Engineered Nanoparticle Applications for Recombinant Influenza Vaccines.

Influenza viruses cause seasonal epidemics and represent a pandemic risk. With current vaccine methods struggling to protect populations against emerging strains, there is a demand for a next-generation flu vaccine capable of providing broad protection. Recombinant biotechnology, combined with nanomedicine techniques, could address this demand by increasing immunogenicity and directing immune responses toward conserved antigenic targets on the virus. Various nanoparticle candidates have been tested for use in vaccines, including virus-like particles, protein and carbohydrate nanoconstructs, antigen-carrying lipid particles, and synthetic and inorganic particles modified for antigen presentation. These methods have yielded some promising results, including protection in animal models against antigenically distinct influenza strains, production of antibodies with broad reactivity, and activation of potent T cell responses. Based on the evidence of current research, it is feasible that the next generation of influenza vaccines will combine recombinant antigens with nanoparticle carriers.

Comparative pharmacokinetic and biodistribution study of two distinct squalene-containing oil-in-water emulsion adjuvants in H5N1 influenza vaccines.

BACKGROUND: In recent years, there has been great interest from academia, industry and government scientists for an increased understanding of the mode of action of vaccine adjuvants to characterize the safety and efficacy of vaccines. In this context, pharmacokinetic (PK) and biodistribution studies are useful for quantifying the concentration of vaccine adjuvants in mechanistically or toxicologically relevant target tissues. METHODS: In this study, we conducted a comparative analysis of the PK and biodistribution profile of radiolabeled squalene for up to 336 h (14 days) after intramuscular injection of mice with adjuvanted H5N1 influenza vaccines. The evaluated adjuvants included an experimental-grade squalene-in-water (SQ/W) emulsion (AddaVax®) and an adjuvant system (AS03®) that contained squalene and α-tocopherol in the oil phase of the emulsion. RESULTS: The half-life of the initial exponential decay from quadriceps muscle was 1.5 h for AS03 versus 12.9 h for AddaVax. At early time points (1-6 h), there was about a 10-fold higher concentration of labeled squalene in draining lymph nodes following AS03 injection compared to AddaVax. The area-under-concentration curve up to 336 h (AUC0-336hr) and peak concentration of squalene in spleen (immune organ) was about 1.7-fold higher following injection of AS03 than AddaVax. The peak systemic tissue concentration of squalene from the two adjuvants, with or without antigen, remained below 1% of injected dose for toxicologically relevant target tissues, such as spinal cord, brain, and kidney. The pharmacokinetics of AS03 was unaffected by the presence of H5N1 antigen. CONCLUSIONS: This study demonstrates a rapid decline of AS03 from the quadriceps muscles of mice as compared to conventional SQ/W emulsion adjuvant, with an increased transfer to mechanistically relevant tissues such as local lymph nodes. Systemic tissue exposure to potential toxicological target tissues was very low.

Efecto de la vacunación antigripal en trabajadores de atención primaria y población general de Gran Canaria: estudio transversal / Effect of influenza vaccination in Primary Healthcare workers and the general population in Gran Canaria: A cross-sectional study

Objetivo: Estimar el efecto de la vacunación antigripal en los trabajadores de atención primaria y en la población atendida durante la campaña de vacunación antigripal 2015/2016. Diseño: Estudio transversal. Emplazamiento: Todos los centros asistenciales de atención primaria del Área de Salud de Gran Canaria. Participantes: Un total de 1.868 profesionales (33,5% hombres; 66,5% mujeres) y 795.605 personas de la población general (49,4% hombres; 50,6% mujeres). Mediciones principales: En profesionales, las variables de resultado fueron: declaraciones de gripe al Sistema de Vigilancia Epidemiológica y días de incapacidad temporal por enfermedad; en población general: gripes declaradas y coberturas vacunales en función del estado vacunal del sanitario. Se estimó la magnitud de asociación entre la vacunación y la morbilidad mediante modelos de regresión logística. Resultados: Los profesionales sanitarios que no se vacunaron tuvieron un riesgo de tener gripe 1,7 veces superior al de los profesionales que se vacunaron, aunque la diferencia no fue estadísticamente significativa; en población general se encontró una asociación significativa solo en mujeres (OR: 1,3; IC95%: 1,1-1,5). La cobertura poblacional fue significativamente mayor cuando médico y enfermero estaban vacunados (OR: 1,3; IC 95%: 1,3-1,3), y el número de gripes declaradas disminuyó cuando el enfermero estaba vacunado (OR: 0,9; IC 95%: 0,9-0,9). Conclusiones: Se observó un posible efecto protector de la vacunación antigripal en la población general, así como una influencia del estado vacunal de los sanitarios en las coberturas de los pacientes. Aun así, las bajas coberturas registradas apuntan a una necesidad de implementar medidas que propicien una actitud más favorable frente a la vacunación antigripal

Objective: To estimate the effect of the influenza vaccination in Primary Healthcare workers and the general population vaccinated during the 2015/2016 campaign. Design: Cross-sectional study. Setting: All the Primary Healthcare centres within the Gran Canaria healthcare region. Participants: A total of 1,868 Primary Healthcare workers (33.5% men; 66.5% women) and 795,605 individuals from the general population (49.4% men; 50.6% women). Principal measurements: The outcome variables in Primary Healthcare workers were: influenza cases reported to the Epidemiological Surveillance System, and the sick leave days due to illness. In the general population: reported flu cases and vaccination coverage in connection with the vaccination status of the healthcare professional. The magnitude of association between vaccination and morbidity was estimated applying logistic regression models. Results: Although not statistically significant, healthcare professionals that were not vaccinated had 1.7-fold increase in the risk of having influenza than those vaccinated. In the general population the association was significant in the female population (OR: 1.3; 95% CI: 1.1-1.5). Population coverage was significantly higher when both the doctor and nurse were vaccinated (OR: 1.3; 95 %CI: 1.3-1.3), and reported flu cases decreased when the nurse was vaccinated (OR: 0.9; 95%CI: 0.9-0.9). Conclusion: A possible protective effect of influenza vaccination was observed in the general population, as well as an influence of Primary Healthcare workers on the patients regarding this. Even so, the low coverages registered point to a need to implement measures that may lead to a more favourable attitude towards influenza vaccination

Vaccination with influenza hemagglutinin-loaded ceramic nanoporous microneedle arrays induces protective immune responses.

Microneedle arrays (MNAs) are a promising mean to administer vaccines. Without the need of highly trained personnel, MNAs can be applied to deliver vaccines into the dermis, which is well equipped to initiate potent immune responses. While vaccination using dissolving microneedle arrays has been extensively investigated, the use of solid nanoporous MNAs (npMNAs) to deliver vaccines remained largely unexplored. In this report we investigated whether npMNAs with an average pore size of 80 nm, can be used for influenza vaccination based on recombinant hemagglutinin (HA) protein of the 2009 pandemic H1N1 (pH1N1) virus. Fluorescently labeled HA loaded in the npMNAs was effectively delivered into the skin of mouse ears, as a result of a diffusion-based process. Compared to intramuscular immunization, intradermal HA vaccination of mice using npMNAs elicited high levels of HA antigen specific antibodies, with pH1N1 hemagglutination inhibition and neutralization activity. Moreover, mice vaccinated with pH1N1 HA loaded npMNAs were completely protected against a potentially lethal challenge with mouse adapted pH1N1 virus. These results illustrate that intradermal subunit vaccine immunization using npMNAs is a promising approach to facilitate effective vaccination.

Pharmacokinetics and biodistribution of squalene-containing emulsion adjuvant following intramuscular injection of H5N1 influenza vaccine in mice.

Squalene is a component of oil-in-water emulsion adjuvants developed for potential use in some influenza vaccines. The biodistribution of the squalene-containing emulsion adjuvant (AddaVax™) alone and as part of complete H5N1 vaccine was quantified in mechanistically and toxicologically relevant target tissues up to 336 h (14 days) following injection into quadriceps muscle. At 1 h, about 55% of the intramuscularly injected dose of squalene was detected in the local quadriceps muscles and this decreased to 26% at 48 h. Twenty-four hours after the injection, approximately 5%, 1%, and 0.6% of the injected dose was detected in inguinal fat, draining lymph nodes, and sciatic nerve, respectively. The peak concentration for kidney, brain, spinal cord, bone marrow, and spleen was each less than 1% of the injected dose, and H5N1 antigen did not significantly alter the biodistribution of squalene to these tissues. The area-under-blood-concentration curve (AUC) and peak blood concentration (Cmax) of squalene were slightly higher (20-25%) in the presence of H5N1 antigen. A population pharmacokinetic model-based statistical analysis identified body weight and H5N1 antigen as covariates influencing the clearance of squalene. The results contribute to the body of knowledge informing benefit-risk analyses of squalene-containing emulsion vaccine adjuvants.

Protection against H5N1 Influenza Virus Induced by Matrix-M Adjuvanted Seasonal Virosomal Vaccine in Mice Requires Both Antibodies and T Cells.

BACKGROUND: It remains important to develop the next generation of influenza vaccines that can provide protection against vaccine mismatched strains and to be prepared for potential pandemic outbreaks. To achieve this, the understanding of the immunological parameters that mediate such broad protection is crucial. METHOD: In the current study we assessed the contribution of humoral and cellular immune responses to heterosubtypic protection against H5N1 induced by a Matrix-M (MM) adjuvanted seasonal influenza vaccine by serum transfer and T-cell depletion studies. RESULTS: We demonstrate that the heterosubtypic protection against H5N1 induced by MM adjuvanted vaccine is partially mediated by antibodies. The serum contained both H5N1 cross-reactive hemagglutinin (HA)- and neuraminidase (NA)-specific antibodies but with limited virus neutralizing and no hemagglutination inhibiting activity. The cross-reactive antibodies induced antibody-dependent cellular cytotoxicity (ADCC) in vitro, suggesting a role for the Fc part of the antibodies in protection against H5N1. Besides H5N1 specific antibody responses, cross-reactive HA- and NA-specific T-cell responses were induced by the adjuvanted vaccine. T-cell depletion experiments demonstrated that both CD4+ and CD8+ T cells contribute to protection. CONCLUSION: Our study demonstrates that cross-protection against H5N1 induced by MM adjuvanted seasonal virosomal influenza vaccine requires both the humoral and cellular arm of the immune system.

Non-clinical safety and biodistribution of AS03-adjuvanted inactivated pandemic influenza vaccines.

Pandemic-influenza vaccines containing split-inactivated-virus antigen have been formulated with the immunostimulatory Adjuvant System AS03 to enhance the antigen immunogenicity and reduce antigen content per dose. AS03 is an oil-in-water emulsion containing α-tocopherol, squalene and polysorbate 80. To support the clinical development of AS03-adjuvanted pandemic-influenza vaccines, the local and systemic toxicity of test articles containing split-influenza A(H5N1) and/or AS03 were evaluated after 3-4 intramuscular (i.m.) injections in rabbits. Treatment-related effects were restricted to mild inflammatory responses and were induced primarily by the test articles containing AS03. The injection-site inflammation was mild at 3 days, and minimal at 4 weeks after the last injection; and was reflected by signs of activation in the draining lymph nodes and by systemic effects in the blood including a transient increase of neutrophils. In addition, a study in mice explored the biodistribution of A(H5N1) vaccines or AS03 through radiolabelling the antigen or constituents of AS03 prior to injection. In this evaluation, 57-73% of AS03's principal constituents had cleared from the injection site 3 days after injection, and their different clearance kinetics were suggestive of AS03's dissociation. All these AS03 constituents entered into the draining lymph nodes within 30 min after injection. In conclusion, the administration of repeated doses of the H5N1/AS03 vaccine was well tolerated in the rabbit, and was primarily associated with transient mild inflammation at the injection site and draining lymph nodes. The biodistribution kinetics of AS03 constituents in the mouse were consistent with AS03 inducing this pattern of inflammation.

Influencia del criterio de selección de pacientes para la toma de frotis en la estimación de la efectividad de la vacuna antigripal / Influence of distinct criteria for selecting patients for swabbing on estimation of the effectiveness of the influenza vaccine

Objetivo: estimar la efectividad de la vacuna antigripal según el criterio de selección en la toma de frotis. Método: estudio de casos y controles de casos confirmados (n = 909) y controles negativos para gripe (n = 732) en las temporadas 2010-2011 a 2012-2013 en Navarra. La efectividad ajustada de la vacuna se estimó incluyendo todos los frotis de pacientes con síndrome gripal y seleccionando sólo los dos primeros por médico y semana. Resultados: los dos primeros pacientes por médico y semana estaban menos vacunados (7,9% frente a 12,5%, p = 0,021) y se confirmaron menos para gripe (53,6% frente a 66,4%, p <0,001), diferencias que se redujeron al ajustar por covariables. La efectividad de la vacuna calculada con todos los frotis fue del 49% (intervalo de confianza del 95% [IC95%]: 23-66%) y del 55% (IC95%: 27-72%) al analizar los dos primeros frotis semanales. Conclusión: la selección de los primeros pacientes semanales puede sesgar la efectividad de la vacuna antigripal, aunque en las temporadas analizadas este sesgo fue pequeño

Objective: to estimate the effectiveness of the influenza vaccine under different criteria for selecting patients for swabbing. Method: a case-control study was performed of laboratory-confirmed cases (n = 909) and negative controls for influenza (n = 732) in the 2010-2011 to 2012-2013 seasons in Navarre (Spain). The adjusted vaccine effectiveness was estimated by including all swabs from patients with influenza-like-illness and selecting only the first two cases per physician and week. Results: the first two patients per physician and week were less frequently vaccinated against influenza (7.9% vs. 12.5%, p = 0.021) and less often received confirmation of influenza (53.6% vs. 66.4%, p <0.001) than subsequent patients. These differences decreased after adjustment for covariates. The effectiveness of the influenza vaccine was 49% (95% CI: 23-66%) when all swabs were included and was 55% (95% CI: 27-72%) when we selected the first two swabs per week and physician. Conclusion: the selection of the first two patients per physician and week may bias assessment of the effectiveness of the influenza vaccine, although this bias was small in the seasons analyzed

Novel vaccine delivery system induces robust humoral and cellular immune responses based on multiple mechanisms.

Aiming to enhance the immunogenicity of H5N1 split vaccine, the development of a novel antigen delivery system based on quaternized chitosan hydrogel microparticles (Gel MPs) with multiple mechanisms of immunity enhancement is attempted. Gel MPs based on ionic cross-linking are prepared in a simple and mild way. Gel MPs are superior as a vaccine delivery system due to their ability to: 1) enhance cellular uptake and endosomal escape of antigens in dendritic cells (DCs); 2) significantly activate DCs; 3) form an antigen depot and recruit immunity cells to improve antigen capture. Further in vivo investigation shows that Gel MPs, in comparison to aluminum salts (Alum), LPS, and covalent cross-linking quaternized chitosan MPs (GC MPs), induce higher humoral and cellular immune responses with a mixed Th1/Th2 immunity. In conclusion, these results demonstrate that Gel MPs are efficient antigen delivery vehicles based on multiple mechanisms to enhance both humoral and cellular immune responses against H5N1 split antigen.

Intranasal vaccination promotes detrimental Th17-mediated immunity against influenza infection.

Influenza disease is a global health issue that causes significant morbidity and mortality through seasonal epidemics. Currently, inactivated influenza virus vaccines given intramuscularly or live attenuated influenza virus vaccines administered intranasally are the only approved options for vaccination against influenza virus in humans. We evaluated the efficacy of a synthetic toll-like receptor 4 agonist CRX-601 as an adjuvant for enhancing vaccine-induced protection against influenza infection. Intranasal administration of CRX-601 adjuvant combined with detergent split-influenza antigen (A/Uruguay/716/2007 (H3N2)) generated strong local and systemic immunity against co-administered influenza antigens while exhibiting high efficacy against two heterotypic influenza challenges. Intranasal vaccination with CRX-601 adjuvanted vaccines promoted antigen-specific IgG and IgA antibody responses and the generation of polyfunctional antigen-specific Th17 cells (CD4(+)IL-17A(+)TNFα(+)). Following challenge with influenza virus, vaccinated mice transiently exhibited increased weight loss and morbidity during early stages of disease but eventually controlled infection. This disease exacerbation following influenza infection in vaccinated mice was dependent on both the route of vaccination and the addition of the adjuvant. Neutralization of IL-17A confirmed a detrimental role for this cytokine during influenza infection. The expansion of vaccine-primed Th17 cells during influenza infection was also accompanied by an augmented lung neutrophilic response, which was partially responsible for mediating the increased morbidity. This discovery is of significance in the field of vaccinology, as it highlights the importance of both route of vaccination and adjuvant selection in vaccine development.

Transdermal delivery of molecules is limited by full epidermis, not just stratum corneum.

PURPOSE: Most methods to increase transdermal drug delivery focus on increasing stratum corneum permeability, without addressing the need to increase permeability of viable epidermis. Here, we assess the hypothesis that viable epidermis offers a significant permeability barrier that becomes rate limiting upon sufficient permeabilization of stratum corneum. METHODS: We tested this hypothesis by using calibrated microdermabrasion to selectively remove stratum corneum or full epidermis in pig and human skin, and then measuring skin permeability to a small molecule (sulforhodamine) and macromolecules (bovine serum albumin, insulin, inactivated influenza vaccine) in vitro. RESULTS: We found that removal of stratum corneum dramatically increased skin permeability to all compounds tested. However, removal of full epidermis increased skin permeability by another 1-2 orders of magnitude. We also studied the effects of removing skin tissue only from localized spots on the skin surface by covering skin with a mask containing 125-µm holes during tissue removal. Skin permeabilized in this less-invasive way showed similar results. This suggests that microdermabrasion of skin using a mask may provide an effective way to increase skin permeability. CONCLUSIONS: We conclude that viable epidermis offers a significant permeability barrier that becomes rate limiting upon removal of stratum corneum.

Rapid kinetics to peak serum antibodies is achieved following influenza vaccination by dry-coated densely packed microprojections to skin.

A rapid time to peak serum antibody response following vaccination is particularly important for influenza: the time window between the availability of appropriate antigen and the start of the seasonal epidemic is very short. In this paper, influenza vaccine was delivered to both the epidermis and dermis of mouse skin using densely packed microprojection arrays for vaccination. We found that, after vaccination, around 75% and 90% of the delivered influenza vaccine migrated away from the ear skin within just 2 days and 1 week - respectively. And the time to peak serum antibody response was as early as 2 weeks. This result matches the kinetics achieved by intramuscular injection of liquid vaccine to muscle. Thus, we demonstrate that skin delivery of small vaccine volumes discretely by thousands of densely packed microprojections neither induces delay in kinetics nor interferes with the long-lasting antibody response; compared to conventional intramuscular injection.

Preparation and immunological effectiveness of a swine influenza DNA vaccine encapsulated in chitosan nanoparticles.

Preparation conditions of a DNA vaccine against swine influenza encapsulated in chitosan nanoparticles were determined. The nanoparticles were prepared according to a complex coacervation method using chitosan as a biodegradable matrix forming polymer. Under the preparation conditions, chitosan nanoparticles containing the DNA vaccine were produced with good morphology, high encapsulation rate and high stability. Transfection test indicated that the vaccine could be expressed as an antigen in cells, and maintained good bioactivity. In addition, better immune responses of mice immunized with the chitosan nanoparticles containing the DNA vaccine were induced and prolonged release of the plasmid DNA was achieved compared to the DNA vaccine alone. These results laid a foundation for further development of DNA vaccines in nanoparticles before ultimate industrial application.

Nonclinical biodistribution, integration, and toxicology evaluations of an H5N1 pandemic influenza plasmid DNA vaccine formulated with Vaxfectin®.

Vaxfectin(®) is a lipid-based adjuvant initially developed for use with plasmid DNA (pDNA) vaccines. Here we present detailed nonclinical assessments performed prior to Vaxfectin(®)'s first-in-man use, as an adjuvant in the H5N1 influenza vaccine VCL-IPT1. Following IM delivery to rabbits, VCL-IPT1 pDNA localized primarily to injection sites, where levels steadily declined over the 2 months examined. Risk of pDNA integration into genomic DNA was negligible. Toxicology studies in rabbits revealed mild inflammatory/immune responses at injection sites characteristic of IM vaccine delivery; Vaxfectin(®) directly contributed to these responses. These data support clinical development of H5N1 pDNA vaccines, and also present an encouraging profile for further development of Vaxfectin(®) as an adjuvant for vaccines in general.

Vaccination in pregnancy.

The recent H1N1 influenza pandemic has highlighted the potential for viral infections to cause severe disease in mothers disproportionate to the general population and have deleterious effects on the fetus. Vaccines have been used in pregnant women for over 200 years. Current guidelines recommend vaccination with only inactivated virus due to potential risk to mother and fetus with live vaccine. The exception is during times of pandemic or biological weapons attack, when the risk of life-threatening disease outweighs the risk of vaccination. A paucity of data is available regarding actual risk and mechanisms of live viral vaccine transfer from mother to fetus. Pregnancy-induced changes to the maternal immune system, effects of maternal infection on neonatal immunity, and the role of the placenta in transmission of infection and passive immunity to the fetus are incompletely understood. The aim of this paper is to review available data pertaining to newer vaccines such as the pandemic H1N1 and HPV vaccines in pregnancy, the role of Fc receptors in active transport of immunoglobulin across the placenta, and cytokine activity during maternal infection and after vaccination. We will also discuss potential areas for future research.

[Protective activity of Immunovac-VP-4 vaccine against avian influenza virus H5N2 administered by different methods].

AIM: To experimentally assess protective effect of Immunovac-VP-4 vaccine against avian influenza virus H5N2. MATERIALS AND METHODS. Immunization of mice with polycomponent vaccine Immunovac-VP-4 was performed using oral or mucosal route of administration (intranasally, orally, and with combined nasal-oral method). Immunized mice were inoculated intranasally by influenza virus H5N2 adapted for mice. Survival of mice in experimental and control (intact) groups was assessed daily during 14 days. Survival and death rates of mice were determined. Levels of cytokines in sera of mice from both groups were measured by enzyme immunoassay. RESULTS: Half of experimental animals survived after triple subcutaneous administration of vaccine in dose 20 mcg and subsequent intranasal challenge with avian influenza virus H5N2. Single subcutaneous immunization with dose 400 mcg resulted in survival of 80 +/- 12.6% of mice after challenge. Triple intranasal and combined intranasal-oral immunization as well as after triple subcutaneous immunization resulted in survival of half of challenged mice. In control group challenge was lethal for 90 - 100% of mice. Same methods of immunization lead to increase of IL-6, IL-12, IL-15, and IFN-gamma levels. CONCLUSION: Data about significant protective effect after immunization with Immunovac-VP-4 against avian influenza virus H5N2 were obtained. Immunovac-VP-4 administered by mentioned routes activated nasal-associated lymphoid tissue providing first line defense at entry site of influenza infection, which demonstrates need to further study of this vaccine during development of strategy for non-specific prophylaxis of influenza infection.

Influenza pandemic (H1N1) 2009 activity during summer 2009. Effectiveness ofthe 2008-9 trivalent vaccine against pandemic influenza in Spain

Introduction: The Spanish influenza surveillance system (SISS) maintained its activity during the summerof 2009 to monitor the influenza pandemic.Objectives: To describe pandemic influenza activity from May to September 2009 and to estimate theeffectiveness of the 2008-9 seasonal influenza vaccine against laboratory-confirmed pandemic (H1N1)2009 influenza.Methods: Data from the SISS were used to identify the trend of pandemic (H1N1) 2009 influenza outsidethe influenza season. For the effectiveness study, we compared the vaccination status of notified cases[influenza-like illnesses (ILI) laboratory confirmed as pandemic influenza] with that of the test-negativecontrols.Results: The first laboratory-confirmed case of the pandemic virus was notified in the system in week20/2009. The ILI rate increased gradually in the study period, exceeding basic activity in week 38. Theproportion of pandemic (H1N1) 2009 influenza viruses detected by the system represented 14% in week20/2009 and rapidly increased to 90% in week 34. The adjusted vaccine effectiveness of the 2008-9seasonal vaccine against laboratory-confirmed pandemic influenza was 12% (-30; 41).Conclusions: The SISS became an essential tool for pandemic monitoring in Spain. The improved SISS willprovide more accurate information on influenza activity in future seasonal or pandemic waves. Usingsurveillance data, we could not demonstrate the effectiveness of the seasonal 2008-9 vaccine againstlaboratory-confirmed pandemic influenza (AU)

Introducción: El Sistema de Vigilancia de Gripe en Espa˜na (SVGE) continuó y reforzó su actividad duranteel verano de 2009 con el objetivo de vigilar la evolución de la pandemia en Espa˜na.Objetivos: Describir la actividad de la gripe pandémica en Espa˜na de mayo a septiembre de 2009 yestimar la efectividad de la vacuna antigripal estacional 2008-2009 frente a casos confirmados de gripepandémica (H1N1) 2009.Métodos: Se utilizaron datos del SVGE para presentar la evolución de la pandemia por virus (H1N1) 2009fuera de la temporada de vigilancia 2008-2009. Para el estudio de la efectividad vacunal se comparó elestado vacunal de los casos de gripe pandémica confirmados por laboratorio con el de los casos negativospara el virus de la gripe (controles negativos).Resultados: El primer caso confirmado de virus pandémico se notificó en la semana 20/2009. La incidenciade gripe aumentó paulatinamente durante el periodo estudiado y sobrepasó el umbral basal en la semana38/2009. La proporción de virus (H1N1) 2009 detectada por elSVGEfue del 14% en la semana 20 y aumentórápidamente, llegando a alcanzar el 90% en la semana 34. La efectividad ajustada de la vacuna antigripal2008-2009 frente a casos confirmados de gripe pandémica fue del 12% (-30; 41).Conclusiones: El SVGE se adaptó y mejoró de forma rápida a las exigencias nacionales e internacionalesde vigilancia de la pandemia. Esta mejora supone información más precisa y de calidad en futuras ondasepidémicas/pandémicas. Con los datos obtenidos en vigilancia no se pudo demostrar alguna efectividadde la vacuna antigripal 2008-2009 frente a los casos de gripe pandémica confirmados por laboratorio (AU)

Determinantes de la vacunación antigripal en personal sanitario, temporada 2009-2010 / Determinants of influenza vaccination in health staff: 2009-2010 season

Objetivos: Determinar las coberturas vacunales frente a la gripe estacional y frente a la nueva gripe A(H1N1) en la temporada 2009-2010 en trabajadores sanitarios y conocer sus factores determinantes.Métodos: Estudio transversal realizado en el Hospital General Universitario de Alicante en trabajadoressanitarios durante las campa˜nas de vacunación antigripal 2008-2009 y 2009-2010. La campa˜na 2009-2010 se subdividió en dos fases: entre el 1-10-09 y el 13-11-09 se administró la vacuna de la gripeestacional 2009-2010; desde el 16-11-09 hasta el 30-12-09 se administró la vacuna frente al nuevo virusde la gripe A (H1N1). Cada fase estuvo precedida por una campa˜na promocional específica. En el momentode la vacunación, el trabajador sanitario cumplimentó un cuestionario que incluía un listado de motivospara vacunarse. Se calculó la frecuencia de vacunación y se compararon las coberturas vacunales de cadacampa˜na, de manera global y por estamentos, utilizando la prueba de ji cuadrado.Resultados: La cobertura frente a la gripe estacional 2009-2010 fue del 31%, y frente a la nueva gripe A(H1N1) fue del 22,2% (p < 0,05). En personal facultativo la cobertura fue del 36% y del 34%, respectivamente(NS); en personal de enfermería fue del 33% y del 24% (p < 0,001); en auxiliares de enfermería fue del 21%y del 12% (p < 0,001). El principal motivo para vacunarse en ambas campa˜nas fue «proteger mi salud».Conclusiones: Las bajas coberturas alcanzadas constituyen un problema de salud pública que hace necesarioel desarrollo de programas de intervención específicos para mejorarlas (AU)

Objectives: To determine vaccination coverage against seasonal influenza and the new A (H1N1)influenza virus among healthcare personnel during the 2009-2010 season and to identify its determiningfactors.Methods: We performed a cross-sectional study among healthcare staff at the General University Hospitalin Alicante (Spain) during the 2008-2009 and 2009-2010 influenza vaccination campaigns. The2009-2010 vaccination campaign was subdivided into two phases. In the first phase, from 1st October to19th November, 2009, the seasonal influenza vaccine was administered; in the second phase, from 16thNovember to 30th December, 2009, vaccination against the new A (H1N1) influenza virus was performed.Each of the vaccine programs was preceded by a specific vaccination promotion campaign. Healthcarestaff were asked to complete a brief self-administered questionnaire containing a list of reasons for beingvaccinated. Coverage during both vaccination campaigns was calculated, and the results, both overalland for each profession, were then compared using a Chi-square test.Results: Coverage against seasonal influenza was 31% and that against the new A (H1N1) influenza viruswas 22.2% (p < 0.05); these percentages were 36% and 34% respectively in medical personnel (NS), 33%and 24% respectively in nursing personnel (p < 0.001), and 21% and 12% respectively in nursing assistants(p < 0.001). The main reason given for being vaccinated was self-protection.Conclusions: The low coverage achieved is a public health problem. Specific intervention programsshould be implemented (AU)

Dissolving polymer microneedle patches for influenza vaccination.

Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin's antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a new technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.

La gripe A/H1N1(2009) y su tratamiento: Resumen de sus principales aspectos / The influenza 2009 A(H1N1) and its treatment: A summary of its main features

A mediados de marzo de 2009 se temía la aparición de una nuevaepidemia (o pandemia) de gripe que se esperaba pudiera procederdel subtipo A/H5Nl causante de la gripe aviar. Pero surgió, inesperadamenteen Méjico y enseguida se propagó a EE.UU. y al restodel mundo, una «nueva gripe», de origen porcino, resultante deun complejo agrupamiento de segmentos de genes (no por mutación)cuyo origen pronto se averiguó que era el siguiente: 1/3 procedentedel aviar de América del Norte, otro 1/3 del porcino deigual procedencia, y el aproximadamente 1/3 restante integrado apartes iguales por los de origen humano y porcino de procedenciaeurasiática.Realmente, lo «nuevo» de este virus no era el subtipo —que esel mismo de la famosa pandemia de 1918-19 (la impropia e injustamentellamada «gripe española»)—, sino el continente de su origen(América del Norte, no Asia); también, la estación del año de suaparición (la primavera, en lugar de finales del otoño); y, finalmente,la mayor letalidad en jóvenes, respecto al virus H1N1 causante de lagripe estacional, aun siendo su mortalidad no superior estadísticamentea la causada por éste.Dada la complejidad génica del «nuevo» virus, se pensó, lógicamente,que no existiría inmunidad significativa en los seres humanosrespecto a él; pero en el otoño de 2009 se ha publicado que sí hay cierto grado de inmunidad, previamente adquirida, en algunos sectores de población, dependiendo de la edad. Pronto se organizó internacionalmente la preparación de vacunasadecuadas, optándose por utilizar las técnicas tradicionales conhuevos de gallina, preferentemente con virus inactivados, y usándoseen la mayoría de ellas adyuvantes que incrementan su poder inmunógeno(AU)

En España, a mediados de noviembre de 2009, se inició lacampaña de vacunación, estableciéndose una prioridad para losdenominados «grupos de riesgo». De forma sorprendente, la aceptaciónde la vacunación ha sido menor de la esperada, incluso entre elpersonal sanitario (e igual ha sucedido en Francia). También se consideró conveniente prever la utilización adecuada(restringida a casos graves de hospitalizados, para evitar la apariciónde cepas resistentes) de los agentes antivirales oseltamivir (tamiflu)y zanamivir (relenza), los cuales interrumpen el ciclo biológicodel virus por inhibir la enzima de éste llamada neuraminidasa (osialidasa), cuya actividad es indispensable para la liberación de losviriones recién formados de la superficie externa de la dañada célulahospedadora.A la vista de la comprobada benignidad de la temida pandemia,a comienzos del año 2010 se ha estimado por ciertos sectores(también algunos sanitarios) que se había exagerado por partede los organismos internacionales responsables el riesgo de lamisma, achacando tal actuación a los intereses de las compañíasfarmacéuticas fabricantes de vacunas.Los responsables de los organismos oficiales han acreditadoque las medidas adoptadas eran las razonables ante un peligrodesconocido, que aún no está desaparecido y que puede inclusoaumentar si resultaran cepas más patógenas por mutación o porreagrupamiento del «nuevo» virus con el H5Nl, causante de la gripeaviar, o con el H9N2. Consideran que con las medidas tomadasse han evitado los errores cometidos en 1918-19, en que (además decarecerse de los conocimientos y recursos actuales) se intentó lucharcon remedios ineficaces, y con un exceso de confianza y engaños ala población(AU)

At the middle of March 2009 an A(H1N1) emerged whose genomecontains segments that are about one-third from «old» NorthAmerican swine influenza, one third from North American avian,and the remaining third evently divided between eurasian swine andhuman origin.The new modality of influenza emerged initially in Mexico andimmediately after in United States of America; its propagation inmany other countries on several continents has been very rapid.Actually, what «was new was not just the virus but also thecontinent origin (North America, not Asia), the season of origin(spring, not late fall), and the cohort at risk for infection and death(children and young adults, not infants and the elderly)».Contrary to earlier speculation, it seems that a certain level ofimmune protection against the new influenza A(H1N1) virus hasbeen previously acquired by some sectors of population, dependingon age.Vaccine production was internationally organized. Most licensedflu vaccines consist of inactivated egg grown virus, then purified andgenerally adjuvants added.Furthermore, the neuraminidase (= sialidase) inhibitorsoseltamivir (Tamiflu) and zanamivir (Relenza) have been usedin treatments, mainly in children, at the hospitals. The risk ofappearance of resistant strains advised cautious dispensation.Certain people considerer that perhaps some official sanitaryauthorities have been influenced by pharmaceutical companies todeliver an exaggerated message about the risk of this pandemics andhave helped to intensify the vaccination campaigns. However, theyargued that the risk of a reassortant virus containing segments ofavian H5N1 or H9N2, which could result in chimaeric viruses withvery dangerous characteristics, should be avoided with preventivevaccination and the use of antiviral agents(AU)