Delivery Of Influenza Vaccine Research Articles

Delivery of subunit influenza vaccine to skin with microneedles improves immunogenicity and long-lived protection

Influenza infection represents a major socio-economic burden worldwide. Novel delivery methods can render influenza vaccination easier and more acceptable by the public, and importantly confer protection equal or superior to that induced by conventional systemic administration. An attractive target for vaccine delivery is the skin. Recent studies have demonstrated improved immune responses after transdermal delivery of inactivated influenza virus with microneedle patches. Here we show that immunization with a licensed influenza subunit vaccine coated on metal microneedles can activate both humoral and cellular arms of the immune response and confer improved long-term protection in the mouse model when compared to the conventional systemic route of delivery. These results demonstrate the promising potential of microneedle delivery of licensed influenza subunit vaccines, that could be beneficial in increasing vaccine coverage and protection and reducing influenza-related mortality worldwide.

“Build it and they will come. Or will they?” Overcoming barriers to optimizing delivery of seasonal influenza vaccine to US adolescents

While vaccines are the most cost-effective strategy to prevent disease, their effectiveness is limited by vaccine uptake. Thus, development of a safe and effective vaccine is not sufficient, in or ...

Dissolvable Microneedle Patches for the Delivery of Cell-Culture-Derived Influenza Vaccine Antigens

Microneedle patches are gaining increasing attention as an alternative approach for the delivery of vaccines. In this study, a licensed seasonal influenza vaccine from 2007 to 2008 was fabricated into dissolvable microneedles using TheraJect's microneedle technology (VaxMat). The tips of the microneedles were made of antigens mixed with trehalose and sodium carboxymethyl cellulose. The patches containing 15 μg per strain of the influenza antigen were characterized extensively to confirm the stability of the antigen following fabrication into microneedles. The presence of excipients and very low concentrations of the vaccine on the microneedle patches made it challenging to characterize using the conventional single radial immunodiffusion analysis. Novel techniques such as capture enzyme-linked immunosorbent assay and enzyme digestion followed by mass spectroscopy were used to characterize the antigens on the microneedle patches. The in vivo studies in mice upon microneedle administration show immunogenicity against monovalent H1N1 at doses 0.1 and 1 μg and trivalent vaccine at a dose of 1 μg. The initial data from the mouse studies is promising and indicates the potential use of microneedle technology for the delivery of influenza vaccine.

Financing and systems barriers to seasonal influenza vaccine delivery in community settings

Recommendations for annual seasonal influenza vaccination have expanded to now include >300 million children and adults each year. Community settings have become increasingly important venues for influenza vaccination. We sought to identify barriers to and solutions for expanding influenza vaccination in community settings. Semi-structured telephone interviews were conducted from 01/09 to 06/10 with a range of stakeholders involved in influenza vaccination, including health plans, medical services firms, retail based clinics, pharmacies, schools, and state and local public health immunization programs. Participants (n=65) were asked about barriers and feasible solutions to influenza vaccine delivery to children and adults in community settings. Key themes were identified through iterative coding using a grounded theory approach. Stakeholders identified specific financial barriers to influenza vaccine delivery in 3 major areas: purchase and distribution, delivery, and reimbursement. Limited purchasing power, the uncertain nature of public demand, and unpredictable timing of influenza vaccine supply were important barriers to enhance delivery in community settings. Barriers to delivery included complexities in running off-site clinics, especially in school settings, the need to manage publicly vs. privately purchased vaccines separately, and state-to-state variability in requirements for credentialing, physician oversight, and reporting. Reimbursement barriers included a protracted credentialing process, the need to determine insurance eligibility at point-of-service, and lack of a billing infrastructure in off-site clinics. Opportunities to mitigate financial barriers to influenza vaccine delivery in community settings focused on coordination across providers and the role of public health as a "trusted broker" to overcome existing challenges. Financial and systems barriers hamper the optimal use of community settings to effectively deliver influenza vaccines. Public health partners at the federal, state, and local levels are well-positioned to facilitate the engagement of all stakeholders in this important and complex vaccine delivery system.

Pediatricians’ Attitudes About Collaborations With Other Community Vaccinators in the Delivery of Seasonal Influenza Vaccine

Objective Achieving universal influenza vaccination among children may necessitate collaborative delivery involving both practices and community vaccinators. We assessed among pediatricians nationally their preferences regarding location of influenza vaccination for patient subgroups and their attitudes about collaborative delivery methods. Methods The design/setting was a national survey conducted from July 2009 to October 2009. Participants included a representative sample of pediatricians from the American Academy of Pediatrics. Results The response rate was 79% (330 of 416). Physicians felt strongly that vaccination should occur in their practice for children with chronic conditions (52%) and healthy 6–24-month-old infants (48%), but few felt strongly about healthy 5–18-year-olds (17%). Most (78%) thought having multiple delivery sites increased vaccination rates, and 86% thought that influenza vaccine should be available at school. Physicians reported being very/somewhat willing to hold joint community clinics with public health entities (76%) and to suggest to patient subgroups that they receive vaccine at community sites, including public clinics or pharmacies (76%). The most frequently reported barriers to collaborative delivery with community sites or school-located delivery included concerns about the following: estimating the amount of vaccine to order if children are vaccinated elsewhere (community 56%; school 80%); transfer of vaccine records (community 57%; school 78%); and reluctance of families to go outside of the office (community 45%; school 74%). Conclusions Most physicians are in favor of school-located or collaborative influenza vaccine delivery with community vaccinators, especially for healthy school-aged children. Collaborative approaches will require planning to ensure transfer of records, effective targeting of subgroups, and provisions to protect providers from being left with extra influenza supply.

Association Between Quality of Care and the Sociodemographic Composition of Physicians’ Patient Panels: A Repeat Cross-Sectional Analysis

Pay-for-performance programs could worsen health disparities if providers who care for disadvantaged patients face systematic barriers to providing high-quality care. Risk adjustment that includes sociodemographic factors could mitigate the financial incentive to avoid disadvantaged patients. To test for associations between quality of care and the composition of a physician's patient panel. Repeat cross-sectional analysis Nationally representative sample of US primary care physicians responding to a panel telephone survey in 2000-2001 and 2004-2005 Quality of primary care as measured by provision of eight recommended preventive services (diabetic monitoring [hemoglobin A1c testing, eye examinations, cholesterol testing and urine protein analysis], cancer screening [screening colonoscopy/sigmoidoscopy and mammography], and vaccinations against influenza and pneumococcus) documented in Medicare claims data and the association between quality and the sociodemographic composition of physicians' patient panels. Across eight quality measures, physicians' quality of care was not consistently associated with the composition of their patient panel either in a single year or between time periods. For example, a substantial number (seven) of the eighteen significant associations seen between sociodemographic characteristics and the delivery of preventive services in the first time period were no longer seen in the second time period. Among sociodemographic characteristics, panel Medicaid eligibility was most consistently associated with differences in the delivery of preventive services between time points; among preventive services, the delivery of influenza vaccine was most likely to demonstrate disparities in both time points. In a Medicare pay-for-performance program, a better understanding of the effect of effect of patient panel composition on physicians' quality of care may be necessary before implementing routine statistical adjustment, since the association of quality and sociodemographic composition is small and inconsistent. In addition, we observed improvements between time periods among physicians with varying panel composition.

Influenza Vaccine Delivery Delays from the Perspective of Primary Care Physicians

The effects of delayed influenza vaccine delivery on primary practices are currently unknown. To describe, among primary care physicians nationally regarding the 2006-2007 influenza season: (1) how physicians defined influenza vaccine delay; (2) the extent of reported vaccine delays; and (3) the perceived effects of vaccine delays. Between March and June 2007, a total of 1268 primary care physicians nationally were surveyed. Survey response was 74% (n=940). The majority of physicians (79%) defined "influenza vaccine delay" as not receiving vaccine by November 1. Fifty-three percent reported a vaccine delay. Providers reported the following as effects of delays: reduced satisfaction of patients or parents in the practice (72%); decreased percentage in their practice who received the vaccination (65%); disruption of scheduling influenza clinics (55%); increased referral of patients elsewhere for vaccination (55%); and negative financial impact caused by unused vaccine (46%). Those who reported experiencing delays more often reported not meeting demand for vaccine (adjusted risk ratio [ARR]=1.83, 95% CI=1.64, 2.07); that grocery stores, retail outlets, or pharmacies had vaccine before their practices did (ARR=1.82, 95% CI=1.53, 2.26); not receiving all vaccine that was ordered (ARR=1.19, 95% CI=1.06, 1.36); and having leftover vaccine (ARR=1.17, 95% CI=1.04, 1.32). During the 2006-2007 influenza season, a non-shortage season, the majority of respondents reported experiencing an influenza vaccine delivery delay. Experiencing a delay was thought to decrease vaccination use, increase referrals elsewhere, and have a negative financial impact on practices. Delayed delivery of influenza vaccine is disruptive for primary care practices, and it consequently may affect vaccination coverage.

Trends in US pediatric influenza vaccination from 2006 to 2010 among children with private insurance

In the United States, recommendations for the annual influenza vaccination of children have expanded significantly in recent years. Additionally, to facilitate influenza vaccination delivery by providers, recent recommendations have encouraged vaccination as soon as vaccine is available and throughout the influenza season. However, until now, there have been limited data published describing pediatric providers’ responses to these recent recommendations. De-identified, patient-level data from an electronic health care reimbursement claims database that contains more than 60% of all medical claims from outpatient settings in the US were analyzed. Only claims from privately insured children were available; administration of federally purchased vaccine (i.e., via the Vaccines for Children program) and vaccinations administered in settings where claims data are not generated were not captured. Weekly counts of influenza vaccinations administered to children 6 months through 18 years of age between August 1 and March 31 for the 2006–2007 through 2009–2010 seasons were projected to yield national estimates. Seasonal vaccination peaked in November for the 2006–2007 and 2007–2008 seasons, October for the 2008–2009 season, and September for the 2009–2010 season. The proportion of vaccinations administered before November 1 increased each season from 2006–2007 through 2009–2010. In all seasons, vaccination dramatically declined in December and continued at a steadily declining rate through the end of the season. Vaccine delivery to children 6–23 months of age was more dispersed over the vaccination season relative to older age groups. Among children 6–23 months and 2–18 years of age, use of preservative-free inactivated vaccine and live attenuated vaccine, respectively, increased significantly over the study period. While pediatric influenza vaccination occurred earlier each year, vaccination in later months has not increased in recent seasons, despite efforts to extend the vaccination season.

Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization

Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23 °C, inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining “cold-chain” for vaccine storage and transport.

FluAlert: A qualitative evaluation of providers' desired characteristics and concerns regarding computerized influenza vaccination alerts

Objective To explore pediatric providers' perceived barriers to influenza vaccine delivery, and desired characteristics and potential concerns regarding an influenza vaccine alert integrated into the electronic health record (EHR). Methods Four focus groups with providers (n = 21) and five individual interviews with practice leaders in an urban, pediatric primary care network affiliated with an academic medical center in New York City were conducted. Data were collected during the 2009–10 influenza season and analyzed using thematic analysis. Results Participants identified several barriers to influenza vaccine delivery, including remembering to vaccinate during sick visits, need to review multiple sources of immunization information, time shortages and inadequate staffing. They felt that an alert could help many of these challenges. They desired the following alert characteristics: 1) alerting providers early in the visit, 2) accurately determining patients' vaccine status by merging multiple sources of immunization information, 3) facilitating vaccine ordering, and 4) generating appropriate documentation in the EHR when vaccines were refused or otherwise not given. Potential concerns regarding the alert included reliability and accuracy of alert, workflow interruptions and forced actions. Conclusions This study highlights providers' interest in a well-integrated, accurate alert that streamlines assessment of vaccination eligibility, ordering and documentation without impeding work-flow.

Influenza Vaccines for the Future

New technologies can revolutionize influenza vaccine design, production, and delivery. In the near future, advances should reduce vaccine production time, provide enhanced protection, and end mismatches between vaccine strains and circulating viruses.

Clinical studies assessing immunogenicity and safety of intradermally administered influenza vaccines

Importance of the field: Human influenza A and B are major respiratory pathogens and cause high mortality and severe morbidity, especially in at-risk populations. Most of the vaccines are administered intramusculary or subcutaneously. Owing to vaccine shortage and low vaccine coverage, intradermal administration of vaccines has gained renewed interest. In addition, higher immune responses with the same quantity of antigen have been elicited with intradermal vaccine administration, offering dose-sparing capacity.Areas covered in this review: This review summarizes the immunogenicity and safety data accumulated from influenza vaccine trials where vaccines were administered intradermally. Clinical trials performed using reduced vaccine antigen doses in healthy volunteers or in at-risk populations and target groups are discussed as well as new devices for intradermal delivery of influenza vaccines. The studies addressed in this review were identified through a MEDLINE search.What the reader will gain: The review provides insights into the potential of intradermal vaccines to overcome hurdles such as vaccine shortage in view of mass vaccination campaigns. Moreover, evidence is provided of improved immunological responses after intradermal vaccination when new intradermal devices are being used.Take home message: In the authors' opinion, intradermal vaccination can be considered an equally immunogenic, safe and feasible alternative to intramuscular and subcutaneous vaccination. The future looks promising because of the recent development of new intradermal vaccine delivery devices.

Dose sparing enabled by skin immunization with influenza virus-like particle vaccine using microneedles

To address the limitations of conventional influenza vaccine manufacturing and delivery, this study investigated administration of virus-like particle (VLP) influenza vaccine using a microneedle patch. The goal was to determine if skin immunization with influenza VLP vaccine using microneedles enables dose sparing. We found that low-dose influenza (A/PR/8/34 H1N1) VLP vaccination using microneedles was more immunogenic than low-dose intramuscular (IM) vaccination and similarly immunogenic as high-dose IM vaccination in a mouse model. With a 1 μg dose of vaccine, both routes showed similar immune responses and protective efficacy, with microneedle vaccination being more effective in inducing recall antibody responses in lungs and antibody secreting cells in bone marrow. With a low dose of vaccine (0.3 μg), microneedle vaccination induced significantly superior protective immunity, which included binding and functional antibodies as well as complete protection against a high dose lethal infection with A/PR/8/34 virus, whereas IM immunization provided only partial (40%) protection. Therefore, this study demonstrates that microneedle vaccination in the skin confers more effective protective immunity at a lower dose, thus providing vaccine dose-sparing effects.

Influenza vaccine delivery to adolescents: Assessment of two multicomponent interventions

Influenza vaccine delivery to adolescents: Assessment of two multicomponent interventions

School-based influenza vaccine delivery, vaccination rates, and healthcare use in the context of a universal influenza immunization program: An ecological study

Influenza vaccines are universally funded in Ontario, Canada. Some public health units (PHUs) vaccinate children in schools. We examined the impact of school-based delivery on vaccination rates and healthcare use of the entire population over seven influenza seasons (2000–2007) using population-based survey and health administrative data. School-based vaccination was associated with higher vaccination rates in school-age children only. Doctors’ office visits were lower for PHUs with school-based vaccination for children aged 12–19 but not for other age groups. Emergency department use and hospitalizations were similar between the two groups. In the context of universal influenza vaccination, school-based delivery is associated with higher vaccination rates and modest reductions in healthcare use in school-age children.

The Daunting Practicalities of In-office Pediatric Influenza Vaccination: 2009–2010

CME Educational Objectives 1. Identify the key barriers to successful delivery of influenza vaccine in the private office setting. 2. Assess proven strategies that improve influenza vaccine delivery in the office setting. 3. Delineate the unique stresses placed on the private office as a result of the need to delivery H1N1 vaccine this influenza season.

Mucoadhesive liposomes for intranasal immunization with an avian influenza virus vaccine in chickens

The aim of this study was to characterize a nasally delivered bioadhesive liposome using an inactivated H5N3 virus as a model antigen. Bioadhesive liposomes were developed using tremella (T) or xanthan gum (XG) as the bioadhesive polysaccharide. Using chickens as the target animal, we evaluated whether delivery of a bioadhesive liposomal influenza vaccine via a mucosal site of infection could improve vaccine effectiveness. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cytotoxicity assays demonstrated that T, XG and liposomes were non toxic to chicken spleen macrophages. Enzyme-linked immunosorbent assay (ELISA) was used to determine the adjuvant effect of the bioadhesive liposomal-vaccines. Chickens immunized with a low dose (200 μL) of bioadhesive liposomal influenza vaccine had significantly higher mucosal and serum antibody levels ( P < 0.05). In addition, liposomes mixed with a low-viscosity bioadhesive gel used for nasal delivery resulted in superior antibody responses compared with liposomes mixed with a high-viscosity gel ( P < 0.05). This suggest that a low-viscosity gel mixed with liposomes is more suitable for nasal delivery, and that chickens elicit higher mucosal secretory immunoglobulin A (s-IgA) and serum IgG after two vaccinations.

Lipid vesicle size of an oral influenza vaccine delivery vehicle influences the Th1/Th2 bias in the immune response and protection against infection

Previous studies, using parenteral administration of antigen in lipid vesicles, have indicated a possible role for vesicle size in determining the Th1/Th2 bias of the resulting immune response. We have also demonstrated that the incorporation of bile salts into lipid vesicles (bilosomes) allows successful induction of mucosal and systemic immunity via the oral route. The following study was therefore carried out to determine whether size could also influence the Th1/Th2 bias in the immune response to bilosome entrapped influenza A antigen containing haemagglutinin administered by the oral route in the mouse and whether this could influence the disease process in the classical ferret model of disease. Consequently we produced two formulations of influenza A antigen entrapped in bilosomes: BV3 which contained a single population (range 10–100 nm, Z-average diameter 250 nm) and BV which had two populations (60–350 and 400–2500 nm, Z-average 980 nm). Following oral vaccination of BALB/c mice, BV was found to generate an immune response that had a significantly greater Th1 bias than BV3 as measured by serum IgG2a production and antigen-induced spleen cell IFN-γ production. In the traditional infection challenge model (ferrets) vaccination with BV (large) vesicles resulted in greater protection in terms of symptom-score and a higher responder number. However, both oral vaccine formulations were an improvement on intramuscular administration in terms of higher antibody production, lower temperatures, and reduced symptoms over time, post-infection. The results presented here demonstrate that oral vaccine formulations can be physically modified to manipulate resultant immune responses following vaccination and consequently can be designed to enhance the effectiveness of candidate vaccine antigens.

Spray-dried powders of starch and crosslinked poly(acrylic acid) as carriers for nasal delivery of inactivated influenza vaccine

Mucosal vaccination has several advantages over parenteral vaccination. In this study, viscosity-enhancing mucosal delivery systems for the induction of an adaptive immune response against viral antigen were investigated. Powder formulations based on spray-dried mixtures of starch (Amioca ®)/poly(acrylic acid) (Carbopol ® 974P) in different ratios were used as carriers of the viral antigen. A comparison of these formulations for intranasal delivery of heat-inactivated influenza virus combined with LTR192G adjuvant was made in vivo in a rabbit model. Individual rabbit sera were tested for seroconversion against hemagglutinin (HA), the major surface antigen of influenza. The powder vaccine formulations were able to induce systemic anti-HA IgG responses. The presence of Carbopol ® 974P improved the kinetics of the immune responses and the level of IgG titers in a dose-dependent way which was correlated with moderately irritating capacities of the formulation. In contrast, mucosal IgA responses were not detected. In conclusion, it was demonstrated that the use of bioadhesive carriers based on Amioca ® starch and poly(acrylic acid) facilitates the induction of a systemic anti-HA antibody response after intranasal vaccination with a whole virus influenza vaccine.

Pulmonary delivery of ISCOMATRIX influenza vaccine induces both systemic and mucosal immunity with antigen dose sparing

Using a large animal model, we evaluated whether delivery of influenza vaccine via its mucosal site of infection could improve vaccine effectiveness. Unexpectedly, pulmonary immunization with extremely low antigen doses (0.04 μg influenza) induced serum antibody levels equivalent to those resulting from a current human vaccine equivalent (15 μg unadjuvanted influenza, subcutaneously) and vastly superior lung mucosal antibodies. Induction of this potent response following lung vaccination was dependent on addition of ISCOMATRIX adjuvant and deep lung delivery. Functional antibody activity, marked by hemagglutination inhibition, was only present in the lungs of animals that received adjuvanted vaccine via the lungs, suggesting this approach could potentially translate to improved protection. The 375-fold reduction in antigen dose and improved mucosal antibody responses, compared to the current vaccine, suggests that mucosal delivery via the pulmonary route may be particularly relevant in the event of an influenza pandemic, when vaccine supplies are unlikely to meet demand.