Potential Effects on Elderly People From Nirsevimab Use in Infants.

Nirsevimab therapy has the potential to revolutionize infant respiratory syncytial virus (RSV) prophylaxis. But other populations suffering RSV, such the elderly or those over 60, may also be protected by using this novel antibody in the infant group. It is true that some studies link the use of nirsevimab to a reduction in the virus's ability to spread by lowering the viral load in infants as a result of the drug's long half-life. However, this protective effect may not be very significant because RSV transmission in the elderly typically comes from other elderly people or from school-aged children. Furthermore, RSV may be transmitted at any time of the year and not just during the period of nirsevimab protection due to its existence in human reservoirs. The reasons made here show that, even though nirsevimab treatment in infants may protect the elderly, this benefit would be limited and testimonial. Therefore, immunizing the elderly with currently licensed and developing vaccines should be a priority.

El uso de nirsevimab puede suponer una revolución en la prevención del virus respiratorio sincitial (VRS) en lactantes. Sin embargo, el uso de este nuevo anticuerpo en dicho grupo de edad podría proteger también a otros grupos que conviven con ellos, como por ejemplo las personas de edad avanzada o grupo de personas mayores de 60 años. Si bien es cierto que algunos estudios sugieren una disminución en la propagación del virus con el uso de nirsevimab, al reducir la carga viral en lactantes como consecuencia de la prolongada vida media del fármaco, este efecto protector podría ser de escasa relevancia, ya que la transmisión del VRS en personas de edad avanzada sucede en la mayor parte de los casos desde personas de la misma edad o desde niños en edad escolar. Adicionalmente, la presencia de VRS en reservorios humanos puede permitir que el VRS se transmita en cualquier época del año, no limitándose únicamente al periodo de protección de nirsevimab. Los argumentos aquí expuestos demuestran que, si bien el uso de nirsevimab en lactantes podría tener un efecto protector en las personas de edad avanzada, este solo sería testimonial y limitado. En consecuencia, debe priorizarse la inmunización de los pacientes de edad avanzada con las vacunas actualmente autorizadas y en desarrollo.

Association of viral loads of influenza A (H3N2) with age and care setting on presentation-a prospective study during the 2022-2023 influenza season in Spain.

OBJECTIVES: The aim of this study was to analyze the viral load (VL) using cycle threshold (Ct) in patients infected with influenza A (H3N2). METHODS: This prospective study was conducted during the 2022-2023 influenza season in sentinel, non-sentinel, and hospitalized patients of Castilla y León (Spain). Respiratory samples were obtained from nasopharyngeal swabs and analyzed by quantitative reverse transcription-polymerase chain reaction specific for influenza A (H3N2) to obtain the Ct value. RESULTS: A total of 1047 individuals were enrolled (174 [16.6%] sentinel, 200 [19.1%] non-sentinel, 673 [64.3%] hospitalized). The mean Ct value was lower in infants, young children, and in the elderly, with a sharp increase in the last from 65 years until 90 years. In addition, the lower Ct values were observed in non-sentinel patients and then in hospitalized patients, probably because non-sentinel are outpatients in the acute phase of the influenza infection. CONCLUSIONS: A higher VL (lower Ct value) is related to the extreme ages of life: children and the elderly. Furthermore, a higher VL is related with the care setting, being probably higher in outpatients because they are in the acute phase of the disease and slightly lower in hospitalized patients because they are attended during the post-acute phase.

Importancia de los Centros Nacionales de Gripe en la vigilancia de virus aviares de alta patogenicidad. El momento para One-Healthes ahora / Importance of National Influenza Centers in the surveillance of highly pathogenic avian viruses. The time for One-Health is now

Desde el año 1996 el subtipo de gripe aviar de alta patogenicidad A(H5N1) ha estado casi de forma ininterrumpida causando brotes en aves salvajes y domésticas, además de casos en seres humanos con una mortalidad cercana al 50%. Sin embargo, los años de mayor circulación han sido precisamente los años posteriores a la pandemia de COVID-19, en los que se han registrado diversos casos en humanos en lugares donde nunca antes habían aparecido, además de múltiples casos en mamíferos salvajes, domésticos y peri domésticos, que entrañan cierta preocupación por el riesgo que puede suponer para el salto del virus al ser humano través de cadenas de transmisión de mayor o menor extensión. El brote actual de A(H5N1) nos muestra que el concepto One-Health debe estar más vivo que nunca para aunar esfuerzos entre profesionales de diferentes sectores de la sanidad humana, animal y medio ambiental para evitar o minimizar estos riesgos, de tal forma que los laboratorios de referencia como los Centros Nacionales de Gripe dispongan de los medios humanos y materiales para ofrecerinformación rápida y relevante en el menor tiempo posible antes emergencias de este tipo. Las herramientas de diagnóstico y seguimiento que se deben utilizar en estos casos deben estar disponibles para cualquier eventualidad, y llegar más allá de los datos básicos debe ser una premisa indispensable para poder hacer un seguimiento pormenorizado que sirva para acotar brotes, limitar la difusión de la enfermedad, y ayudar al diseño de futuras vacunas pandémicas frente a virus aviares. (AU)

Since 1996, the highly pathogenic avian influenza subtype A(H5N1) has been causing almost uninterrupted outbreaks in wild and domestic birds, as well as cases in humans with a mortality rate close to 50%. However, the years of greatest circulation have been precisely the years following the COVID-19 pandemic, in which several cases have been recorded in humans in places where they had never appeared before, in addition to multiple cases in wild, domestic and peri-domestic mammals, which raise some concern about the risk that the virus may jump to humans through chains of transmission of greater or lesser extent. The current outbreak of A(H5N1) shows us that the One-Health concept should be more alive than ever to join efforts between professionals from different sectors of human, animal and environmental health to avoid or minimize these risks, so that reference laboratories such as the National Influenza Centers have the human and material resources to provide rapid and relevant information in the shortest possible time before emergencies of this type. The diagnostic and monitoring tools to be used in these cases must be available for any eventuality, and going beyond the basic data must be an indispensable premise to be able to carry out a detailed monitoring that serves to limit outbreaks, limit the spread of the disease, and help in the design of future pandemic vaccines against avian viruses. (AU)

Factors associated to the presence of headache in patients with influenza infection and its consequences: a 2010-2020 surveillance-based study.

Headache is a common symptom of influenza infection; however, its causes and consequences remain uncertain. In this manuscript, we analyzed which demographic and clinical factors were associated with the presence of headache during the course of influenza infection and whether patients with headache had a different prognosis, evaluated by need of hospitalization, sick leave or school absenteeism. The influence study (NCT05704335) was an observational study that analyzed data routinely collected from the Health Sentinel Network between 2010 and 2020. During the study period, 7832 cases were considered, among which, 5275 (67.4%) reported headache. The presence of headache was independently associated with myalgia (2.753; 95%CI: 2.456-3.087, P < 0.001), asthenia (OR: 1.958; 95%CI: 1.732-2.214, P < 0.001), shivering (OR: 1.925; 95%CI: 1.718-2.156, P < 0.001), nasopharyngeal erythema (OR: 1.505; 95%CI: 1.293-1.753, P < 0.001), fever (OR: 1.469; 95%CI: 1.159-1.861; P = 0.001), sudden onset of symptoms (OR: 1.380; 95%CI: 1.120-1.702, p = 0.004), female sex (OR: 1.134; 95%CI: 1.023-1.257, P = 0.018), and gastrointestinal symptoms (OR: 1.169; 95%CI: 1.039-1.315; P = 0.01). Patients with headache had a sex and age adjusted lower odds of being referred to the hospital (OR: 0.463; 95%CI: 0.264-0.812, P = 0.007) and a higher odd of having a sick leave and/or school absenteeism (absenteeism (OR: 1.342; 95%CI: 1.190-1.514, P < 0.001). In conclusion, the presence of headache seems associated with symptoms caused by the innate immune response. These findings support a headache pathophysiology linked with the innate immune response. Due to the potential negative consequences and its treatable nature, clinicians should systematically evaluate it and, whenever necessary, treat it too.

Early estimates of nirsevimab immunoprophylaxis effectiveness against hospital admission for respiratory syncytial virus lower respiratory tract infections in infants, Spain, October 2023 to January 2024.

The monoclonal antibody nirsevimab was at least 70% effective in preventing hospitalisations in infants with lower respiratory tract infections (LRTI) positive for respiratory syncytial virus (RSV) in Spain (Oct 2023-Jan 2024), where a universal immunisation programme began late September (coverage range: 79-99%). High protection was confirmed by two methodological designs (screening and test-negative) in a multicentre active surveillance in nine hospitals in three regions. No protection against RSV-negative LRTI-hospitalisations was shown. These interim results could guide public-health decision-making.

Impact on the time elapsed since SARS-CoV-2 infection, vaccination history, and number of doses, on protection against reinfection.

SARS-CoV-2 reinfections have been frequent, even among those vaccinated. The aim of this study is to know if hybrid immunity (infection + vaccination) is affected by the moment of vaccination and number of doses received. We conducted a retrospective study in 746 patients with a history of COVID-19 reinfection and recovered the dates of infection and reinfection and vaccination status (date and number of doses). To assess differences in the time to reinfection(tRI) between unvaccinated, vaccinated before 6 months, and later; and comparing one, two or three doses (incomplete, complete and booster regime) we performed the log-rank test of the cumulative incidence calculated as 1 minus the Kaplan-Meier estimator. Also, an adjusted Cox-regression was performed to evaluate the risk of reinfection in all groups. The tRI was significantly higher in those vaccinated vs. non-vaccinated (p < 0.001). However, an early incomplete regime protects similar time than not receiving a vaccine. Vaccination before 6 months after infection showed a lower tRI compared to those vaccinated later with the same regime (adj-p < 0.001). Actually, early vaccination with complete and booster regimes provided lower length of protection compared to vaccinating later with incomplete and complete regime, respectively. Vaccination with complete and booster regimes significantly increases the tRI (adj-p < 0.001). Vaccination increases the time it takes for a person to become reinfected with SARS-CoV-2. Increasing the time from infection to vaccination increases the time in which a person could be reinfected and reduces the risk of reinfection, especially in complete and booster regimes. Those results emphasize the role of vaccines and boosters during the pandemic and can guide strategies on future vaccination policy.

InfluenCEF study: Clinical phenotype and duration of headache attributed to influenza infection.

INTRODUCTION: Headache is a frequent symptom of infections. We aimed to characterize the clinical phenotype and duration of headache attributed to influenza infection. METHODS: Prospective cohort study done in 53 primary care centers between January and April 2023. Patients were included if they had a confirmed influenza diagnosis, were older than 15 years and had a new-onset headache. Patients' demographics, prior medical history, headache phenotype and duration, associated symptoms and patients' outcomes were assessed. The International Classification of Headache Disorders criteria for headache attributed to a systemic viral infection, migraine and tension-type headache were assessed. RESULTS: Of the 478 patients 75 fulfilled eligibility criteria. The mean age was 43, 56% were men, and 27% had a prior headache history. The headache phenotype was a bilateral headache (52%), with frontal topography (48%), pressing quality (61%), moderate intensity, rhinorrhea (79%), nasal congestion (76%), and photophobia (59%). All patients fulfilled headache attributed to acute systemic viral infection criteria, 43% fulfilled migraine criteria and 31% tension-type headache criteria. The median duration of the headache was four (Inter-quartile range: two-six) days. CONCLUSION: The clinical phenotype of headache attributed to influenza infection was similar to other infections, with more pronounced cranial autonomic symptoms. The headache was an early symptom and was self-limited within a few days.Trial Registration: The study protocol is registered in ClinicalTrial.gov (NCT05704335).

The Impact of the COVID-19 Pandemic on Influenza Vaccination Attitudes and Actions in Spain's Adult Population.

Seasonal influenza is an acute respiratory infection caused by the influenza virus which constitutes a significant public health issue associated with high morbidity and mortality. The aim of this study was to investigate changes in attitudes, perceptions, and practices regarding influenza vaccination in the Spanish adult population during the COVID-19 pandemic, as well as their vaccination intentions, with special attention paid to those over 65 years old and in high-risk groups. To this end, a cross-sectional study was conducted through 2219 telephone interviews, and the results were compared with results obtained a year earlier. Regarding the reasons for deciding to get vaccinated in the 2022/23 season, a significant increase was observed in vaccine confidence (36.7% vs. 42.8%), social responsibility (32.5% vs. 43.8%), and in awareness of the importance of vaccination due to COVID-19 (21.7% vs. 25.4%). Advanced age (OR 2.8, 95% CI 2.0-3.9), belonging to high-risk groups (OR 2.7, 95% CI 2.0-3.7), and prior vaccination (OR 25.3, 95% CI 19.5-32.7) emerged as significant predictors for the intent to receive the influenza vaccine in the 2022/23 season. Continuously observing shifts in perceptions and behaviors related to influenza immunization is crucial to pinpoint factors that may influence the willingness to receive the vaccine and, in this way, design public health strategies that achieve a greater acceptance of it.

Nuevos y viejos aspectos de la gripe / Old and new aspects of influenza

La gripe es una enfermedad infecciosa clásica que, a través de la continua variación que experimentan los virus que la producen, nos impone nuevos retos que debemos solventar con la mayor celeridad posible. La pandemia de COVID-19 ha modificado sustancialmente el comportamiento de la gripe y de otros virus respiratorios, y en los próximos años tendremos que convivir con un nuevo patógeno que probablemente interactuará con los existentes bajo un prisma que de momento no alcanzamos a vislumbrar. Sin embargo, los conocimientos previos a la pandemia nos permiten focalizar en los aspectos que se deben modificar para que la gripe sea un reto asumible a futuro. En esta revisión se hace hincapié en los aspectos más relevantes de la epidemiología, la carga de enfermedad, el diagnóstico y la prevención mediante vacunas, y cómo fluyen las tendencias científicas y clínicas en dichos aspectos desde lo anteriormente conocido a los retos futuros (AU)

Influenza is a classic infectious disease that, through the continuous variation of the viruses that produce it, imposes new challenges that we must solve as quickly as possible. The COVID-19 pandemic has substantially modified the behavior of influenza and other respiratory viruses, and in the coming years we will have to coexist with a new pathogen that will probably interact with existing pathogens in a way that we cannot yet glimpse. However, knowledge prior to the pandemic allows us to focus on the aspects that must be modified to make influenza an acceptable challenge for the future. In this review, emphasis is placed on the most relevant aspects of epidemiology, disease burden, diagnosis, and vaccine prevention, and how scientific and clinical trends in these aspects flow from the previously known to future challenges (AU)

Long-term influenza antibodies profiles in previously vaccinated and non-vaccinated adults.

The aim of this work is to describe the dynamics of influenza antibodies after vaccination in adults. We conducted a case-cohort serological study in the automobile manufacturing plants of the Renault España S.A. group in Valladolid and Palencia (Spain), including 550 workers (66.9%) previously vaccinated against influenza (group V), and 272 (33.1%) never vaccinated (group NV). A pre-vaccination serum sample was collected, another after 30-40 days and another after 6 months. The dynamics of antibodies were analyzed. A lower seroprotection of NV before vaccination was observed, but an antibody response between 2 and 4 times higher than in V was assessed. After 6 months, antibodies declined in both groups until equalize. Antibodies titers decrease with age, and no differences were found among underlying pathologies. Adults never vaccinated against influenza had lower seroprotection than those previously vaccinated, but influenza vaccination produces a more intense serological response in them, acquiring significantly higher antibody titers than those previously vaccinated. The antibodies, although in lower titers, persist and equalize among both groups at least 6 months after vaccination, which allows the individual to be protected during the entire circulation of the influenza virus in the same season.

Old and new aspects of influenza. / Nuevos y viejos aspectos de la gripe.

Influenza is a classic infectious disease that, through the continuous variation of the viruses that produce it, imposes new challenges that we must solve as quickly as possible. The COVID-19 pandemic has substantially modified the behavior of influenza and other respiratory viruses, and in the coming years we will have to coexist with a new pathogen that will probably interact with existing pathogens in a way that we cannot yet glimpse. However, knowledge prior to the pandemic allows us to focus on the aspects that must be modified to make influenza an acceptable challenge for the future. In this review, emphasis is placed on the most relevant aspects of epidemiology, disease burden, diagnosis, and vaccine prevention, and how scientific and clinical trends in these aspects flow from the previously known to future challenges.

Group 1 and group 2 hemagglutinin stalk antibody response according to age.

Objective: Antibodies elicited by seasonal influenza vaccines mainly target the head of hemagglutinin (HA). However, antibodies against the stalk domain are cross-reactive and have been proven to play a role in reducing influenza disease severity. We investigated the induction of HA stalk-specific antibodies after seasonal influenza vaccination, considering the age of the cohorts. Methods: A total of 166 individuals were recruited during the 2018 influenza vaccine campaign (IVC) and divided into groups: <50 (n = 14), 50-64 (n = 34), 65-79 (n = 61), and ≥80 (n = 57) years old. Stalk-specific antibodies were quantified by ELISA at day 0 and day 28 using recombinant viruses (cH6/1 and cH14/3) containing an HA head domain (H6 or H14) from wild bird origin with a stalk domain from human H1 or H3, respectively. The geometric mean titer (GMT) and the fold rise (GMFR) were calculated, and differences were assessed using ANOVA adjusted by the false discovery rate (FDR) and the Wilcoxon tests (p <0.05). Results: All age groups elicited some level of increase in anti-stalk antibodies after receiving the influenza vaccine, except for the ≥80-year-old cohort. Additionally, <65-year-old vaccinees had higher group 1 antibody titers versus group 2 before and after vaccination. Similarly, vaccinees within the <50-year-old group showed a higher increase in anti-stalk antibody titers when compared to older individuals (≥80 years old), especially for group 1 anti-stalk antibodies. Conclusion: Seasonal influenza vaccines can the induction of cross-reactive anti-stalk antibodies against group 1 and group 2 HAs. However, low responses were observed in older groups, highlighting the impact of immunosenescence in adequate humoral immune responses.

Impact of COVID-19 on Adherence to Treatment in Patients with HIV.

In patients with human immunodeficiency virus (HIV), adherence to treatment is affected by the adverse effects of treatment, the presence of additional comorbidities, the complexity of dosage, and family and community support. However, one recent circumstance that was likely to have influenced therapeutic adherence was the COVID-19 pandemic and the applied containment measures. An observational retrospective study of a sample of patients with HIV was conducted to establish the relationship between sociodemographic, clinical, and pharmacological variables and therapeutic adherence before and after the pandemic. Adherence was measured using the validated simplified medication adherence questionnaire (SMAQ) and medication possession rate. A statistical analysis was performed to determine the mean, standard deviation, and median of the quantitative variables and the frequencies of the qualitative variables, and the relationship between the dependent and independent variables was analysed using the chi-squared test and Student's t-test. No statistically significant differences were found between treatment adherence measured before and 22 months after the start of the pandemic. Sex, occupation, treatment regimen, viral load levels, and COVID-19 disease status did not influence adherence during either period. However, the age of patients with HIV had an impact on adherence during both periods (p = 0.008 and p = 0.002, respectively), with the age group under 45 years being less adherent. In addition, experiencing adverse drug reactions (ADRs) was shown to have an impact on adherence before the pandemic (p = 0.006) but not afterwards. The COVID-19 pandemic was not shown to have an impact on the degree of adherence to antiretroviral treatment in patients with HIV. Instead, adherence was influenced by patient age and ADR occurrence; therefore, measures must be taken in this regard. The SMAQ demonstrated sensitivity in assessing adherence.

Adjuvants for COVID-19 Vaccines.

In recent decades, the improvement of traditional vaccines has meant that we have moved from inactivated whole virus vaccines, which provoke a moderate immune response but notable adverse effects, to much more processed vaccines such as protein subunit vaccines, which despite being less immunogenic have better tolerability profiles. This reduction in immunogenicity is detrimental to the prevention of people at risk. For this reason, adjuvants are a good solution to improve the immunogenicity of this type of vaccine, with much better tolerability profiles and a low prevalence of side effects. During the COVID-19 pandemic, vaccination focused on mRNA-type and viral vector vaccines. However, during the years 2022 and 2023, the first protein-based vaccines began to be approved. Adjuvanted vaccines are capable of inducing potent responses, not only humoral but also cellular, in populations whose immune systems are weak or do not respond properly, such as the elderly. Therefore, this type of vaccine should complete the portfolio of existing vaccines, and could help to complete vaccination against COVID-19 worldwide now and over the coming years. In this review we analyze the advantages and disadvantages of adjuvants, as well as their use in current and future vaccines against COVID-19.

Evolution of antibody profiles against SARS-CoV-2 in experienced and naïve vaccinated elderly people.

Introduction: The third dose of the COVID-19 vaccine is especially necessary in people over 65 years of age due to their lower immune response. Methods: We designed a multicentre, prospective observational study including 98 people ≤65 years old who lived in two nursing homes in Valladolid, Spain. One of the groups had previous experience with SARS-CoV-2 (n=68;69.4%) and the other was naïve (n=30;30.6%). We evaluated the response to the three doses of the Comirnaty vaccine and the dynamics of antibodies during 5 consecutive serum samplings: 2 after the first two doses of vaccination, one three months after the first dose, another at 6 months and the last one month after the third dose. IgG antibodies against SARS-CoV-2 S1, RBD and N antigens were analysed. Results: Both groups increased the level of Abs against S1 and RBD, but the experienced group showed a 130-fold higher humoral response due to hybrid immunisation (infection+vaccination). The response to vaccination with Comirnaty against COVID-19 was higher in those ≤65 years with previous experience than those who were naïve. However, the amount of antibodies against S1 and RBD equalised at 6 months. After the third dose, both groups raised the amount of antibodies to a similar level. The reinfections suggested by the analysis of antibodies against N were frequent in both groups. Discussion: The third dose showed a clear benefit for elderly people, with the reinforcement of the antibody levels after the decline suffered after six months of the first two doses.

An external quality assessment feasibility study; cross laboratory comparison of haemagglutination inhibition assay and microneutralization assay performance for seasonal influenza serology testing: A FLUCOP study.

Introduction: External Quality Assessment (EQA) schemes are designed to provide a snapshot of laboratory proficiency, identifying issues and providing feedback to improve laboratory performance and inter-laboratory agreement in testing. Currently there are no international EQA schemes for seasonal influenza serology testing. Here we present a feasibility study for conducting an EQA scheme for influenza serology methods. Methods: We invited participant laboratories from industry, contract research organizations (CROs), academia and public health institutions who regularly conduct hemagglutination inhibition (HAI) and microneutralization (MN) assays and have an interest in serology standardization. In total 16 laboratories returned data including 19 data sets for HAI assays and 9 data sets for MN assays. Results: Within run analysis demonstrated good laboratory performance for HAI, with intrinsically higher levels of intra-assay variation for MN assays. Between run analysis showed laboratory and strain specific issues, particularly with B strains for HAI, whilst MN testing was consistently good across labs and strains. Inter-laboratory variability was higher for MN assays than HAI, however both assays showed a significant reduction in inter-laboratory variation when a human sera pool is used as a standard for normalization. Discussion: This study has received positive feedback from participants, highlighting the benefit such an EQA scheme would have on improving laboratory performance, reducing inter laboratory variation and raising awareness of both harmonized protocol use and the benefit of biological standards for seasonal influenza serology testing.

Possible Mpox Protection from Smallpox Vaccine-Generated Antibodies among Older Adults.

Smallpox vaccination may confer cross-protection to mpox. We evaluated vaccinia virus antibodies in 162 persons ≥50 years of age in Spain; 68.5% had detectable antibodies. Highest coverage (78%) was among persons 71-80 years of age. Low antibody levels in 31.5% of this population indicates that addressing their vaccination should be a priority.

Immunodominance hierarchy after seasonal influenza vaccination.

Current influenza vaccines elicit humoral immune responses against the haemagglutinin (HA) protein of influenza viruses. Different antigenic sites have been identified in the HA head as the main target of haemagglutination inhibition (HAI) antibodies (Sb, Sa, Cb, Ca1 and Ca2). To determine immunodominance (ID) of each site, we performed HAI assays against a panel of mutant viruses, each one lacking one of the classically defined antigenic sites and compared it to wild type (Wt). Agglutinating antibodies were measured before and after vaccination in two different regimens: Quadrivalent Influenza Vaccine (QIV) in young adults; or Adjuvanted Trivalent influenza Vaccine (ATIV) in elderly. Our results showed abs before vaccination were significantly reduced against all antigenic sites in the elderly and only against Sb and Ca2 in young adults compared to the Wt. Humoral response to vaccination was significantly reduced against all viruses compared to the Wt for the ATIV and only against Sb and Ca2 for the QIV. The strongest reduction was observed in all cases against Sb followed by Ca2. We concluded that ID profile was clearly dominated by Sb followed by Ca2. Additionally, the antibody response evolved with age, increasing the response towards less immunodominant epitopes of HA head. Adjuvants can positively influence ID hierarchy broadening responses towards multiple antigenic sites of HA head.