preclinical need for testing of candidate human vaccines requires translational models resembling susceptibility to the natural human virus. Moreover, we need to gain insight into waning immunity at old age, as this is a special concern in vaccine development. In this study, we explored the effect of age on protection and immunity against an experimental HRSV vaccine in aged cotton rats (Sigmodon hispidus), a rodent species that provides a model representing natural susceptibility to human viruses. Older animals generate fewer antibodies upon vaccination and require a higher vaccine dose for protection. Notably, during the early secondary immune response to subsequent HRSV infection, older animals showed less protection and a slower increase of the virus-neutralizing antibody titer.