Molecular characteristics, epidemiological trends, and public health implications of human metapneumovirus (hMPV): a review.

A comparative analysis of confirmed cases of human influenza virus (HIFV), human respiratory syncytial virus (HRSV), and human metapneumovirus(HMPV) was conducted to describe their clinical and epidemiological characteristics.During 2009-2021, active surveillance of acute respiratory infections (ARIs) was performed in nine provinces of China. Clinical and epidemiological information and laboratory testing results of HIFV, HRSV, and HMPV were analyzed.Among 11591 ARI patients, the single-infection rates of HIFV, HRSV, and HMPV were 15.00%, 9.59%, and 2.24%, respectively; the coinfection rate of these three viruses was 0.64%. HIFV infection was mainly in adults aged 15-59 years, accounting for 39.10%. HRSV and HMPV infections were mainly in children under 5 years old, accounting for 87.13% and 83.46%, respectively. Patients with HRSV infection were younger than HMPV. HRSV and HMPV had high similarities in clinical manifestations, presenting with lower respiratory symptoms. HIFV mainly presented with an upper respiratory infection. The epidemic peak of HRSV was earlier than that of HIFV, and that of HMPV was later than those of HRSV and HFIV. A total of 85.14% of coinfection cases were children under 5 years old. Coinfection might increase the risk of pneumonia in HIFV cases. During 2020-2021, the positive rates and seasonal patterns of these three viruses changed due to the impact of the COVID-19 pandemic.Certain clinical and epidemiological features were observed in HIFV, HRSV, and HMPV infections, which could be beneficial for guiding clinical diagnosis, treatment, and prevention of these three viruses in China.

ABSTRACTRespiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease of children, the elderly, and immunocompromised individuals. Currently, there are no FDA-approved RSV vaccines. The RSV G glycoprotein is used for viral attachment to host cells and impairment of host immunity by interacting with the human chemokine receptor CX3CR1. Antibodies that disrupt this interaction are protective against infection and disease. Nevertheless, development of an RSV G vaccine antigen has been hindered by its low immunogenicity and safety concerns. A previous study described three engineered RSV G proteins containing single-point mutations that induce higher levels of IgG antibodies and have improved safety profiles compared to wild-type RSV G (H. C. Bergeron, J. Murray, A. M. Nuñez Castrejon, et al., Viruses 13:352, 2021, https://doi.org/10.3390/v13020352). However, it is unclear if the mutations affect RSV G protein folding and display of its conformational epitopes. In this study, we show that the RSV G S177Q protein retains high-affinity binding to protective human and mouse monoclonal antibodies and has equal reactivity as wild-type RSV G protein to human reference immunoglobulin to RSV. Additionally, we determined the high-resolution crystal structure of RSV G S177Q protein in complex with the anti-RSV G antibody 3G12, further validating its antigenic structure. These studies show for the first time that an engineered RSV G protein with increased immunogenicity and safety retains conformational epitopes to high-affinity protective antibodies, supporting its further development as an RSV vaccine immunogen.IMPORTANCE Respiratory syncytial virus (RSV) causes severe lower respiratory diseases of children, the elderly, and immunocompromised populations. There currently are no FDA-approved RSV vaccines. Most vaccine development efforts have focused on the RSV F protein, and the field has generally overlooked the receptor-binding antigen RSV G due to its poor immunogenicity and safety concerns. However, single-point mutant RSV G proteins have been previously identified that have increased immunogenicity and safety. In this study, we investigate the antibody reactivities of three known RSV G mutant proteins. We show that one mutant RSV G protein retains high-affinity binding to protective monoclonal antibodies, is equally recognized by anti-RSV antibodies in human sera, and forms the same three-dimensional structure as the wild-type RSV G protein. Our study validates the structure-guided design of the RSV G protein as an RSV vaccine antigen.

An off-season outbreak of human metapneumovirus infections after ending of a COVID-19 lockdown

Human metapneumovirus (HMPV) causes acute lower respiratory infections, primarily affecting young children and older adults, with seasonal outbreaks peaking annually in March or April in the United States and other temperate regions in the Northern hemisphere. However, the factors driving HMPV seasonality in the United States remain poorly understood. We analyzed laboratory-confirmed HMPV cases and age-specific emergency department visits across 10 US regions, fitting an age-stratified dynamic transmission model to assess spatiotemporal patterns and investigate the influence of environmental variables and viral interference from RSV on HMPV transmission rates. We found that models incorporating climate variables into the transmission rate, including vapor pressure, precipitation, potential evapotranspiration, and minimum temperature, could not capture the timing of HMPV activity across all regions. Instead, HMPV timing was associated with RSV activity, with the HMPV transmission rate reduced in the presence of RSV. We showed that, unlike RSV, only models incorporating viral interference could reproduce the biennial pattern of HMPV observed in some regions, characterized by alternating “late-small” and “early-large” epidemics. Furthermore, our model successfully reproduced post-COVID-19 HMPV and RSV epidemics and predicted that RSV interventions are not likely to lead to a substantial increase in HMPV activity despite decreasing competition from RSV. Our work unravels the spatiotemporal dynamics of HMPV and its interaction with RSV, informing future seasonal forecasting and intervention strategies for HMPV.Author SummaryHuman metapneumovirus (HMPV) circulates each year in the United States and contributes to respiratory illness, particularly among young children and older adults. Although HMPV epidemics show clear seasonal patterns, the mechanisms underlying these patterns are not well understood. In this study, we combined surveillance data from multiple regions in the United States with mathematical modeling to investigate the drivers of HMPV transmission. We evaluated whether environmental factors or interactions with respiratory syncytial virus (RSV) better explained differences in epidemic timing and intensity. Our findings indicate that interactions between HMPV and RSV play an important role in shaping HMPV epidemics. In particular, RSV circulation appeared to suppress HMPV transmission, helping explain the alternating epidemic patterns observed in some regions. Our model also suggested that expanded RSV prevention programs are unlikely to substantially increase HMPV burden. This work provides new insights into respiratory virus interactions and highlights the importance of considering pathogen interactions when predicting seasonal outbreaks and evaluating intervention strategies.

To explore the epidemiology of common pediatric respiratory viruses among children in the post-COVID-19 era. Retrospective analysis of children with respiratory symptoms who visited our hospital between March 2023 and May 2025 was conducted. Influenza A/B (IAV/IBV) antigen testing was performed for 151,809 children; nucleic acid testing for respiratory syncytial virus (RSV), adenovirus (ADV), human metapneumovirus (HMPV), and parainfluenza viruses (PIV) I-III was performed for 35,326 children. Demographic and laboratory data were analyzed. Across two post-pandemic seasons, most viruses resurged; HMPV and PIV II peaked more prominently in season 2. RSV showed the highest positivity, whereas IAV had the most positive cases. RSV and PIV III predominated in infants; IAV, HMPV, and PIV I/II predominated in preschoolers; and IBV and ADV predominated in school-aged children. IAV, IBV, and the RSV shared a winter peak and summer trough, whereas the PIV subtypes displayed distinct seasonality. Clinically, IAV and IBV were associated mainly with acute upper respiratory infections; non-severe pneumonia was associated predominantly with RSV, ADV, HMPV, and PIVs. Coinfections were most frequent with ADV and HMPV and least frequent with IAV and IBV; the most common dual and triple coinfections were "RSV + ADV" and "RSV + ADV + IBV". In the post-COVID-19 era, the age distribution, seasonality, and coinfection patterns of pediatric respiratory viruses shifted. Viruses with high detection and coinfection propensities warrant strengthened surveillance and tailored control strategies.

Transforming or tinkering: the world remains unprepared for the next pandemic threat

Background: Investigation of transmission of respiratory viruses (RV) in healthcare setting is understudied. To investigate the transmission dynamics of common healthcare-associated RV infections, we performed retrospective whole genome sequencing (WGS) surveillance of rhinovirus, influenza, human metapneumovirus (HMPV), and respiratory syncytial virus (RSV) at one children’s and two adult teaching hospitals in the Pittsburgh area. Methods: From Jan 2, 2018 to Jan 4, 2020, nasal swab specimens positive for rhinovirus, influenza, HMPV or RSV were collected from patients who had been hospitalized for ≥3 days. Specimens with qPCR Ct values ≤30, HMPV specimens were sequenced using tiled PCR amplicons regardless of their qPCR Ct value. Genomes passed WGS QC if ≥90% of the genome had ≥10× average coverage depth. High-quality genomes were assessed for genetic relatedness using ≤3 single nucleotide polymorphisms (SNPs) as a cut-off. Review of patient health records was performed on all genetically related clusters to identify common epidemiological connections. Results: We collected 436 rhinovirus (n = 291), influenza (n = 50), HMPV (n=47) and RSV (n=48) specimens from 360 patients. Of these, 55% (197/360 patients) were from the children’s hospital and 45% were from the two adult hospitals. Patients ranged in age from 14 days to 93 years old, 61% were male, and 74% were white. We sequenced 61.2% (178/291) of rhinovirus, 78% (39/50) of influenza, and 92% (44/48) of RSV specimens that met qPCR criteria. Among these, 63.5% (113/178) of rhinovirus, 87% (34/39) of influenza, and 89% (39/44) of RSV genomes passed WGS QC. Additionally, 79% (37/47) of the HMPV genomes passed WGS QC. We identified 13 genetically related clusters (n=5 rhinovirus; n=2 influenza; n=3 RSV; n=3 HMPV) containing 34 patients and ranging in size from 2-5 patients per cluster. We identified common epidemiological links between 56% (19/34) of clustered patients. Of these, 63% (12/19) of patients had a same-unit stay, 11% (2/19) shared a common provider, and 26% (5/19) had overlapping hospital stays. On average, genetically related clusters spanned a duration of 17 days (range: 0−55 days). Conclusion: WGS offered valuable insights into RV transmission dynamics in hospitals, which until now have not been rigorously studied. While healthcare-associated RV transmission is common, absence of epidemiological links in 44% of genetically-related cases and the distribution of cluster durations, given the incubation period, highlights the complex transmission dynamics.

To investigate the features of paramyxovirus respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (HMPV) infection and determine the effect of meteorological conditions in Guangzhou, a subtropical region of southern China. We collected 11,398 respiratory samples from hospitalized pediatric patients with acute respiratory illness between July 2009 and June 2016 in Guangzhou. The samples were tested simultaneously for 18 respiratory pathogens using real-time PCR. Local meteorological data were also collected for correlation analysis. Of 11,398 patients tested, 5606 (49.2%) patients tested positive for one or more pathogens; RSV, PIV, and HMPV were the first, sixth, and ninth most frequently detected pathogens, in 1690 (14.8%), 502 (4.4%), and 321 (2.8%) patients, respectively. A total 17.9% (4605/5606) of patients with positive results had coinfection with other pathogens. Significant differences were found in the prevalence of RSV, PIV, and HMPV among all age groups (p < 0.001). RSV and HMPV had similar seasonal patterns, with two prevalence peaks every year. PIV appeared alternatively with RSV and HMPV. Multiple linear regression models were established for RSV, PIV, and HMPV prevalence and meteorological factors (p < 0.05). RSV and PIV incidence was negatively correlated with monthly mean relative humidity; RSV and HMPV incidence was negatively correlated with sunshine duration; PIV incidence was positively correlated with mean temperature. We described the features of paramyxovirus infection in a subtropical region of China and highlighted the correlation with meteorological factors. These findings will assist public health authorities and clinicians in improving strategies for controlling paramyxovirus infection.

PurposeWe aimed to study the changes in respiratory virus detection rates during the control of the COVID-19 outbreak and to elucidate possible epidemiologic disturbances after the lifting of control measures.MethodsSevere acute respiratory infection (SARI) specimens were collected from hospitalized children in Baiyin, China, from 2021 to 2023. We conducted real-time fluorescence quantitative PCR (RT-qPCR) to detect various respiratory viruses, including influenza virus (IFV), human respiratory syncytial virus (HRSV), human rhinovirus (HRV), human parainfluenza virus (HPIV), human metapneumovirus (HMPV), human adenovirus (HADV), enterovirus (EV), and human coronavirus (HCoV). The results were statistically analyzed using SPSS 26.0 software.ResultsA total of 1353 nasopharyngeal swab specimens were collected from children with SARI between 2021 and 2023. The male-to-female ratio of 1.49:1, the total virus detection rate of 33.85% (458/1353). Data were analyzed by comparing two distinct periods: before the lifting of the COVID-19 control measures (January 1, 2021 – December 6, 2022) and after the lifting of the control measures (December 7, 2022 – December 31, 2023). During the three-year study period, there was no significant difference in the detection rate of pathogen positivity between the ≤ 1 year (OR: 0.986, 95% CI: 0.960–1.013) and 1–3 years (OR: 1.018, 95% CI: 0.997–1.060) age groups (P > 0.05). However, there were significant differences in pathogen positivity rates between the 3–6 years (OR: 1.097, 95% CI: 1.049–1.146) and > 6 years (OR: 1.099, 95% CI: 1.063–1.138) age groups (P < 0.05). Significant differences in pathogen positivity rates were observed between male (OR: 1.293, 95% CI: 1.156–1.445) and female (OR: 1.354, 95% CI: 1.157–1.583) children (P < 0.05). The positive detection rates for various viruses showed a decreasing trend in January and February 2023; however, IFV showed a significant rebound in 2023. Following the lifting of COVID-19 control measures, the overall positive detection rate for respiratory viruses increased significantly from 27.84 to 45.03% (OR: 1.313, 95% CI: 1.198–1.438) (P < 0.05). Prior to the lifting of control measures, the ranking of positive detection rates for respiratory viruses in children was as follows: HPIV > HRSV > HADV > HRV > HMPV > EV > HCOV > influenza virus (IFV). After the measures were lifted, the order was as follows: EV > IFV > HADV > HCOV > HPIV > HRV > HMPV > HRSV. The peak detection periods for HRV, HMPV, HADV, and EV shifted to later time points compared to those before the measures were lifted. After the lifting of control measures, the positive detection rates of IFV (OR: 1.090, 95% CI: 1.059–1.122), EV (OR: 1.102, 95% CI: 1.064–1.141), HCOV (OR: 1.043, 95% CI: 1.017–1.070), and HADV (OR: 1.028, 95% CI: 0.999–1.059) all significantly increased (P < 0.05); HRV (OR: 1.019, 95% CI: 0.994–1.044) and HMPV (OR: 1.010, 95% CI: 0.989–1.032) showed non-significant increases in positive detection rates (P > 0.05); HRSV (OR: 0.965, 95% CI: 0.946–0.985) was significantly reduced (P < 0.05), while the positive detection rate for HPIV (OR: 0.971, 95% CI: 0.943–1.001) showed no significant decrease(P > 0.05).ConclusionsThese findings help clarify that social interventions can influence the prevalence of respiratory viruses in children during unique historical periods. The implementation of COVID-19 control measures may have curbed the spread of respiratory viruses in children during the study period. After the lifting of control measures, monitoring of respiratory pathogens must be strengthened to reduce the harm caused by respiratory viruses to children’s health.

Nuclear-localized human respiratory syncytial virus NS1 protein modulates host gene transcription.

Underestimation of Influenza Viral Infection in Childhood Asthma Exacerbations

Acute respiratory infections (ARI) cause significant childhood mortality. Nutritional homeostasis, particularly micronutrient levels, is important in modulating response to infection. More information is required regarding micronutrient levels in ARI viral infections, especially newly identified viruses such as human metapneumovirus (HMPV). To describe zinc, copper, selenium and vitamins A and E concentrations in children with respiratory syncytial virus (RSV) and/or HMPV in relation to levels of C-reactive protein (CRP). The presence of RSV/HMPV in nasopharyngeal aspirates (NPA) was identified in 246 children using RTPCR. Zinc, copper, selenium and vitamins A and E concentrations were measured using inductive coupled plasma mass spectrometry and high performance liquid chromatography. 183 children had RSV, 39 had HMPV and 24 were co-infected. Zinc concentrations were lower in children with HMPV than in children with RSV or RSV/HMPV co-infection. Copper concentrations were lower in children with RSV than in children with RSV/HMPV or HMPV and zinc/copper ratios were lower in children with HMPV/RSV or RSV than in children with HMPV alone. Retinol and a alpha-tocopherol were lower in children with RSV than in children with HMPV. Most children had low selenium concentrations. Children with RSV and raised CRP (>5 mg/L) had higher copper and lower zinc/copper ratios than those with low CRP (< or =5 mg/L). Children with HMPV and raised CRP had higher copper and lower zinc concentrations than children with low CRP. Children with RSV/HMPV and raised CRP had higher copper concentrations. Children with RSV/HMPV and raised CRP had higher a alpha-tocopherol concentrations. The profiles of micronutrients differ in children with RSV and HMPV and are confounded by CRP. These results may guide strategies for micronutrient supplementation in ARI.

Globally, it is estimated that respiratory syncytial virus (RSV) causes 33 million new episodes of acute lower respiratory tract infection (LRTI) in children <5 years of age and ≈120,000 deaths annually. In infants, RSV represents the leading cause of hospitalization worldwide and the second commonest cause of mortality in low- and middle-income countries.1,2 RSV also causes significant disease in immunocompromised hosts and the elderly and has been associated with the development of asthma.3 The increasingly recognized burden of RSV disease has made the development of a vaccine(s) a global health priority. The World Health Organization recently released a roadmap to facilitate the development and implementation of vaccines and monoclonal antibodies (mAbs) and estimated that RSV vaccination will be available in the next 5–10 years.4 This review summarizes the strategies and challenges associated with RSV vaccine development and the vaccine candidates undergoing clinical evaluation, with a focus on those geared toward the pediatric population. THE STRUCTURE OF RSV RSV has a negative sense nonsegmented RNA genome that encodes 11 proteins: 3 are nonstructural (NS1/NS2—that counteract interferon responses—and M2-2), and 8 are structural proteins. Of those 8 proteins, 5 are internal [N, P, M, M2-1, L]), and 3 are embedded in the virion membrane: the small hydrophobic (SH), fusion (F) and attachment (G) glycoproteins. RSV G and F carry antigenic determinants that elicit neutralizing antibodies. However, F is the preferred target for vaccine, mAb and antiviral development because it plays an essential role in host cell viral entry, is highly conserved within and among RSV A and B subtypes and because of its 6 antigenic sites that elicit the production of high-potency neutralizing antibodies (≥90% of neutralizing antibodies are directed against this protein).5 Most of the G protein is covered in glycans, leaving the central conserved domain available for neutralizing antibody binding. Except for this domain, G is not well conserved and it is recognized by few neutralizing antibodies, which has reduced enthusiasm for it as a vaccine target. Our understanding of the F protein in its 2 conformations, prefusion (pre-F) and postfusion (post-F), has revolutionized the field of RSV biology. Pre-F, the active form of F on the virion, is metastable and switches unpredictably to the stable post-F conformation that once it is folded cannot return to the pre-F form. Antibodies that bind to pre-F are more efficient at neutralizing RSV than those against post-F. As examples, antibodies against site ϕ, a pre-F-specific epitope, are 150 times more potent than palivizumab that binds to site-II, present in both F conformations, while antibodies against site I, exclusively present in post-F, show weak or no neutralization.5 In addition, non-neutralizing antibodies to F, G and also SH, may inhibit infection by complement-mediated neutralization or antibody-dependent cell-mediated cytotoxicity. Furthermore, all viral antigens have the potential to induce protection by T-cell-mediated immunity. CHALLENGES FOR RSV VACCINE DEVELOPMENT Despite the burden associated with RSV, and after 60 years of active research, there is no licensed vaccine due in part of our incomplete understanding of the pathogenesis of the disease. In general, primary RSV infections are more severe; however, reinfections are common throughout life as immunity is neither complete nor long-lasting. The ideal vaccine should induce a more durable and improved immune response than natural infection. Legacy of the Formalin-inactivated Vaccine RSV vaccine development has been hindered after the safety concerns of the first RSV vaccine that was developed in the 1960s. The formalin-inactivated-whole virus alum-precipitated vaccine, which recent evidence indicating that it was directed against post-F, was associated in naive infants, but not older children, with enhanced RSV disease (ERD) and 2 deaths upon subsequent exposure to natural RSV. The mechanisms of ERD are not well understood, but it appears that an excess of non-neutralizing antibodies coupled with a skewed T-helper 2 (Th2) immune response, and complement deposition in the lungs contributed to its development. This is a critical aspect that is being considered for the development of inactivated vaccines, and strategies to assess safety risks according to the different vaccine platforms in the infant population are required. Target Populations There are different age groups that will benefit from RSV vaccines, and these might require different approaches: young RSV-naive infants (<4–6 months), children >6 months and the elderly. Vaccination of older children (2–5 years of age) may also limit transmission, as older siblings frequently introduce RSV into the household. Infants <4–6 Months This age group has an immature/developing immune system characterized by low expression of interferon, abundance of regulatory T cells with tolerogenic reactivity and a limited B-cell repertoire because of inefficient generation of somatic hypermutations. All these factors are associated with a poor response to foreign antigens and the generation of high-affinity matured antibodies. In addition, the presence of maternal antibodies may interfere with vaccine immunogenicity. Young infants represent the main target population because the peak of severe RSV disease occurs in the first 2–3 months of life. This age group would likely benefit from maternal vaccination or neutralizing mAbs administered at birth. The main goal of maternal vaccination is to boost neutralizing RSV titers and thereby transplacental antibody transfer. However, the optimal timing for vaccination (2nd or 3rd trimester) and the durability of protection in the infant need to be defined. This coupled with the high prevalence of hypergammaglobulinemia in low- and middle-income countries, associated with HIV or malaria, which impairs transplacental antibody transfer, suggest the need for high maternal antibody titers to compete for transfer. Nevertheless, RSV antibody transfer through breast-feeding (IgG > IgA) may complement the maternal vaccination strategy.6 Vaccinating pregnant women could be questioned if it exclusively benefits the infant and not the mother. The limited data available in pregnant women are mostly derived from influenza surveillance studies with rates of RSV infection varying from 0.2% to 13%, which likely underestimates the real incidence of RSV during pregnancy. The concerns regarding adverse fetal outcomes are relatively low, because this would not be the first time the mother's immune system encounters RSV antigens and the safety profile of other vaccines used in pregnancy, such as tetanus, diptheria and acellular pertussis (Tdap) or influenza, is excellent. A number of RSV maternal vaccines are currently in clinical development (Table 1).TABLE 1.: Landscape of RSV Vaccines Undergoing Clinical TrialsOlder Infants and Children Based on the experience of the formalin-inactivated-RSV vaccine, within this age group those who are naive at the time of vaccination might be at risk of ERD with protein vaccines. This target population would likely benefit most from live-attenuated or vectored vaccines. The Elderly On the other side of the spectrum, the immunosenescence of adults >65 years of age and the presence of additional comorbidities may compromise vaccine responses and the ability to assess efficacy. This population might benefit most from adjuvanted vaccines. Clinical Endpoints The ideal vaccine should be able to prevent severe disease and limit transmission, but the lack of a standard definition of severe disease or precise markers to assess severity in infants has been a barrier for vaccine development. Clinical endpoints that define a successful vaccine might be different depending on the target population. Hospitalization and other endpoints that capture the inpatient/outpatient burden of the disease, such as a reduction in medically significant visits for RSV infection, should be considered.7 Developing composite endpoints that include a combination of viral (and possibly bacterial) factors, clinical parameters, and fast turn-around point of care biomarkers could help with patient classification and to standardize definitions.8 Also, long-term follow-up is recommended, as studies suggest that interventions reducing the acute burden of RSV disease may also impact the development of recurrent wheezing/asthma.9 Immune Correlates of Protection Serum neutralizing antibodies (IgG against pre-F > post-F and G) represent the main surrogate of protection, as shown by the effectiveness of immunoprophylaxis with anti-F mAb (palivizumab) in high risk infants. However, a standardized protective threshold has not been defined yet. Newer systems biology approaches are helping to define the optimal correlates of protection, which are complex and depend on multiple factors, rather than a single cutoff value in antibody assays, and will need to be adjusted to each target population. Other cocorrelates of protection may include, F-specific epitope antibodies, mucosal IgA, interferon responses, antibody-dependent cell-mediated cytotoxicity and cell-mediated immunity. In addition, a balanced Th1/Th2 immune response, indicated by a high IgG2a/IgG1 ratio, is desirable. Other Factors The lack of an ideal animal model has also slowed down RSV vaccine development. Human challenge models mostly reproduce upper but not LRTI, limiting the generalizability of the results or the ability to assess the impact of vaccines on disease severity. There are also gaps in RSV epidemiology with lack of accurate information defining the temporal and geographic patterns of RSV circulation in inpatients/outpatients, across different age groups or RSV-associated mortality. Implementing robust multiplex polymerase chain reaction-based surveillance platforms could help to assess the impact of interventions on the burden of RSV disease, to identify possible escape mutants, or the contribution of other respiratory viruses causing RSV-like illnesses. VACCINE STRATEGIES The most effective approach to protect young infants and children from severe RSV infection may be a combined strategy using passive and active immunization: either maternal vaccination with stabilized pre-F or virus-like particles containing the F protein or mAb against pre-F at birth; followed by pediatric active immunization with a live vaccine, either attenuated RSV or the pre-F protein expressed from a virus vector. There are 39 vaccines candidates under development (http://www.path.org); of those 19 are undergoing clinical trials (Table 1).10 Protein Vaccines Particle Based The recombinant adjuvanted RSV post-F nanoparticle vaccine is the most advanced vaccine in clinical development. Results from a phase-3 clinical trial that enrolled 4636 pregnant women on the third trimester demonstrated a decrease in RSV hospitalizations in the offspring; however, the study did not meet the primary endpoint defined as prevention of medically significant RSV LRTI. The potential approval of this vaccine is being evaluated. It also aims to target elderly individuals and children >6 months to 5 years of age. Subunit Vaccines These vaccines consist of purified, adjuvanted proteins and use stabilized pre-F as the main antigen with promising results. They are mainly directed at pregnant women or the elderly because of the risk of ERD in RSV-naive infants. Other subunit vaccines in clinical or preclinical stages are using SH or G as main vaccine antigens. Live Vaccines Vector Based There are 5 vector-based vaccines in clinical development. The first 4 use adenovirus as a vector, while the other uses a modified vaccinia Ankara virus. Two of them are intended for use in pediatric seronegative patients. All of these vaccines express RSV F (pre-F > post-F depending on the vaccine) and 2 of them also express other viral antigens (N, M2 or G proteins). Live-attenuated vaccines (LAVs) represent an attractive alternative for older infants and young children. LAVs are administered intranasally and are able to elicit broad innate, humoral and cellular responses and replicate in the respiratory tract despite the presence of maternal antibodies. Importantly, these vaccines have not been associated with ERD and are considered safer in infants. The use of reverse genetics has made possible to incorporate different mutations in the viral genome, making LAV sufficiently immunogenic and, except for rhinorrhea, not associated with adverse events. There are 6 intranasal LAVs undergoing phase-1 clinical trials; 4 are using attenuated RSV, one Sendai virus as a backbone expressing RSV F and the last one is a chimeric vaccine using bacille Calmette-Guerin (BCG). The BCG/RSV vaccine is the only LAV intended to be administered systemically (subdermal) and in newborns. MONOCLONAL ANTIBODIES mAbs are also being evaluated for the prevention of RSV LRTI in young infants. Of those, suptavumab (REGN-2222), that targeted the pre-F-specific site V, has been discontinued from the market after it failed to prevent serious RSV LRTI in premature infants (primary endpoint). During the study, RSV type B was the predominant circulating strain and developed escape mutations that conferred resistance to this mAb. MK-1654 is an extended half-life mAb currently undergoing phase-I clinical trials and it is directed against antigenic site-IV (present the pre-F and post-F forms). Nirsevimab (MEDI8897) is a highly potent human neutralizing IgG1Κ targeting the pre-F-specific antigenic site ϕ. It also has an extended half-life because of modifications in the FC region using YTE technology. MEDI8897 is entering phase-3 clinical trials with the intent to provide passive immunization for prevention of severe RSV LRTI to all infants (preterm and full term), using a fixed, once per season intramuscular dose. SUMMARY Over the past decade, there have been significant advances in our knowledge of RSV molecular and structural biology and in the understanding of the human immune response to RSV. Despite the barriers, there are several opportunities for RSV vaccine development to protect the most vulnerable populations. The increasing interest of academic, industry and international bodies, such as the World Health Organization or Bill & Melinda Gates Foundation, is helping to move the field forward, promoting the implementation of surveillance platforms and standardization of clinical definitions, assays and surrogate markers of protection.

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause acute respiratory infections (ARI) in persons of all ages. The viruses are structurally similar although HMPV lacks 2 nonstructural proteins of RSV known to suppress interferon signaling. We analyzed data from 2 studies that prospectively enrolled hospitalized adults with ARI and compared clinical characteristics and outcomes of HMPV and RSV infection. Gene expression was compared between subjects with HMPV and RSV using DESeq2 to analyze read counts from samples of globin-reduced RNA from whole blood, sequenced using Illumina NovaSeq. Of 1914 illnesses evaluated, 127 (6.6%) had RSV and 90 (4.7%) had HMPV identified as a sole viral pathogen. Demographics and preexisting conditions were similar although HMPV patients had significantly less active tobacco use and numerically less underlying heart and lung disease. Sore throat, temperature >38°C, and clinically adjudicated pneumonia were significantly more frequent with HMPV compared to RSV. Restricting analysis to those subjects adjudicated as viral alone without bacterial coinfection, we identified 197 differentially expressed genes between RSV- and HMPV-infected subjects. Genes with higher expression in HMPV-infected individuals were associated with antigen binding, immunoglobulin production, and adaptive immunity. Genes increased in RSV-infected individuals were associated with NK T cells. Although RSV and HMPV are closely related viruses, we found differences in the clinical features of adults with HMPV patients presenting with more flu-like symptoms and viral pneumonia. Peripheral blood gene expression of hospitalized HMPV-infected patients also differed compared to those hospitalized and infected with RSV.

BackgroundIt is unclarified as to whether viral co-detection and human metapneumovirus (HMPV) genotypes relate to clinical manifestations in children with HMPV and lower respiratory tract infection (LRTI), and if the clinical course and risk factors for severe LRTI differ between HMPV and respiratory syncytial virus (RSV).MethodsWe prospectively enrolled hospitalized children aged <16 years with LRTI from 2006 to 2015. Children were clinically examined, and nasopharyngeal aspirates were analyzed using semi-quantitative, real-time polymerase chain reaction tests for HMPV, RSV and 17 other pathogens. HMPV-positive samples were genotyped.ResultsA total of 171 children had HMPV infection. HMPV-infected children with single virus (n = 106) and co-detections (n = 65) had similar clinical manifestations. No clinical differences were found between HMPV genotypes A (n = 67) and B (n = 80). The HMPV-infected children were older (median 17.2 months) than RSV-infected children (median 7.3 months, n = 859). Among single virus-infected children, no differences in age-adjusted LRTI diagnoses were found between HMPV and RSV. Age was an important factor for disease severity among single virus-infected children, where children <6 months old with HMPV had a milder disease than those with RSV, while in children 12–23 months old, the pattern was the opposite. In multivariable logistic regression analysis for each virus type, age ≥12 months (HMPV), and age <6 months (RSV), prematurity, ≥1 chronic disease and high viral loads of RSV, but not high HMPV viral loads, were risk factors for severe disease.ConclusionsAmong hospitalized children with LRTI, HMPV manifests independently of viral co-detections and HMPV genotypes. Disease severity in HMPV- and RSV-infected children varies in relation to age. A history of prematurity and chronic disease increases the risk of severe LRTI among HMPV- and RSV-infected children.