Respiratory Disease In Infants Research Articles

Bronchiolitis in an infant due to influenza A, necropsy findings: a case report

The influenza virus is an important cause of respiratory disease in infants and presents challenging differential diagnoses to investigate. This is a case report that involves a necroscopic study of a 2-month-old male infant, without previous comorbidities, with a serological diagnosis of influenza A and histopathological presentation of non-obliterating bronchiolitis. Infants are considered a high-risk group for flu complications due to the immaturity of the immune system and the ability to respond to respiratory infections. Furthermore, the severity of infection in infants may be worsened by the difficulty in quickly considering and treating the symptoms of the disease.

Development and validation of a respiratory syncytial virus multiplex immunoassay.

Respiratory syncytial virus (RSV) is one of the leading causes of severe respiratory disease in infants and adults. While vaccines and monoclonal therapeutic antibodies either are or will shortly become available, correlates of protection remain unclear. For this purpose, we developed an RSV multiplex immunoassay that analyses antibody titers toward the post-F, Nucleoprotein, and a diverse mix of G proteins. A bead-based multiplex RSV immunoassay was developed, technically validated to standard FDA bioanalytical guidelines, and clinically validated using samples from human challenge studies. RSV antibody titers were then investigated in children aged under 2 and a population-based cohort. Technical and clinical validation showed outstanding performance, while methodological developments enabled identification of the subtype of previous infections through use of the diverse G proteins for approximately 50% of samples. As a proof of concept to show the suitability of the assay in serosurveillance studies, we then evaluated titer decay and age-dependent antibody responses within population cohorts. Overall, the developed assay shows robust performance, is scalable, provides additional information on infection subtype, and is therefore ideally suited to be used in future population cohort studies.

Chronic lung disease in children due to SARS-CoV-2 pneumonia: Case series.

The reported prevalence of chronic lung disease (CLD) due to coronavirus 2 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2)]) pneumonia with the severe acute respiratory syndrome in children is unknown and rarely reported in English literature. In contrast to most other respiratory viruses, children generally have less severe symptoms when infected with SARS-CoV-2. Although only a minority of children with SARS-CoV-2 infection require hospitalization, severe cases have been reported. More severe SARS-CoV-2 respiratory disease in infants has been reported in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe our experience of five cases of CLD in children due to SARS-CoV-2 collected between April 2020 and August 2022.We included children who had a history of a positive SARS-CoV-2 polymerase chain reaction (PCR) or antigen test or a positive antibody test in the serum.Three patterns of CLD related to SARS-CoV-2 were identified: (1) CLD in infants postventilation for severe pneumonia (n = 3); (2) small airway disease with bronchiolitis obliterans picture (n = 1) and (3) adolescent with adult-like post-SARS-CoV-2 disease (n = 1). Chest computerizedtomographyscans showed airspace disease and ground-glass opacities involving both lungs with the development of coarse interstitial markings seen in four patients, reflecting the long-term fibrotic consequences of diffuse alveolar damage that occur in children post-SARS-CoV-2 infection.Children with SARS-CoV-2 infection mostly have mild symptoms with little to no long-term sequelae, but the severe long-term respiratory disease can develop.

Development of a Kinetic ELISA and Reactive B Cell Frequency Assay to Detect Respiratory Syncytial Virus Pre-Fusion F Protein-Specific Immune Responses in Infants.

Respiratory syncytial virus (RSV) is a major cause of respiratory disease in infants, making vaccination an attractive preventive strategy. Due to earlier reports of vaccine-enhanced disease in RSV-naive children, assessing prior RSV infection is critical for determining eligibility for future infant vaccine trials. However, this is complicated by the presence of maternally transferred maternal antibodies. We sought to develop assays that measure immune responses to RSV pre-fusion (F) protein that discriminates between maternal and infant responses. We measured RSV-specific responses in two groups of children <3 years of age; those with laboratory-confirmed RSV (RSV-infected) and those enrolled prior to their first RSV season (RSV-uninfected). Serial blood samples were obtained and recent infections with RSV and other respiratory viruses were assessed during follow-up. An RSV pre-F-specific kinetic enzyme-linked immunosorbent assay (kELISA) and an F-specific reactive B cell frequency (RBF) assay were developed. One hundred two young children were enrolled between July 2015 and April 2017; 74 were in the RSV-uninfected group and 28 were in the RSV-infected group. Participants were asked to provide sequential blood samples over time, but only 53 participants in the RSV-uninfected group and 22 participants in the RSV-infected groups provided multiple samples. In the RSV-infected group, most had positive kELISA and RBF during the study. In the RSV-uninfected group, two patterns emerged: declining kELISA values without reactive B cells, due to maternal transplacental antibody transfer, and persistently positive kELISA with reactive B cells, due to asymptomatic undiagnosed RSV infection. A kELISA targeting RSV pre-F epitopes and an RBF assay targeting RSV F-specific B cells generally allow discrimination between maternally and infant-derived antibodies.

Rational design of a highly immunogenic prefusion-stabilized F glycoprotein antigen for a respiratory syncytial virus vaccine.

Respiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and is an important cause of respiratory illness in older adults. No RSV vaccine is currently available. The RSV fusion (F) glycoprotein is a key antigen for vaccine development, and its prefusion conformation is the target of the most potent neutralizing antibodies. Here, we describe a computational and experimental strategy for designing immunogens that enhance the conformational stability and immunogenicity of RSV prefusion F.We obtained an optimized vaccine antigen after screening nearly 400 engineered F constructs. Through in vitro and in vivo characterization studies, we identified F constructs that are more stable in the prefusion conformation and elicit ~10-fold higher serum-neutralizing titers in cotton rats than DS-Cav1. The stabilizing mutations of the lead construct (847) were introduced onto F glycoprotein backbones of strains representing the dominant circulating genotypes of the two major RSV subgroups, A and B.Immunization of cotton rats with a bivalent vaccine formulation of these antigens conferred complete protection against RSV challenge, with no evidence of disease enhancement. The resulting bivalent RSV prefusion F investigational vaccine has recently been shown to be efficacious against RSV disease in two pivotal phase 3 efficacy trials, one for passive protection of infants by immunization of pregnant women and the second for active protection of older adults by direct immunization.

Clinical epidemiology and disease burden of bronchiolitis in hospitalized children in China: a national cross-sectional study.

Bronchiolitis is a common acute lower respiratory tract infection (ALRTI) and the most frequent cause of hospitalization of infants and young children with ALRTI. Respiratory syncytial virus is the main pathogen that leads to severe bronchiolitis. The disease burden is relatively high. To date, few descriptions of the clinical epidemiology and disease burden of children hospitalized for bronchiolitis are available. This study reports the general clinical epidemiological characteristics and disease burden of bronchiolitis in hospitalized children in China. This study included the face sheet of discharge medical records collected from 27 tertiary children's hospitals from January 2016 to December 2020 that were aggregated into the FUTang Update medical REcords (FUTURE) database. The sociodemographic variables, length of stay (LOS) and disease burden of children with bronchiolitis were analyzed and compared using appropriate statistical tests. In total, 42,928 children aged 0-3years were hospitalized due to bronchiolitis from January 2016 to December 2020, accounting for 1.5% of the total number of hospitalized children of the same age in the database during the period and 5.31% of the hospitalizations for ALRTI. The male to female ratio was 2.01:1. Meanwhile, more boys than girls were observed in different regions, age groups, years, and residences. The 1-2year age group had the greatest number of hospitalizations for bronchiolitis, while the 29days-6months group had the largest proportion of the total inpatients and inpatients with ALRTI in the same age group. In terms of region, the hospitalization rate of bronchiolitis was the highest in East China. Overall, the number of hospitalizations from 2017 to 2020 showed a decreasing trend from that in 2016. Seasonally, the peak hospitalizations for bronchiolitis occurred in winter. Hospitalization rates in North China in autumn and winter were higher than those in South China, while hospitalization rates in South China were higher in spring and summer. Approximately, half of the patients with bronchiolitis had no complications. Among the complications, myocardial injury, abnormal liver function and diarrhea were more common. The median LOS was 6days [interquartile range (IQR) = 5-8], and the median hospitalization cost was 758 United States dollars (IQR = 601.96-1029.53). Bronchiolitis is a common respiratory disease in infants and young children in China, and it accounts for a higher proportion of both total hospitalizations and hospitalizations due to ALRTI in children. Among them, children aged 29days-2years are the main hospitalized population, and the hospitalization rate of boys is significantly higher than that of girls. The peak season for bronchiolitis is winter. Bronchiolitis causes few complications and has a low mortality rate, but the burden of this disease is heavy.

Anti-G protein antibodies targeting the RSV G protein CX3C chemokine region improve the interferon response.

Respiratory syncytial virus (RSV) is a poor inducer of antiviral interferon (IFN) responses which result in incomplete immunity and RSV disease. Several RSV proteins alter antiviral responses, including the non-structural proteins (NS1, NS2) and the major viral surface proteins, that is, fusion (F) and attachment (G) proteins. The G protein modifies the host immune response to infection linked in part through a CX3 C chemokine motif. Anti-G protein monoclonal antibodies (mAbs), that is, clones 3D3 and 2D10 that target the G protein CX3C chemokine motif can neutralize RSV and inhibit G protein-CX3CR1 mediated chemotaxis. Determine how monoclonal antibodies against the RSV F and G proteins modify the type I and III IFN responses to RSV infection. As the G protein CX3 C motif is implicated in IFN antagonism, we evaluated two mAbs that block G protein CX3C-CX3CR1 interaction and compared responses to isotype mAb control using a functional cellular assay and mouse model. Mouse lung epithelial cells (MLE-15 cells) and BALB/c mice were infected with RSV Line19 F following prophylactic mAb treatment. Cell supernatant or bronchoalveolar lavage fluid (BALF) were assayed for types I and III IFNs. Cells were interrogated for changes in IFN-related gene expression. Treatment with an anti-G protein mAb (3D3) resulted in improved IFN responses compared with isotype control following infection with RSV, partially independently of neutralization, and this was linked to upregulated SOCS1 expression. These findings show that anti-G protein antibodies improve the protective early antiviral response, which has important implications for vaccine and therapeutic design. RSV is a leading cause of respiratory disease in infants and the elderly. The only Food and Drug Administration-approved prophylactic treatment is limited to an anti-F protein monoclonal antibody (mAb), that is, palivizumab which has modest efficacy against RSV disease. Accumulating evidence suggests that targeting the RSV attachment (G) protein may provide improved protection from RSV disease. It is known that the G protein is an IFN antagonist, and IFN has been shown to be protective against RSV disease. In this study, we compared IFN responses in mouse lung epithelial (MLE-15) cells and in mice infected with RSV Line19 F treated with anti-G protein or anti-F protein mAbs. The levels of type I and III IFNs were determined. Anti-G protein mAbs improved the levels of IFNs compared with isotype-treated controls. These findings support the concept that anti-G protein mAbs mediate improved IFN responses against RSV disease, which may enable improved treatment of RSV infections.

Treatment activity of budesonide-loaded poly(lactic-co-glycolic acid) microspheres in infant bronchiolitis

Bronchiolitis is a common respiratory disease in infants with poor autoimmune function and narrow airways, resulting in a higher incidence. Despite great advances in medical technology, infants remain vulnerable to complications affecting the effectiveness of treatments. Therefore, suitable drug carriers for long-term local administration are the key to improve treatment efficiency. In this study, budesonide-loaded PLGA microspheres were successfully prepared by emulsification–solvent volatilization method. The microspheres had smooth and nearly spherical surfaces, and the size was 8.0–11.8 μm, with a high encapsulation rate and drug loading capacity. The slow degradation of PLGA allows enables budesonide to exert long-term and sustained effects, representing a novel method for treating infant bronchiolitis. The application value of the method for infant bronchiolitis was determined, and the relevant mechanism was explored.

Primary Nasal Epithelial Cells as a Surrogate Cell Culture Model for Type-II Alveolar Cells to Study ABCA-3 Deficiency.

ATP Binding Cassette Subfamily A Member 3 (ABCA-3) is a lipid transporter protein highly expressed in type-II alveolar (AT-II) cells. Mutations in ABCA3 can result in severe respiratory disease in infants and children. To study ABCA-3 deficiency in vitro, primary AT-II cells would be the cell culture of choice although sample accessibility is limited. Our aim was to investigate the suitability of primary nasal epithelial cells, as a surrogate culture model for AT-II cells, to study ABCA-3 deficiency. Expression of ABCA3, and surfactant protein genes, SFTPB and SFTPC, was detected in primary nasal epithelial cells but at a significantly lower level than in AT-II cells. ABCA-3, SP-B, and SP-C were detected by immunofluorescence microscopy in primary nasal epithelial cells. However, SP-B and SP-C were undetectable in primary nasal epithelial cells using western blotting. Structurally imperfect lamellar bodies were observed in primary nasal epithelial cells using transmission electron microscopy. Functional assessment of the ABCA-3 protein demonstrated that higher concentrations of doxorubicin reduced cell viability in ABCA-3 deficient nasal epithelial cells compared to controls in an assay-dependent manner. Our results indicate that there may be a role for primary nasal epithelial cell cultures to model ABCA-3 deficiency in vitro, although additional cell culture models that more effectively recapitulate the AT-II phenotype may be required.

La muqueuse pulmonaire en période périnatale : un monde à comprendre pour lutter contre la sensibilité du jeune à la bronchiolite

Due to infection with the respiratory syncytial virus (RSV), bronchiolitis is the main respiratory disease in infants, and no effective treatments currently exist. The perinatal period is an important stage in the maturation of the lung mucosa, insofar as it largely determines the host's pulmonary reactivity to pathogens. Understanding the physiological, immunological and microbiological characteristics of the lungs in early life may lead to new innovative strategies against infectious agents. We hypothesize that the lung microbiota represents a regulatory factor of paramount importance in young people's health.

Основные аспекты изучения факторов риска развития заболеваний респираторного тракта у детей раннего и дошкольного возраста

Представленный обзор литературы позволил выделить основные причины, влияющие на развитие заболеваний у детей раннего и дошкольного возраста. Знание различных факторов риска, способствующих развитию заболеваний респираторного тракта, позволит более эффективно планировать и осуществлять профилактические и оздоровительные мероприятия у детей. Необходима реализация комплекса превентивных мер, направленных на подготовку будущих родителей к рождению здоровых детей, работу с семьями по пропаганде здорового образа жизни и рационального питания, вовлечению родителей в процесс оздоровления детей, закаливания, применения лечебной физкультуры и массажа, нормализации режима дня, а также санация очагов хронических инфекций, лечение сопутствующих заболеваний, использование иммунотропных препаратов, создание и внедрение оздоровительных программ в детских дошкольных учреждениях.

Field testing two existing, standardized respiratory severity scores (LIBSS and ReSViNET) in infants presenting with acute respiratory illness to tertiary hospitals in Rwanda - a validation and inter-rater reliability study.

There is a substantial burden of respiratory disease in infants in the sub-Saharan Africa region. Many health care providers (HCPs) that initially receive infants with respiratory distress may not be adequately skilled to differentiate between mild, moderate and severe respiratory symptoms, which may contribute to poor management and outcome. Therefore, respiratory severity scores have the potential to contributing to address this gap. to field-test the use of two existing standardized bronchiolitis severity scores (LIBSS and ReSViNET) in a population of Rwandan infants (1-12 months) presenting with respiratory illnesses to urban, tertiary, pediatric hospitals and to assess the severity of respiratory distress in these infants and the treatments used. A cross-sectional, validation study, was conducted in four tertiary hospitals in Rwanda. Infants presenting with difficulty in breathing were included. The LIBSS and ReSViNET scores were independently employed by nurses and residents to assess the severity of disease in each infant. 100 infants were recruited with a mean age of seven months. Infants presented with pneumonia (n = 51), bronchiolitis (n = 36) and other infectious respiratory illnesses (n = 13). Thirty-three infants had severe disease and survival was 94% using nurse applied LIBSS. Regarding inter-rater reliability, the intra-class correlation coefficient (ICC) for LIBSS and ReSViNET between nurses and residents was 0.985 (95% CI: 0.98-0.99) and 0.980 (0.97-0.99). The convergent validity (Pearson's correlation) between LIBSS and ReSViNET for nurses and residents was R = 0.836 (p<0.001) and R = 0.815 (p<0.001). The area under the Receiver Operator Curve (aROC) for admission to PICU or HDU was 0.956 (CI: 0.92-0.99, p<0.001) and 0.880 (CI: 0.80-0.96, p<0.001) for nurse completed LIBSS and ReSViNET respectively. LIBSS and ReSViNET were designed for infants with bronchiolitis in resource-rich settings. Both LIBSS and ReSViNET demonstrated good reliability and validity results, in this cohort of patients presenting to tertiary level hospitals. This early data demonstrate that these two scores have the potential to be used in conjunction with clinical reasoning to identify infants at increased risk of clinical deterioration and allow timely admission, treatment escalation and therefore support resource allocation in Rwanda.

Coexpression of respiratory syncytial virus (RSV) fusion (F) protein and attachment glycoprotein (G) in a vesicular stomatitis virus (VSV) vector system provides synergistic effects against RSV infection in a cotton rat model

Respiratory syncytial virus (RSV) is one of the most important causes of respiratory disease in infants, immunocompromised individuals, and the elderly. Natural infection does not result in long-term immunity, and there is no licensed vaccine. Vesicular stomatitis virus (VSV) is a commonly used vaccine vector platform against infectious diseases, and has been used as a vector for a licensed Ebola vaccine. In this study, we expressed the RSV fusion (F) protein, the RSV F protein stabilized in either a pre-fusion or a post-fusion configuration, the attachment glycoprotein (G), or the G and F proteins of RSV in combination in a VSV vector. Cotton rats were immunized with these recombinants intranasally or subcutaneously to test immunogenicity. RSV F stabilized in either a pre-fusion or a post-fusion configuration proved to be poorly immunogenic and protective when compared to unmodified F. RSV G provided partial protection and moderate levels of neutralizing antibody production, both of which improved with intranasal administration compared to subcutaneous inoculation. The most successful vaccine vector was VSV expressing both the G and F proteins after intranasal inoculation. Immunization with this recombinant induced neutralizing antibodies and provided protection from RSV challenge in the upper and lower respiratory tract for at least 80 days. Our results demonstrate that co-expression of F and G proteins in a VSV vector provides synergistic effects in inducing RSV-specific neutralizing antibodies and protection against RSV infection.

Effect of prenatal and postnatal exposure to tobacco in the development of acute bronchiolitis in the first two years of life

IntroductionEnvironmental exposure to tobacco increases the risk of respiratory disease in infants. However, the impact of maternal smoking on the development of acute bronchiolitis has hardly been assessed. The aim of this study was to determine the incidence of acute bronchiolitis and to analyse the effect of prenatal and postnatal maternal smoking on the development of this disease. Patients and methodsA prospective, observational study was performed on healthy newborns from a third level hospital born between October 2015 and February 2016. Questionnaires were completed by the mothers at discharge from maternity and followed-up for two years. These collected information about prenatal and postnatal smoking, lifestyle, family and personal history, and the development of bronchiolitis. A bivariate and multivariate logistic regression analysis was performed. ResultsA total of 223 newborns were included, of whom 13.9% were exposed to tobacco smoking during gestation, 21.4% in the postnatal period, and 12.4% in both times. The incidence of bronchiolitis was 28.7% at one year of life, and 34.5% at two years. The multivariate analysis demonstrated that the prenatal and postnatal exposure to tobacco is an independent risk factor for the development of bronchiolitis (OR 4.38; 95% CI; 1.63–11.76), while prolonged breastfeeding is a protective factor (OR 0.13; 95% CI; 0.04–0.48). Other factors that were statistically significant were: atopic dermatitis (OR 2.91; 95% CI; 1.26–6.73), and gestational age (OR 1.42; 95% CI; 1.08–1.88). ConclusionsChildren exposed to prenatal and postnatal maternal smoking have a higher risk of suffering bronchiolitis. Reducing the smoking habit in women that intend to become pregnant must be a priority in preventive medicine.

Respiratory syncytial virus M2-1 protein associates non-specifically with viral messenger RNA and with specific cellular messenger RNA transcripts.

Respiratory syncytial virus (RSV) is a major cause of respiratory disease in infants and the elderly. RSV is a non-segmented negative strand RNA virus. The viral M2-1 protein plays a key role in viral transcription, serving as an elongation factor to enable synthesis of full-length mRNAs. M2-1 contains an unusual CCCH zinc-finger motif that is conserved in the related human metapneumovirus M2-1 protein and filovirus VP30 proteins. Previous biochemical studies have suggested that RSV M2-1 might bind to specific virus RNA sequences, such as the transcription gene end signals or poly A tails, but there was no clear consensus on what RSV sequences it binds. To determine if M2-1 binds to specific RSV RNA sequences during infection, we mapped points of M2-1:RNA interactions in RSV-infected cells at 8 and 18 hours post infection using crosslinking immunoprecipitation with RNA sequencing (CLIP-Seq). This analysis revealed that M2-1 interacts specifically with positive sense RSV RNA, but not negative sense genome RNA. It also showed that M2-1 makes contacts along the length of each viral mRNA, indicating that M2-1 functions as a component of the transcriptase complex, transiently associating with nascent mRNA being extruded from the polymerase. In addition, we found that M2-1 binds specific cellular mRNAs. In contrast to the situation with RSV mRNA, M2-1 binds discrete sites within cellular mRNAs, with a preference for A/U rich sequences. These results suggest that in addition to its previously described role in transcription elongation, M2-1 might have an additional role involving cellular RNA interactions.

Early Life RSV: Can Vaccines Help Fix Societal Ills?

* Abbreviations: LRI — : lower respiratory infection RSV — : respiratory syncytial virus SDOH — : social determinants of health During this pandemic, the impact of health disparities on mortality due to COVID-19 has been high among our concerns about this illness.1–4 Unfortunately, disparities related to respiratory infections are not limited to COVID-19. There are decades of research revealing that morbidity and mortality are strongly influenced by the social determinants of health (SDOH). Respiratory syncytial virus (RSV) is the leading cause of lower respiratory infection (LRI) in infants and a major cause of hospitalization in the first 2 years of life.5–7 In this issue of Pediatrics , Fitzpatrick et al8 report on the impact of sociodemographic and psychosocial factors on the risk for RSV hospitalization in children <3 years of age in Ontario, Canada. The authors used linked sociodemographic and health administrative data sets covering the period from 2012 to 2018 to identify factors associated with hospitalization. Their findings reveal the increased risk of hospitalization associated with maternal characteristics consistent with social vulnerability, including younger age, involvement with the criminal justice system, and mental health problems or addiction. The use of low-income drug benefits, a measure of socioeconomic status, was also associated with RSV hospitalization, as was an area level measure of income showing an increased risk of hospitalization with the lowest two quartiles of income. In their study, Fitzpatrick et al8 reinforce the important, enduring, and widespread influence of SDOH on our youngest patients. These … Address correspondence to Mary T. Caserta, MD, Department of Pediatrics, University of Rochester Medical Center, Golisano Children’s Hospital at Strong, 601 Elmwood Ave, Box 690, Rochester, NY 14642. E-mail: mary_caserta{at}urmc.rochester.edu

A post-incorporation study on the use of palivizumab in the Brazilian public health system.

ABSTRACTRespiratory syncytial virus (RSV) is the main cause of lower respiratory disease in infants and children under five years of age. As there is no specific treatment for RSV infections, prophylaxis with the specific monoclonal antibody palivizumab (PVZ) has been widely recommended for high-risk cases during the RSV season. The present study aimed to evaluate the effectiveness of a public prophylaxis program with palivizumab on the incidence of hospitalizations for lower respiratory tract infections and RSV in children at high risk for severe RSV infections. A retrospective cohort study was carried out with preterm children or children under two years of age with chronic lung disease or hemodynamically significant congenital heart disease; the children were selected on the basis of their exposure status, which was defined as the prophylactic use of palivizumab during the RSV season. Children were enrolled retrospectively in two hospitals located in Southern Brazil, from May 2009 to August 2016. In a sample of 129 children, 69 (53.5%) received palivizumab and adherence to three or more doses was observed in 78%; 60 (46.5%) children did not receive palivizumab. PVZ prophylaxis was independently associated with a 66% reduction in hospitalizations for any cause (26/69 - 37.7%) in the PVZ group and 34/60 (56.7%) in the control group). A 52% reduction in hospitalizations due to lower respiratory tract infection was observed in the PVZ group (15/69 -21.7%) and 25/60 (41.7%) in the control group. These findings suggest that, for the group of studied patients, the adoption of an RSV prophylaxis scheme reached the same effectiveness as those described in previous clinical trials.

Harnessing Cellular Immunity for Vaccination against Respiratory Viruses.

Severe respiratory viral infections, such as influenza, metapneumovirus (HMPV), respiratory syncytial virus (RSV), rhinovirus (RV), and coronaviruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), cause significant mortality and morbidity worldwide. These viruses have been identified as important causative agents of acute respiratory disease in infants, the elderly, and immunocompromised individuals. Clinical signs of infection range from mild upper respiratory illness to more serious lower respiratory illness, including bronchiolitis and pneumonia. Additionally, these illnesses can have long-lasting impact on patient health well beyond resolution of the viral infection. Aside from influenza, there are currently no licensed vaccines against these viruses. However, several research groups have tested various vaccine candidates, including those that utilize attenuated virus, virus-like particles (VLPs), protein subunits, and nanoparticles, as well as recent RNA vaccines, with several of these approaches showing promise. Historically, vaccine candidates have advanced, dependent upon the ability to activate the humoral immune response, specifically leading to strong B cell responses and neutralizing antibody production. More recently, it has been recognized that the cellular immune response is also critical in proper resolution of viral infection and protection against detrimental immunopathology associated with severe disease and therefore, must also be considered when analyzing the efficacy and safety of vaccine candidates. These candidates would ideally result in robust CD4+ and CD8+ T cell responses as well as high-affinity neutralizing antibody. This review will aim to summarize established and new approaches that are being examined to harness the cellular immune response during respiratory viral vaccination.

Sumoylation of Human Parainfluenza Virus Type 3 Phosphoprotein Correlates with A Reduction in Viral Replication

Human parainfluenza virus type 3 (HPIV3), a member of the Paramyxoviridae family, can cause lower respiratory disease in infants and young children. The phosphoprotein (P) of HPIV3 is an essential cofactor of the viral RNA-dependent RNA polymerase large protein (L). P connects nucleocapsid protein (N) with L to initiate genome transcription and replication. Sumoylation influences many important pathways of the target proteins, and many viral proteins are also themselves sumoylated. In this study, we found that the P of HPIV3 could be sumoylated, and mutation of K492 and K532 to arginine (PK492R/K532R) failed to be sumoylated within P, which enhances HPIV3 minigenome activity. Biochemical studies showed that PK492R/K532R had no effect on its interactions with N, formation of homo-tetramers and formation of inclusion bodies. Finally, we found that incorporation of K492R/K532R into a recombinant HPIV3 (rHPIV3-PK492R/K532R) increased viral production in culture cells, suggesting that sumoylation attenuates functions of P and down-regulates viral replication.

Nanoparticle vaccines against respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a leading cause of respiratory disease in infants, the elderly and immunocompromised individuals. Despite the global burden, there is no licensed vaccine for RSV. Recent advances in the use of nanoparticle technology have provided new opportunities to address some of the limitations of conventional vaccines. Precise control over particle size and surface properties enhance antigen stability and prolong antigen release. Particle size can also be modified to target specific antigen-presenting cells in order to induce specific types of effector T-cell responses. Numerous nanoparticle-based vaccines are currently being evaluated for RSV including inorganic, polymeric and virus-like particle-based formulations. Here, we review the potential advantages of using different nanoparticle formulations in a vaccine for RSV, and discuss many examples of safe, and effective vaccines currently in both preclinical and clinical stages of testing.