Background: Anaphylaxis following influenza vaccination is a rare but serious problem. The underlying immune responses are not well understood. This study elucidated the IgE and IgG antibody responses in healthy children and adolescents following inactivated influenza vaccines (IIVs). Methods: The efficacy and safety of quadrivalent IIV (QIV) and trivalent IIV (TIV) were compared in healthy subjects aged 0-18 years. Serum IIV-specific IgE, IgG and IgG4 levels (sIgE, sIgG, sIgG4) were measured with ImmunoCAP. Hemagglutinin inhibition (HI) assay was performed for each influenza virus subtype. Sera from earlier patients who developed anaphylaxis to different IIVs were similarly tested. Results: A total of 393 subjects were enrolled: 96 were 6 months -2 years old, 100 were 3-5 years old, 100 were 6-12 years old, and 97 were 13-18 years old. No anaphylaxis was observed. Generally, QIV and TIV induced similar antibody responses. IIV-sIgE levels rose significantly after vaccination in the 6m-2y and 3-5y groups, did not change in the 6-12y group, and decreased in the 13-18y group. In contrast, the IIV-sIgG4/sIgE ratio increased significantly after vaccination in all age groups. Sensitized subjects had significantly higher HI titers and IIV-sIgG levels in the youngest age group and higher IIV-sIgG4 levels in all age groups compared with the non-sensitized. The IIV-sIgG4/sIgE ratio in 5 patients with anaphylaxis was significantly lower than in age-matched healthy subjects. Conclusion: IIVs induce IgE sensitization in healthy children, but also robust IgG4 responses that may protect them from anaphylaxis.

Background: The Omicron (lineage B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wales, UK on 3rd December 2021. The aim of the study was to describe the first 1000 cases of the Omicron variant by demographic, vaccination status, travel and severe outcome status and compare this to contemporaneous cases of the Delta variant. Methods: Testing, typing and contact tracing data were collected by Public Health Wales and analysis undertaken by the Communicable Disease Surveillance Centre (CDSC). Risk ratios for demographic factors and symptoms were calculated comparing Omicron cases to Delta cases identified over the same time period. Results: By 14th December 2021, 1000 cases of the Omicron variant had been identified in Wales. Of the first 1000, just 3% of cases had a prior history of travel revealing rapid community transmission. A higher proportion of Omicron cases were identified in individuals aged 20-39 and most cases were double vaccinated (65.9%) or boosted (15.7%). Age adjusted analysis also revealed that Omicron cases were less likely to be hospitalised (0.4%) or report symptoms (60.8%). Specifically a significant reduction was observed in the proportion of Omicron cases reporting anosmia (8.9%). Conclusion: Key findings include a lower risk of anosmia and a reduced risk of hospitalisation in the first 1000 Omicron cases compared to co-circulating Delta cases. We also identify that existing measures for travel restrictions to control importations of new variants identified outside the UK did not prevent the rapid ingress of Omicron within Wales.

Objective: To assess the utility of a test-based approach to shorten isolation of healthcare workers with COVID-19 in the setting of the highly transmissible omicron variant Methods: Between December 24th, 2021, to January 5th, 2022 HCWs who tested positive for SARS-CoV-2 were re-tested at least five days since onset of symptoms. Results: 46 sequential fully COVID-19 vaccinated HCWs who had tested positive for SARS-CoV-2 underwent follow up testing. All the isolates were confirmed as omicron variants and only 4 (8.7%) were negative 5 days or more since onset of symptoms., Conclusions: Implementation of a test-based strategy is logistically challenging, increases costs and did not lead to shorter isolation in our institution.

Pandemic influenza viruses may emerge from animal reservoirs and spread among humans in the absence of cross-reactive antibodies in the human population. Immune response to highly conserved T cell epitopes in vaccines may still reduce morbidity and limit the spread of the new virus even when cross-protective antibody responses are lacking. We used an established epitope content prediction and comparison tool, EpiCC, to assess the potential for emergent H1N1 G4 swine influenza A virus (G4) to impact swine and human populations. We identified and computed the total cross-conserved T cell epitope content in HA sequences of human seasonal and experimental influenza vaccines, swine influenza vaccines from Europe and the United States (US) against G4. The overall T cell epitope content of US commercial swine vaccines was poorly conserved with G4, with an average T cell epitope coverage of 35.7%. EpiCC scores for the comparison between current human influenza vaccines and circulating human influenza strains were also very low. In contrast, the T cell epitope coverage of a recent European swine influenza vaccine (HL03) was 65.8% against G4. Poor T cell epitope cross-conservation between emergent G4 and swine and human influenza vaccines in the US may enable G4 to spread in swine and spillover to human populations in the absence of protective antibody response. One European influenza vaccine, HL03, may protect against emergent G4. This study illustrates the use of the EpiCC tool for prospective assessment of existing vaccine strains against emergent viruses in swine and human populations.

Background: The nucleoprotein (N protein) of respiratory syncytial virus (RSV) is a candidate antigen for new RSV vaccine development. The aim of the present study was to investigate the association between maternal antibody titers against the RSV N protein at birth and the newborns’ risk of developing very-severe lower respiratory tract infection (VS-LRTI). Methods: In this single-center prospective cohort study, 578 infants born during the RSV epidemic season in France were included. Among these, 36 were hospitalized for RSV VS-LRTI. A generalized linear model was used to test the occurrence of a VS-LRTI in function of sex, mode of delivery, parity of the mother, type of pregnancy, date of birth in relation to the peak of the epidemic, and antibody titer against N protein. Results: All cord blood samples had detectable antibodies against N protein. The mean titers were significantly lower in newborns with risk factors for RSV severe LRTI (preterm infants, birth before the peak epidemic, multiparous mother). There was no association between antibody titer against the N protein and a protection against VS-LRTI. Conclusions The present study found that transfer of maternal antibodies against the RSV N protein may not provide a significant immune protection early in infancy. Clinical Trials Registration. NCT04144816.

Background: With the emergence of SARS-CoV-2, influenza surveillance systems in Spain were transformed into a new syndromic sentinel surveillance system. The Acute Respiratory Infection Surveillance System (SiVIRA in Spanish) is based on a sentinel network for Acute Respiratory Infection (ARI) surveillance in Primary care, and a network of sentinel hospitals for Severe ARI (SARI) surveillance in hospitals. Methods: Using a test-negative design and data from SARI admissions notified to SiVIRA between January 1 and October 3, 2021, we estimated COVID-19 VE against hospitalization, by age group, vaccine type, time since vaccination and SARS-CoV-2 variant. Results: VE was 89% (95% CI: 83-93) against COVID-19 hospitalization overall in persons aged 20 years and older. VE was higher for mRNA vaccines, and lower for those aged 80 years and older, with a decrease in protection beyond 3 months of completing vaccination, and a further decrease after 5 months. We found no differences between periods with circulation of Alpha or Delta SARS-CoV-2 variants, although variant-specific VE was slightly higher against Alpha. Conclusions: The SiVIRA surveillance system, with a network of sentinel hospitals in Spain was able to describe clinical and epidemiological characteristics of SARI hospitalizations, monitor the circulation of SARS-CoV-2 and other respiratory viruses, and provide data to measure the effectiveness of COVID-19 vaccination in the population under surveillance. Our results add to evidence of high VE of mRNA vaccines against severe COVID-19 and waning protection with time since vaccination.

We evaluated uptake and factors associated with COVID-19 vaccination among health workers (HWs) in Azerbaijan. Among 1,575 HWs, 73% had received at least one dose and 67% received two doses; all received CoronaVac. Factors associated with vaccination uptake included no previous COVID-19 infection, older age, belief in the vaccine’s safety, previous vaccination for influenza, having patient-facing roles, and good or excellent health by self-assessment. These findings could inform strategies to increase vaccination uptake as the campaign continues.

Background Human Parainfluenza viruses (HPIV) comprise of four members of the genetically distinct genera of Respirovirus (HPIV1&3) and Orthorubulavirus (HPIV2&4), causing significant upper and lower respiratory tract infections worldwide, particularly in children. However, despite frequent molecular diagnosis, they are frequently considered collectively or with HPIV4 overlooked entirely. We therefore investigated clinical and viral epidemiological distinctions of the relatively less prevalent Orthorubulaviruses HPIV2&4 at a regional UK hospital across four autumn/winter epidemic seasons. Methods A retrospective audit of clinical features of all HPIV2 or HPIV4 RT-PCR-positive patients, diagnosed between 1st September 2013 and 12th April 2017 was undertaken, alongside sequencing of viral genome fragments in a representative subset of samples. Results Infection was observed across all age groups, but predominantly in children under nine and adults over 40, with almost twice as many HPIV4 as HPIV2 cases. Fever, abnormal haematology, elevated C-reactive protein and hospital admission were more frequently seen in HPIV2 than HPIV4 infection. Each of the four seasonal peaks of either HPIV2, HPIV4 or both, closely matched that of RSV, occurring in November and December and preceding that of Influenza A. A subset of viruses were partially sequenced, indicating co-circulation of multiple subtypes of both HPIV2&4, but with little variation between each epidemic season or from limited global reference sequences. Conclusions Despite being closest known genetic relatives, our data indicates a potential difference in associated disease between HPIV2 and HPIV4, with more hospitalisation seen in HPIV2 mono-infected individuals, but a greater overall number of HPIV4 cases.

Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory infection and therefore, a major threat to global health. In the Philippines, RSV is the second most common respiratory viral pathogen next to rhinovirus among children with severe pneumonia. Since 2006, national influenza-like illness (ILI) and severe acute respiratory infection (SARI) surveillances have been mainly focused only on influenza viruses. The prevalence and genetic diversity of RSV in the last decades were not completely elucidated. This study determined the epidemiological and molecular characteristics of RSV among (ILI) and (SARI) cases of children in the Philippines. The Philippine National Influenza Centre (PNIC) collected oropharyngeal swab and nasopharyngeal swab samples from patients under the age of five who are presented with ILI and SARI for the period of 2006-2016. These swabs have been examined for RSV subgroup by multiplex real-time qRT-PCR. Sequencing and phylogenetic analyses were used to determine the genotype of RSV samples. A total of 1,036 samples were systematically selected and tested. Of these samples, 122 were RSV-positive at 11.8 % prevalence rate, and 58.2% (71/122) were classified as RSV-A. Six genotypes were identified, which included NA1 (27/122, 22.1%), ON1 (5/122, 4.1%), GA2 (1/122, 0.8%) and GA5 (1/123, 0.8%) for RSV-A; and BA2 (13/122, 10.7%) and BA9 (1/122, 0.8%) for RSV-B. Most RSV-related cases were significantly associated with pneumonia and bronchitis. The pattern of RSV activity in the Philippines resembles the transmission of RSV globally.

Background: In France, each year, influenza viruses are responsible for seasonal epidemics leading to 2-6 million cases. Influenza can cause severe disease that may lead to hospitalization or death. As severe disease may be due to the virus itself or to disease complications, estimating the burden of severe influenza is complex. The present study aimed at estimating the epidemiological and economic burden of severe influenza in France during eight consecutive influenza seasons (2010-2018). Methods: Influenza-related hospitalization and mortality data and patient characteristics were taken from the French hospital information database, PMSI. An ecological approach using cyclic regression models integrating the incidence of influenza syndrome from the Sentinelles Network supplemented the PMSI data analysis in estimating excess hospitalization and mortality (CépiDc – 2010-2015) and medical costs. Results: Each season, the average number of influenza-related hospitalizations was 18,979 (range: 8,627-44,024), with an average length of stay of 8 days. The average number of respiratory hospitalizations indirectly related with influenza (i.e., influenza-associated) was 31,490 (95% CI: 24,542-39,012), with an average cost of \euro141 million (range: 54-217); 70% of these hospitalizations and 77% of their costs concerned individuals ≥ 65 years of age (65+). More than 90% of excess mortality was in 65+ subjects. Conclusions: The combination of two complementary approaches allowed estimation of both influenza-related and associated hospitalizations and deaths and their burden in France, showing the substantial impact of complications. The present study highlighted the major public health burden of influenza and its severe complications, especially in 65+ subjects.

Background: While the high burden of illness caused by seasonal influenza in children and the elderly is well-recognized, less is known about the burden in adults 50-64 years of age. The lack of data for this age group is a key challenge in evaluating the cost-effectiveness of vaccination programs. We aimed to assess influenza-associated hospitalization and mortality rates, and case fatality rates for hospitalized cases among adults aged 50-64 years. Methods: This review was conducted according to the PRISMA: we searched MEDLINE, EMBASE, Cochrane, Web of Science, and grey literature for articles and reports published since 2010. Studies reporting rates of hospitalization and/or mortality associated with laboratory-confirmed influenza among adults 50-64 or 45-64 years of age for the 2010-11 through 2019-20 seasons were included. Results: Twenty studies from 13 countries were included. Reported hospitalization rates associated with laboratory-confirmed influenza 5.7 to 112.8 per 100,000. Rates tended to be higher in 2015-2019 compared to 2010-2014, and were higher in studies reporting data from high income versus low and middle-income countries. Mortality rates were reported in only one study, with rates ranging from 0.8-3.5 per 100,000 in four different seasons. The case fatality rate among those hospitalized with influenza, as reported by population-based studies, ranged from 1.3% to 5.6%. Conclusions: Seasonal influenza imposes a significant burden of morbidity in adults 50-64 years of age, but with high heterogeneity across seasons and geographic regions. Ongoing surveillance is required to improve estimates of burden to better inform influenza vaccination and other public health policy.

Background: Human respiratory syncytial virus (HRSV) is a major cause of severe viral acute respiratory illness and contributes significantly to severe pneumonia cases in Africa. Little is known about its spatial-temporal distribution as defined by its genetic diversity. Methods: A retrospective study conducted utilizing archived nasopharyngeal specimens from patients attending outpatient clinics in hospitals located in five demographically and climatically distinct regions of Kenya; Coast, Western, Highlands, Eastern and Nairobi. The viral total RNA was extracted and tested using multiplex real time RT-PCR (reverse transcriptase polymerase chain reaction). A segment of the G-gene was amplified using one-step RT-PCR and sequenced by Sanger di-deoxy method. Bayesian analysis of phylogeny was utilized and subsequently median joining methods for haplotype network reconstruction. Results: Three genotypes of HRSVA were detected; GA5 (14.0%), GA2 (33.1%) and NA1 (52.9%). HRSVA prevalence varied by location from 33% to 13.2% in the Highlands and the Eastern regions respectively. The mean nucleotide diversity (Pi(π)) varied by genotype: highest of 0.018 for GA5 and lowest of 0.005 for NA1. A total of 58 haplotypes were identified (GA5 10; GA2 20; NA1 28). These haplotypes were introduced into the population locally by single haplotypes and additional subsidiary seeds amongst the GA2 and the NA1 haplotypes. Conclusions: HRSVA was found across all the regions throughout the study period and comprised three genotypes; GA5, GA2 and NA1 genotypes. The genotypes were disproportionately distributed across the regions with GA5 gradually increasing towards the Western zones and decreasing towards the Eastern zones of the country.

Background: Data on disease burden of respiratory syncytial virus (RSV) associated acute lower respiratory infection (ALRI) among young children are limited in China. This study aimed to estimate the hospitalization rate of RSV-associated ALRI (RSV-ALRI) among children aged 0~59 months in Suzhou, China. Methods: We retrospectively identified all hospitalized ALRI children aged 0~59 months in Suzhou University Affiliated Children’s Hospital during January 2010 to December 2014. Detailed diagnosis and treatment data were collected by individual medical chart review. Referring to WHO influenza disease burden estimation method, we estimated the hospitalization rate of RSV-ALRI among children aged 0~59 months in Suzhou, China. Results: Among 28,209 ALRI cases, 19,317 (68.5%) were tested for RSV and the RSV positive proportion was 21.3% (4,107/19,317). The average hospitalization rate of RSV-ALRI for children aged 0~59 months was 14 (95% confidence interval [CI]:14~14)/1,000 children-years, for children aged 0~5, 6~11, 12~23, and 24~59 months were 70 (95%CI: 67~73), 31 (95%CI: 29~33), 11 (95%CI: 10~12), and 3 (95%CI: 3~3) /1,000 children-years, respectively. Conclusion: There is considerable RSV-ALRI hospitalization among children aged 0~59 months, particularly among children aged <1 years. An effective monoclonal antibody or vaccine is urgently needed to address the substantial hospitalization burden owing to RSV infection. Key words: Respiratory syncytial virus, Hospitalization rate, Acute lower respiratory infection, Children, China

Background. We sought to evaluate the impact of changes in estimates of COVID-19 vaccine effectiveness on the incidence of laboratory-confirmed infection among frontline workers at high risk for SARS-CoV-2. Methods. We analyzed data from a prospective frontline worker cohort to estimate the incidence of COVID-19 by month as well as the association of COVID-19 vaccination, occupation, demographics, physical distancing and mask use with infection risk. Participants completed baseline and quarterly surveys, and each week self-collected mid-turbinate nasal swabs and reported symptoms. Results. Among 1,018 unvaccinated and 3,531 fully vaccinated workers, the monthly incidence of laboratory-confirmed SARS-CoV-2 infection in January 2021 was 13.9 (95% confidence interval [CI]: 10.4-17.4), declining to 0.5 (95% CI -0.4-1.4) per 1000 person-weeks in June. By September 2021, when the Delta variant predominated, incidence had once again risen to 13.6 (95% CI 7.8-19.4) per 1000 person-weeks. In contrast, there was no reportable incidence among fully vaccinated participants at the end of January 2021, and incidence remained low until September 2021 when it rose modestly to 4.1 (95% CI 1.9-3.8) per 1000. Below average facemask use was associated with a higher risk of infection for unvaccinated participants during exposure to persons who may have COVID-19, and vaccinated participants during hours in the community. Conclusions. COVID-19 vaccination was significantly associated with a lower risk of SARS-CoV-2 infection despite Delta variant predominance. Our data demonstrate the added protective benefit of facemask use among both unvaccinated and vaccinated frontline workers.

Background Estimates of the disease burden associated with different respiratory viruses are severely limited in low- and middle-income countries, especially in Africa. Methods We estimated age-specific numbers and rates of medically and non-medically attended influenza-like illness (ILI) and severe respiratory illness (SRI) that were associated with influenza, respiratory syncytial virus (RSV), rhinovirus, human metapneumovirus, adenovirus, enterovirus and parainfluenza virus types 1-3 after adjusting for the attributable fraction (AF) of virus detection to illness in South Africa during 2013-2015. Rates were reported per 100,000 population. Results The mean annual rates were 51,383 and 4,196 for ILI and SRI, respectively. Of these, 26% (for ILI) and 46% (for SRI) were medically attended. Among outpatients with ILI, rhinovirus had the highest AF-adjusted rate (7,221), followed by influenza (6,443) and adenovirus (1,364); whereas, among inpatients with SRI, rhinovirus had the highest AF-adjusted rate (400), followed by RSV (247) and influenza (130). Rhinovirus (9,424) and RSV (2,026) had the highest AF-adjusted rates among children aged <5 years with ILI or SRI, respectively; whereas rhinovirus (757) and influenza (306) had the highest AF-adjusted rates among individuals aged ≥65 years with ILI or SRI, respectively Conclusions There was a substantial burden of ILI and SRI in South Africa during 2013-2015. Rhinovirus and influenza had a prominent disease burden among patients with ILI. Rhinovirus had the highest burden of illness among patients of any age with SRI, followed by RSV. RSV and influenza were the most prominent causes of SRI in children and the elderly, respectively.

Background: In response to the coronavirus disease (COVID-19) outbreak that unfolded across Europe in 2020, the World Health Organisation called for repurposing existing influenza surveillance systems to monitor COVID-19. This analysis aimed to compare descriptively the extent to which influenza surveillance systems were adapted and enhanced, and how COVID-19 surveillance could ultimately benefit or disrupt routine influenza surveillance. Methods: We used a previously developed framework in France, Germany, Italy, Spain and the United Kingdom to describe COVID-19 surveillance and its impact on influenza surveillance. The framework divides surveillance systems into 7 sub-systems and 20 comparable outcomes of interest, and uses 5 evaluation criteria based on WHO guidance. Information on influenza and COVID-19 surveillance systems were collected from publicly available resources shared by European and national public health agencies. Results: Overall, non-medically attended, virological, primary care and mortality surveillance were adapted in most countries to monitor COVID-19, whilst community, outbreak, and hospital surveillance were reinforced in all countries. Data granularity improved, with more detailed demographic and medical information recorded. A shift to systematic notification for cases and deaths enhanced both geographic and population representativeness whilst the sampling strategy benefited from the roll out of widespread molecular testing. Data communication was greatly enhanced, contributing to improved public awareness. Conclusions: Well-established influenza surveillance systems are a key component of pandemic preparedness and their upgrade allowed European countries to respond to the COVID-19 pandemic. However, uncertainties remain on how both influenza and COVID-19 surveillance can be jointly and durably implemented.

INTRODUCTION. Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract illness in young children and can also cause influenza-like illness (ILI). Here we investigated the epidemiological features of RSV infection in pediatric ILI cases in Lombardy (a region in Northern Italy accounting nearly 10-million inhabitants) from 2014-2015 to 2020-2021 winter seasons. MATERIAL AND METHODS. Data for this study were retrieved and statistically analyzed from the database of virological influenza surveillance of the regional reference laboratory for Lombardy within the Italian influenza surveillance network (InfluNet). RESULTS. RSV accounting for nearly 19% of pediatric ILI with a risk of infection nearly 2-fold greater than that of individuals ≥15 years. The RSV positivity rate increased to 28% considering 0-5 years old children. Although in children ≤5 years the risk of infection from influenza viruses resulted nearly 2-fold higher than the risk of RSV infection, the age group 4-6 months and 7-12 months showed 5-fold greater risk of infection from RSV than from influenza. Children ≤5 years of age with presence of one or more comorbidities had a nearly 5-fold greater risk of getting RSV infection than otherwise healthy 0-5 years old children. DISCUSSION. The use of the ILI sentinel surveillance allowed us to identify groups at higher risk of RSV and influenza infection and to define the start, duration, timing and intensity of the RSV and influenza community circulation, determining thresholds based on historical data. This surveillance approach can be implemented to assess the nearly real-time RSV circulation and impact.

In March 2021, Lao People’s Democratic Republic (Laos) reported an avian influenza A(H5N6) virus infection in a 5-year-old child identified through sentinel surveillance. This was the first human A(H5N6) infection reported outside of China. A multidisciplinary investigation undertook contact tracing and enhanced human and animal surveillance in surrounding villages and live bird markets. Seven Muscovy ducks tested positive for highly pathogenic avian influenza A(H5N6) viruses. Sequenced viruses belonged to clade 2.3.4.4h and were closely related to viruses detected in poultry in Vietnam, and to previous viruses detected in Laos. Surveillance and coordinated outbreak response remain essential to global health security.