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Influenza pandemics pose a serious risk to the global population, with the potential for high morbidity and mortality. An adjuvanted H5N1 vaccine (aH5N1) has been approved for prophylaxis against the avian influenza virus H5N1, which is a likely cause of future pandemics. In this phase-III, stratified, randomized, controlled, observer-blind, multicenter study, we evaluated the safety and immunogenicity of aH5N1 in four separate groups of adults: adults 18–60 years of age who were healthy or had high-risk medical conditions and older adults ≥61 years of age who were healthy or had high-risk medical conditions. Subjects were randomly assigned to aH5N1 or the comparator, adjuvanted trivalent seasonal influenza vaccine (aTIV). Antibody responses to aH5N1 were increased in all four subgroups and, within each age stratum, largely consistent between healthy subjects and those with medical conditions. Injection-site pain was reported by 66–73% of younger and 36–42% of older–aH5N1 recipients, and fatigue and myalgia were reported by 22–41% of subjects across age and health subgroups. No serious adverse events or deaths were considered related to the study vaccine. In conclusion, aH5N1 increased antibody responses regardless of age or health status and demonstrated a clinically acceptable safety and tolerability profile. [ABSTRACT FROM AUTHOR]

Due to the inherent risk of a further pandemic influenza outbreak, there is a need and growing interest in investigating combinations of prophylactic vaccines and novel adjuvants, particularly to achieve antigen dose sparing and improved immunogenicity. Influenza is a highly variable virus, where the specific vaccine target is constantly changing, representing a major challenge to influenza vaccine development. Currently, commercial inactivated influenza vaccines have a poor CD8+ T response, which impacts cross-reactivity and the duration of response. Adjuvanted influenza vaccines can increase immune responses, thereby achieving better protection and cross-reactivity to help contain the spread of the disease. An early exploration of a hybrid cholesterol-PLGA nanoparticle delivery system containing the saponin tomatine and a NOD2 (nucleotide-binding oligomerization domain 2) agonist called SG101 was conducted. This combination was preliminarily evaluated for its ability to induce cellular immunity when combined with whole inactivated virus (WIV) influenza vaccine. After the adjuvants were manufactured using a single emulsion process, two formulations with different drug loadings were selected and physico-chemically characterized, showing sizes between 224 ± 32 and 309 ± 45 nm and different morphologies. After ensuring the lack of in vitro toxicity and hemolytic activity, a pilot in vivo assay evaluated the hybrid nanoparticle formulation for its ability to induce humoral and cellular immunity when combined with whole inactivated virus (WIV) H5N1 influenza vaccine by intramuscular administration in mice. Hemagglutinin inhibition (HAI) titers for adjuvanted groups showed no significant difference compared to the group vaccinated with the antigen alone. It was similar for CD4+ and CD8+ T cell responses, although the high drug loading formulation induced higher titers of IFNγ-positive CD8+ T cells. These proof-of-concept results encourage further investigations to develop the hybrid formulation with increased or different loading ratios, to investigate manufacturing optimization, and to evaluate the role of the individual immunostimulatory compounds in immune responses.

Influenza pandemics pose a serious risk to the global population, with the potential for high morbidity and mortality. An adjuvanted H5N1 vaccine (aH5N1) has been approved for prophylaxis against the avian influenza virus H5N1, which is a likely cause of future pandemics. In this phase-III, stratified, randomized, controlled, observer-blind, multicenter study, we evaluated the safety and immunogenicity of aH5N1 in four separate groups of adults: adults 18–60 years of age who were healthy or had high-risk medical conditions and older adults ≥61 years of age who were healthy or had high-risk medical conditions. Subjects were randomly assigned to aH5N1 or the comparator, adjuvanted trivalent seasonal influenza vaccine (aTIV). Antibody responses to aH5N1 were increased in all four subgroups and, within each age stratum, largely consistent between healthy subjects and those with medical conditions. Injection-site pain was reported by 66–73% of younger and 36–42% of older–aH5N1 recipients, and fatigue and myalgia were reported by 22–41% of subjects across age and health subgroups. No serious adverse events or deaths were considered related to the study vaccine. In conclusion, aH5N1 increased antibody responses regardless of age or health status and demonstrated a clinically acceptable safety and tolerability profile.

Influenza viruses are responsible for millions of cases globally and significantly threaten public health. Since pandemic and zoonotic influenza viruses have emerged in the last 20 years and some of the viruses have resulted in high mortality in humans, a universal influenza vaccine is needed to provide comprehensive protection against a wide range of influenza viruses. Current seasonal influenza vaccines provide strain-specific protection and are less effective against mismatched strains. The rapid antigenic drift and shift in influenza viruses resulted in time-consuming surveillance and uncertainty in the vaccine protection efficacy. Most recent universal influenza vaccine studies target the conserved antigen domains of the viral surface glycoproteins and internal proteins to provide broader protection. Following the development of advanced vaccine technologies, several innovative strategies and vaccine platforms are being explored to generate robust cross-protective immunity. This review provides the latest progress in the development of universal influenza vaccines. [ABSTRACT FROM AUTHOR]

The influenza hemagglutinin (HA) isolated from avian H7N9 influenza virus strains elicit weak immune responses. This low immunogenicity may be due to a regulatory T cell (Treg)–stimulating epitopes in HA from the H7N9 isolate A/Anhui/1/2013 (Anh/13). In this report, this Treg stimulating sequence was removed from the wild-type (WT) H7 HA amino acid sequence and replaced with a conserved CD4 + T cell stimulating sequences from human seasonal H3N2 strains and designed OPT1 H7 HA. The effectiveness of this optimized H7 HA protein was determined using a humanized mouse (HLA-DR3) expressing the human leukocyte antigen (HLA) DR3 allele. HLA-DR3 mice were pre-immunized by infecting with H3N2 influenza virus, A/Hong Kong/4108/2014 and then vaccinated intramuscularly with either the WT H7 HA from Anh/13 or the OPT1 H7 HA antigen without adjuvant. The OPT1 H7 HA vaccination group elicited higher H7 HA-specific IgG titers that resulted in a lower mortality, weight loss, and lung viral titer following lethal challenge with the H7N9 Anh/13 influenza virus compared to WT-vaccinated mice. Overall, T-cell epitope-engineered vaccines can improve the immunogenicity of H7 HA antigens resulting in enhanced survival and lower morbidity against H7N9 influenza virus challenge.

Genetic reassortment of influenza A viruses through cross-species transmission contributes to the generation of pandemic influenza viruses. To provide information on the ecology of influenza viruses, we have been conducting a global surveillance of zoonotic influenza and establishing an influenza virus library. Of 4580 influenza virus strains in the library, 3891 have been isolated from over 70 different bird species. The remaining 689 strains were isolated from humans, pigs, horses, seal, whale, and the environment. Phylogenetic analyses of the HA genes of the library isolates demonstrate that the library strains are distributed to all major known clusters of the H1, H2 and H3 subtypes of HA genes that are prevalent in humans. Since past pandemic influenza viruses are most likely genetic reassortants of zoonotic and seasonal influenza viruses, a vast collection of influenza A virus strains from various hosts should be useful for vaccine preparation and diagnosis for future pandemics. • Genetic reassortment of influenza A viruses through cross-species transmission contributes to the generation of pandemic influenza viruses. • To provide information on the ecology of influenza viruses, we have been conducting a global surveillance of zoonotic influenza and establishing an influenza virus library. • Of 4580 influenza virus strains in the library, 3891 have been isolated from over 70 different bird species, and the remaining 689 strains were isolated from humans, pigs, horses, seal, whale, and the environment. • Phylogenetic analyses of the HA genes of the library isolates demonstrate that the library strains are distributed to all major known clusters of the H1, H2 and H3 subtypes of HA genes that are prevalent in humans. • Since past pandemic influenza viruses are most likely genetic reassortants of zoonotic and seasonal influenza viruses, a vast collection of influenza A virus strains from various hosts should be useful for vaccine preparation and diagnosis for future pandemics. [ABSTRACT FROM AUTHOR]

Influenza viruses are responsible for millions of cases globally and significantly threaten public health. Since pandemic and zoonotic influenza viruses have emerged in the last 20 years and some of the viruses have resulted in high mortality in humans, a universal influenza vaccine is needed to provide comprehensive protection against a wide range of influenza viruses. Current seasonal influenza vaccines provide strain-specific protection and are less effective against mismatched strains. The rapid antigenic drift and shift in influenza viruses resulted in time-consuming surveillance and uncertainty in the vaccine protection efficacy. Most recent universal influenza vaccine studies target the conserved antigen domains of the viral surface glycoproteins and internal proteins to provide broader protection. Following the development of advanced vaccine technologies, several innovative strategies and vaccine platforms are being explored to generate robust cross-protective immunity. This review provides the latest progress in the development of universal influenza vaccines.

To investigate a potential risk for multiple sclerosis (MS) after vaccination with Arepanrix, the GlaxoSmithKline AS03-adjuvanted influenza A(H1N1)pdm09 vaccine, we used the provincewide immunization registry for Manitoba, Canada, to match 341,347 persons vaccinated during the 2009 pandemic to 485,941 unvaccinated persons on age, sex, address, and a propensity score measuring the probability of vaccination. We used a previously validated algorithm to identify MS cases from provincial hospital, physician, and prescription drug claims databases. After 12 months of follow-up, the age-adjusted incidence rate of MS was 17.7 cases per 100,000 person-years in the Arepanrix cohort and 24.2 per 100,000 in the unvaccinated cohort. The corresponding adjusted hazard ratio was 0.9. We observed similar patterns when we measured incidence over the entire follow-up period. The AS03 adjuvant, a candidate for inclusion in future pandemic vaccines, does not appear to increase the short-term risk for MS when included in influenza vaccines.

An increased risk of narcolepsy following administration of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine (Pandemrix™) was described in children and adolescents in certain European countries. We investigated the potential effects of administration of the AS03-adjuvanted vaccine, non-adjuvanted vaccine antigen and AS03 Adjuvant System alone, on the central nervous system (CNS) in one-month-old cotton rats. Naïve or A(H1N1)pdm09 virus-primed animals received 2 or 3 intramuscular injections, respectively, of test article or saline at 2-week intervals. Parameters related to systemic inflammation (hematology, serum IL-6/IFN-γ/TNF-α) were assessed. Potential effects on the CNS were investigated by histopathological evaluation of brain sections stained with hematoxylin-and-eosin, or by immunohistochemical staining of microglia, using Iba1 and CD68 as markers for microglia identification/activation, albumin as indicator of vascular leakage, and hypocretin. We also determined cerebrospinal fluid (CSF) hypocretin levels and hemagglutination-inhibiting antibody titers. Immunogenicity of the AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine was confirmed by the induction of hemagglutination-inhibiting antibodies. Both AS03-adjuvanted vaccine and AS03 alone activated transient innate (neutrophils/eosinophils) immune responses. No serum cytokines were detected. CNS analyses revealed neither microglia activation nor inflammatory cellular infiltrates in the brain. No differences between treatment groups were detected for albumin extravascular leakage, CSF hypocretin levels, numbers of hypocretin-positive neuronal bodies or distributions of hypocretin-positive axonal/dendritic projections. Consequently, there was no evidence that intramuscular administration of the test articles promoted inflammation or damage in the CNS, or blood-brain barrier disruption, in this model.

Background In 2009, a novel influenza A (pH1N1) was identified, resulting in a pandemic with significant morbidity and mortality. A monovalent pH1N1 vaccine was separately produced in addition to the seasonal trivalent influenza vaccine. Formulation of the seasonal influenza vaccine (injectable trivalent inactivated influenza vaccine [TIV] vs. intranasal live, attenuated influenza vaccine [LAIV]) was postulated to have impacted the efficacy of the pH1N1 vaccination. Methods We reviewed electronic health and databases, which included vaccination records, and healthcare encounters for influenza-like illness (ILI), influenza, and pneumonia among US military members. We examined rates by vaccination type to identify factors associated with the risk for study outcomes. Results Compared with those receiving the seasonal influenza vaccine alone, subjects receiving the pH1N1 vaccine, either alone (RR, 0.49) or in addition to the seasonal vaccine (RR, 0.51), had an approximately 50% reduction in ILI, 88% reduction in influenza (RR, 0.11 and 0.12, respectively), and 63% reduction in pneumonia (RR, 0.37 and 0.35, respectively). There was no clinically significant difference in ILI, influenza, or pneumonia attack rates among those receiving the pH1N1 vaccine with or without presence of the seasonal vaccine. Similarly, there was no clinically relevant difference in pH1N1 effectiveness between seasonal TIV and LAIV recipients. Conclusions During the 2009–2010 pandemic, the pH1N1 vaccination was effective in reducing rates of ILI, influenza, and pneumonia. Administration of the seasonal vaccine should continue without concern of potential interference with a novel pandemic vaccine, though more studies are needed to determine if this is applicable to other influenza seasons. [ABSTRACT FROM AUTHOR]

In August 2016, the World Health Organization (WHO) convened the “Eighth meeting on development of influenza vaccines that induce broadly protective and long-lasting immune responses” to discuss the regulatory requirements and pathways for licensure of next-generation influenza vaccines, and to identify areas where WHO can promote the development of such vaccines. Participants included approximately 120 representatives of academia, the vaccine industry, research and development funders, and regulatory and public health agencies. They reviewed the draft WHO preferred product characteristics (PPCs) of vaccines that could address prioritized unmet public health needs and discussed the challenges facing the development of such vaccines, especially for low- and middle-income countries (LMIC). They defined the data desired by public-health decision makers globally and explored how to support the progression of promising candidates into late-stage clinical trials and for all countries. This report highlights the major discussions of the meeting. [ABSTRACT FROM AUTHOR]

In 2009, the New York City Department of Health and Mental Hygiene delivered influenza A(H1N1)pdm09 (pH1N1) vaccine to health care providers, who were required to report all administered doses to the Citywide Immunization Registry. Using data from this registry and a provider survey, we estimated the number of all pH1N1 vaccine doses administered. Of 2.8 million doses distributed during October 1, 2009–March 4, 2010, a total of 988,298 doses were administered and reported; another 172,289 doses were administered but not reported, for a total of 1,160,587 doses administered during this period. Reported doses represented an estimated 80%–85% of actual doses administered. Reporting by a wide range of provider types was feasible during a pandemic. Pediatric-care providers had the highest reporting rate (93%). Other private-care providers who routinely did not report vaccinations indicated that they had few, if any, problems, thereby suggesting that mandatory reporting of all vaccines would be feasible.

Objectives: The single radial immunodiffusion (SRID) assay, used to quantify hemagglutinin (HA) in influenza vaccines, requires reference reagents; however, because centralized production of reference reagents may slow the emergency deployment of vaccines, alternatives are needed. Results: We investigated the production of HA proteins using recombinant DNA technology, rather than a traditional egg-based production process. The HA proteins were then used in an SRID assay as a reference antigen. We found that HA can be quantified in both egg-based and cell-based influenza vaccines when recombinant HAs (rHAs) are used as the reference antigen. Furthermore, we confirmed that rHAs obtained from strains with pandemic potential, such as H5N1, H7N3, H7N9, and H9N2 strains, can be utilized in the SRID assay. The rHA production process takes just one month, in contrast to the traditional process that takes three to four months. Conclusions: The use of rHAs may reduce the time required to produce reference reagents and facilitate timely introduction of vaccines during emergencies. [ABSTRACT FROM AUTHOR]

Although mentioned in the UK pandemic plan, essential service providers were not among the priority groups. They may be important targets of future influenza pandemic vaccination campaigns. Therefore, we conducted a cross-sectional survey among 380 employees from West Midlands police headquarters and 15 operational command units in the West Midlands Area during December 2009–February 2010 to identify factors affecting intention to accept the pandemic influenza A (H1N1) vaccine. One hundred and ninety nine (52.4%) employees completed the questionnaire. 39.7% were willing to accept the vaccine. The most common reasons for intention to accept were worry about catching Swine Flu (n = 42, 53.2%) and about infecting others (n = 40, 50.6%). The most common reason for declination was worry about side effects (n = 45, 57.0%). The most important factor predicting vaccine uptake was previous receipt of seasonal vaccine (OR 7.9 (95% CI 3.4, 18.5)). Employees aged

We tested an inactivated egg-grown whole virus influenza A/H5N1 vaccine candidate developed by the Institute of Vaccines and Medical Biologicals (IVAC), a state-run vaccine manufacturer in Vietnam, in a Phase 1, placebo controlled, double blinded, randomized trial. The vaccine was adjuvanted with aluminum hydroxide. The trial enrolled 75 subjects who were randomized to receive two injections of one of the following: low-dose of vaccine (7.5 mcg HA), high-dose of vaccine (15 mcg HA), or placebo. The vaccine candidate was well tolerated with minimal local reactogenicity consisting of mild, short-lived injection site pain and/or tenderness. No systemic reactogenicity was observed other than transient low-grade fever in about 13% of the subjects and no unsolicited adverse events were attributable to product administration. Immune responses were assessed at baseline and after the first and second dose by hemagglutination inhibition (HAI) and microneutralization (MN) assays, with 72% of the high-dose and 68% of the low-dose vaccine recipients presenting a ⩾4-fold response in the HAI assay and 72% of the high-dose and 61% of the low-dose vaccine recipients exhibiting a ⩾4-fold response in the MN assay. These promising results support further development. ClinicalTrials.gov number NCT02171819 , June 20, 2014. [ABSTRACT FROM AUTHOR]

Objective This study aims to describe the frequency and quality of spontaneous narcolepsy case reports following administration of pandemic influenza vaccine as captured in the Eudravigilance database. Methods We conducted a retrospective descriptive study of spontaneous Individual Case Safety Reports (ICSRs), reporting narcolepsy following administration of pandemic influenza vaccine as received by Eudravigilance until July 2014. De-duplication was carried out by Eudravigilance. Frequency of reporting is described as number of ICSRs received per month over time. The quality of the ICSRs was evaluated by completeness of information and diagnostic certainty using the Automated Brighton Collaboration case definition tool (ABC-tool) for narcolepsy. Results After de-duplication, a total of 1333 ICSRs of narcolepsy and/or cataplexy following pandemic influenza vaccine were identified, originating from 18 countries worldwide. Most of the ICSRs (61.9%) originated from the signaling countries, Sweden and Finland. Although de-duplication of case reports was carried out, it is suspected that many duplicates exist, in particular from Sweden. The majority of the ICSRs (95.3%), reported exposure to Pandemrix®. Only few reports were received for Arepanrix® (1.6%) or Focetria® (0.5%), and Celvapan® (0.1%). Of those ICSRs reporting age, 73.1% concerned persons below age of 20 years. When using the ABC-tool, all ICSRs were classified as having insufficient information to meet the Brighton Collaboration case definition of narcolepsy. Conclusion An increase in reporting of narcolepsy appeared in Eudravigilance only after awareness was raised by the national authorities. Most narcolepsy reports were received from countries where the signal initially occurred, and were related to Pandemrix® in children/adolescents. Basic information about the patient and the exposure was present in most of the ICSRs. The ICSRs captured by Eudravigilance however, do not collect enough information to assess the diagnostic certainty according to the Brighton Collaboration case definition. [ABSTRACT FROM AUTHOR]

On 5–7 May 2014, the World Health Organization (WHO) convened the second integrated meeting on “influenza vaccines that induce broadly protective and long-lasting immune responses”. Around 100 invited experts from academia, the vaccine industry, research and development funders, and regulatory and public health agencies attended the meeting. Areas covered included mechanisms of protection in natural influenza-virus infection and vaccine-induced immunity, new approaches to influenza-vaccine design and production, and novel routes of vaccine administration. A timely focus was on how this knowledge could be applied to both seasonal influenza and emerging viruses with pandemic potential such as influenza A (H7N9), currently circulating in China. Special attention was given to the development of possible universal influenza vaccines, given that the Global Vaccine Action Plan calls for at least one licensed universal influenza vaccine by 2020. This report highlights some of the topics discussed and provides an update on studies published since the report of the previous meeting. [ABSTRACT FROM AUTHOR]

Background: Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand.Methods: A CC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, "CC-H5N1") was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12.Results: AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. No vaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine.Conclusions: The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CC-H5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic.Clinical Trials Registration: NCT01236040. [ABSTRACT FROM AUTHOR]

Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection. [ABSTRACT FROM AUTHOR]

Background. Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. Methods. ACC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, "CC-H5N1") was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. Results. AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. No vaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine. Conclusions. The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CCH5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. [ABSTRACT FROM AUTHOR]

Introduction Influenza is a major concern across healthcare environments. Annual vaccination of healthcare workers (HCW) remains a key mode of influenza prevention in healthcare settings. Yet influenza vaccine coverage among HCWs continues to be below recommended targets, in pandemic and non-pandemic settings. Thus, the primary objective of this analysis is to identify motivators and barriers to pandemic (panINFLU) and seasonal influenza vaccination (sINFLU) through the qualitative analysis of HCW provided reasons driving HCW's personal vaccination decisions. Methods Data were collected from a multi-professional sample of HCWs via a cross-sectional survey study, conducted at a tertiary-care hospital in Ontario, Canada. HCW provided and ranked qualitative reasons for personal (1) panINFLU (pH1N1) and (2) sINFLU (2008/2009 season) vaccine uptake and avoidance were used to identify key vaccination motivators and barriers through content analysis methodology. Results Most HCW vaccination motivators and barriers were found to be similar for panINFLU and sINFLU vaccines. Personal motivators had the greatest impact on vaccination (panINFLU 29.9% and sINFLU 33.9%). Other motivators included preventing influenza in loved ones, patients, and community, and awareness of HCW role in influenza transmission. In contrast, concerns of vaccine safety and limited HCW knowledge of influenza vaccines (panINFLU 46.2% and sINFLU 37.3%). HCW vaccination during the pandemic was motivated by panINFLU related fear, epidemiology, and workplace pro-vaccination policies. HCW perceptions of accelerated panINFLU vaccine development and vaccine safety compromises, negative views of external sources (i.e. media, pharmaceutical companies, and regulatory agencies) and pandemic management strategies were barriers specific to panINFLU vaccine. Conclusions HCW panINFLU and sINFLU vaccine coverage can increase if future vaccination programs (1) highlight personal vaccination benefits (2) emphasize the impact HCW non-vaccination on family members, patients and community, (3) address HCW vaccine related knowledge gaps, and (4) implement pro-vaccination workplace policies consistent with those in place at the study site during pH1N1. [ABSTRACT FROM AUTHOR]

Background. The vaccine efficacy (VE) of 1 or 2 doses of AS03-adjuvanted influenza A(H1N1) vaccine relative to that of 2 doses of nonadjuvanted influenza A(H1N1) vaccine in children 6 months to <10 years of age in a multinational study conducted during 2010–2011.Methods. A total of 6145 children were randomly assigned at a ratio of 1:1:1 to receive 2 injections 21 days apart of A/California/7/2009(H1N1)-AS03 vaccine at dose 1 and saline placebo at dose 2, 2 doses 21 days apart of A/California/7/2009(H1N1)-AS03 vaccine (the Ad2 group), or 2 doses 21 days apart of nonadjuvanted A/California/7/2009(H1N1) vaccine (the NAd2 group). Active surveillance for influenza-like illnesses continued from days 14 to 385. Nose and throat samples obtained during influenza-like illnesses were tested for A/California/7/2009(H1N1), using reverse-transcriptase polymerase chain reaction. Immunogenicity, reactogenicity, and safety were assessed.Results. There were 23 cases of confirmed 2009 pandemic influenza A(H1N1) (A[H1N1]pdm09) infection for the primary relative VE analysis. The VE in the Ad2 group relative to that in the NAd2 group was 76.8% (95% confidence interval, 18.5%–93.4%). The benefit of the AS03 adjuvant was demonstrated in terms of the greater immunogenicity observed in the Ad2 group, compared with the NAd2 group.Conclusion. The 4–8-fold antigen-sparing adjuvanted pandemic influenza vaccine demonstrated superior and clinically important prevention of A(H1N1)pdm09 infection, compared with nonadjuvanted vaccine, with no observed increase in medically attended or serious adverse events. These data support the use of adjuvanted influenza vaccines during influenza pandemics.Clinical Trials Registration. NCT01051661. [ABSTRACT FROM PUBLISHER]

Avian and animal influenza viruses can sporadically transmit to humans, causing outbreaks of varying severity. In some cases, further human-to-human virus transmission does not occur, and the outbreak in humans is limited. In other cases, sustained human-to-human transmission occurs, resulting in worldwide influenza pandemics. Preparation for future pandemics is an important global public health goal. A key objective of preparedness is to gain an understanding of how to design, test, and manufacture effective vaccines that could be stockpiled for use in a pandemic. This review summarizes results of an ongoing collaboration to produce, characterize, and clinically test a library of live attenuated influenza vaccine strains (based on Ann Arbor attenuated Type A strain) containing protective antigens from influenza viruses considered to be of high pandemic potential. [ABSTRACT FROM AUTHOR]

A variety of platforms are being explored for the development of vaccines for pandemic influenza. Observations that traditional inactivated subvirion vaccines and live-attenuated vaccines against H5 and some H7 influenza viruses were poorly immunogenic spurred efforts to evaluate new approaches, including whole virus vaccines, higher doses of antigen, addition of adjuvants and combinations of different vaccine modalities in heterologous prime-boost regimens to potentiate immune responses. Results from clinical trials of prime-boost regimens have been very promising. Further studies are needed to determine optimal combinations of platforms, intervals between doses of vaccines and the logistics of deployment in pre-pandemic and early pandemic settings. [ABSTRACT FROM AUTHOR]

Highlights: [•] Mbd2 enhances Ad vaccine-induced immune response early post vaccination. [•] Mbd2 immunostimulation confers protection against H5N1 by day 7 post vaccination. [•] This vaccine strategy has implications for pandemic influenza preparedness. [Copyright &y& Elsevier]

Please cite this paper as: Li et al. (2012) Immunogenicity and safety of a 2009 pandemic influenza A (H1N1) monovalent vaccine in Chinese infants aged 6-35 months: a randomized, double-blind, controlled phase I clinical trial. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12028. Objectives The goal of this double-blind, randomized, controlled clinical trial was to assess the safety and immunogenicity of two different doses of a monovalent split-virion 2009 pandemic influenza A/H1N1 vaccine without adjuvant in Chinese infants aged 6-35 months. Design and setting Subjects were randomly assigned to receive either a 2009 pandemic (H1N1) vaccine containing 7.5 or 15 μg haemagglutinin (HA) or a seasonal influenza vaccine. 2 doses of the H1N1 vaccines or the seasonal influenza vaccine were given 21 days apart in younger infants aged 6-23 months or older infants aged 24-35 months. Sample Serum samples were collected immediately before the first injection and before and 21 days after the second injection. Main outcome measures Primary outcomes were haemagglutinin inhibition (HI) antibody responses 21 days following each vaccination. Safety was monitoring throughout the study. Results The first vaccination of 7.5 μg and 15 μg H1N1 vaccine induced seroprotective antibody titers (HI titers ≥ 1: 40) in 42.9-57.4% of younger infants and 49.1-61.0% older infants. Immune responses after completion of the two dose schedule were comparable in both age groups with seroprotective rates of 91-98% in each vaccine and age group and GMTs of 173-263. The H1N1 vaccine elicited similar rates of local and systemic adverse reactions as the seasonal influenza vaccine. Conclusions The 2009 pandemic influenza A /H1N1 vaccine were highly immunogenic in infants aged 6-35 months, and displayed a safety and reactogenicity profile similar to the seasonal influenza vaccine. Trial registration ClinicalTrial.gov identifier: NCT01047202 [ABSTRACT FROM AUTHOR]

Background: Pandemic influenza vaccine manufacturing capacity and distribution agility is enhanced through the availability of equivalent antigen-sparing vaccines. We evaluated equivalence in terms of immunogenicity between GlaxoSmithKline Vaccines' A/California/7/2009 (H1N1)v-like-AS03 vaccines manufactured in Dresden (D-Pan), and Quebec (Q-Pan). Methods: In two studies, 334 adults 18-60 years of age received 2 doses of D-Pan or Q-Pan containing 3.75 μg haemagglutinin antigen (HA) adjuvanted with AS03A administered 21 days apart, and 209 children 3-9 years of age received 1 reduced dose of D-Panor Q-Pan (0.9 μg HA) or Q-Pan (1.9 μg HA) with AS03B. Haemagglutination inhibition (HI) titres were assessed before and 21 days post-vaccination. HI persistence was assessed after 12 months in adults and 6 months in children. Results: Pre-defined criteria for immunological equivalence of Q-Pan versus D-Pan were achieved in both populations. After one vaccine dose, ⩾97.6% of adults and children had HI titres ⩾1:40, with increases in titre ⩾25.7-fold. CHMP and CBER regulatory acceptance criteria for influenza vaccines were exceeded by all groups in both studies at Day 21. In adults,the percentage with HI titres ⩾1:40 at Month 12 was 82.9% (Q-Pan) and 84.0% (D-Pan). In children, the percentages at Month 6 were 75.3.3% (Q-Pan0.9), 85.1% (D-Pan0.9) and 79.3% (Q-Pan1.9). Safety profile of the study vaccines was consistent with previously published data. Conclusion: Two studies indicate that A/California/7/2009 (H1N1)v-like HA manufactured at two sites and combined with AS03 are equivalent in terms of immunogenicity in adults and children and highly immunogenic. Different HA doses elicited an adequate immune response through 180 days post-vaccination in children 3-9 years of age. [ABSTRACT FROM AUTHOR]

Abstract: With the current enzootic circulation of highly pathogenic avian influenza viruses, the ability to increase global pandemic influenza vaccine production capacity is of paramount importance. This has been highlighted by, and is one of the main pillars of, the WHO Global Action Plan for Influenza Vaccines (GAP). Such capacity expansion is especially relevant in developing countries. The Vaccine Formulation Laboratory at University of Lausanne is engaged in the technology transfer of an antigen-sparing oil-in-water adjuvant in order to empower developing countries vaccine manufacturers to increase pandemic influenza vaccine capacity. In a one-year project funded by United States Department of Health and Human Services, the Vaccine Formulation Laboratory transferred the process know-how and associated equipment for the pilot-scale manufacturing of an oil-in-water adjuvant to Bio Farma, Indonesia''s state-owned vaccine manufacturer, for subsequent formulation with H5N1 pandemic influenza vaccines. This paper describes the experience acquired and lessons learnt from this technology transfer project. [Copyright &y& Elsevier]

Abstract: Vaccination is the most effective method used to reduce the morbidity and mortality of influenza infections. However, as exemplified in the current swine-origin influenza virus (S-OIV) pandemic, the global manufacturing capacity of influenza vaccines is severely limited. In the present proof-of-concept study, we combined cell substrate selection and antigen engineering with adjuvant development to design a potential pandemic influenza vaccine candidate, in which CpG oligodeoxynucleotides (CpG-ODN) plus alum was used as a composite adjuvant to enhance the immunogenicity of insect cell-expressed recombinant hemagglutinin (rHA). Our candidate vaccine was found to be effective in inducing protective humoral as well as cellular immunity in mice and able to protect the immunized mice from related influenza virus challenge. If this candidate vaccine is validated in humans, vaccine development can be started immediately after the release of the first HA sequence of any pandemic influenza virus. Moreover, given the potential of large-scale manufacturing capacity of the recombinant antigen, in combination with the antigen-sparing effect of the composite adjuvant, this technology could be an invaluable asset in the fight against pandemic influenza. [Copyright &y& Elsevier]

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Abstract: Adverse events following pandemic (H1N1) 2009 vaccines (“2009 H1N1 vaccines”) in Taiwan were passively reported to the National Adverse Drug Reaction Reporting System. To evaluate the completeness of spontaneous reporting, cases of death, Guillain–Barré syndrome (GBS), convulsion, Bell''s palsy, and idiopathic thrombocytopenic purpura (ITP) after 2009 H1N1 vaccination that occurred between November 1, 2009 and August 31, 2010 were selected from the National Adverse Drug Reaction Reporting System (NADRRS) database and an additionally constructed nationwide large-linked database (LLDB), and matched on a unique personal identifier, date of vaccination (within ±7 days), and date of diagnosis (within ±7 days). Overall, matches occurred between the two data sources included 21 for death, 5 for GBS, 19 for convulsion, 22 for Bell''s palsy, and 5 for ITP. The Chapman capture–recapture estimated spontaneous reporting completeness within 0–42 days of vaccination was 4% for death, 71% for GBS, 3% for convulsion, 9% for Bell''s palsy, and 15% for ITP. For the interval ≥43 days after vaccination, reporting completeness was 0.1% for death, 14% for GBS, 0.1% for convulsion, <0.1% for Bell''s palsy, and 0% for ITP. The estimated-to-expected ratio for Bell''s palsy in the interval 0–42 days after vaccination was 1.48 (95% CI 1.11–1.98). Reporting completeness was higher for GBS than other adverse events after 2009 H1N1 vaccination. Linking the NADRRS to existing data sources in a capture–recapture analysis can be considered as an alternative to enhance Taiwan''s postlicensure safety assessment of other routine vaccines. Nevertheless, the possibility of an increased risk for Bell''s palsy detected by capture–recapture analyses needs further evaluation by controlled studies. [Copyright &y& Elsevier]

Abstract: In 1976 a swine influenza vaccine was associated with an increased risk of Guillain–Barré syndrome (GBS). Although subsequent studies did not find an increased risk of GBS following seasonal influenza vaccine, there was concern that the monovalent H1N1 vaccines developed against the swine influenza pandemic of 2009 might increase the risk of GBS. In the UK a split-virion AS03 oil-in-water adjuvanted vaccine (Pandemrix™) was predominantly used. To determine whether the risk of GBS increased after Pandemrix administration, we sought GBS cases during the period of vaccine use from neurologists and a patient support group, and following the vaccination period from hospital episode statistics (HES) in England. We obtained cases’ vaccination histories and illness onset dates from general practitioners. We determined the relative incidence of GBS in the 6 weeks after vaccination using the self-controlled case series method on the cases identified in HES. We included 327 GBS cases, of whom 37 received pandemic vaccine in the study period, nine of whom developed GBS within 6 weeks of vaccination (relative incidence 1.05 [95% confidence interval (CI) 0.37 to 2.24]). We found no evidence of an increased risk of GBS in the 6 weeks following pandemic influenza vaccination. [Copyright &y& Elsevier]

Abstract: Prior to marketing of pandemic influenza vaccines, the only safety data were those from clinical trials. The objective of this study was to compare information coming from spontaneous reporting with that systematically collected in a formal observation study; this also permits to further evaluate safety of pandemic influenza vaccines in the targeted patients’ population. Out of a sample of 507 vaccinated subjects, 103 (20.3%) developed some complication. In the same period 83 reports corresponding to all vaccinated people of Castilla y León (n =131,462) were collected. Severe cases were 1 (1%) and 7 (8.4%), respectively, with the two procedures. The spontaneous reporting rate was 322-fold lower than that identified through the follow-up study; when considered the severe cases, it was 37-fold lower. Under certain circumstances reporting might be performing better than usual due to strengthening of the surveillance system. Adverse events observed for the pandemic H1N1 vaccines lie within the expected safety profile for common events with influenza vaccines. An overall benefit-risk assessment of these vaccines should be done. [Copyright &y& Elsevier]

Abstract: It is predicted that in case of an influenza pandemic, there will be a significant gap between potentially available vaccine supply and international demand. This paved the way for a WHO Global Pandemic Influenza Action Plan (GAP) aiming at increasing the world''s production capacity for pandemic vaccine. In November 2006, six developing country manufacturers were awarded grants either to develop processes for production of inactivated or live attenuated seasonal and/or H5N1 influenza vaccines or for establishing filling facilities using imported antigens. In April 2009, spread of a new H1N1 influenza virus was identified which took a pandemic form. This paper gives an overview of influenza vaccine capacity building of developing country''s manufacturers identified in WHO''s GAP. Further, an account of developments at Serum Institute of India Limited (SIIL), one of recipients of WHO grant to develop pandemic influenza vaccine, are presented as a case study. Such initiatives have strengthened developing country vaccine manufacturers ability to respond to a pandemic situation in the future. [Copyright &y& Elsevier]

H9N2 subtype avian influenza viruses (AIVs) are widely distributed in avian species and were isolated from humans in Hong Kong and Guangdong province, China in 1999 raising concern of their potential for pandemic spread. We generated a high-growth reassortant virus (G9/PR8) that contains the hemagglutinin (HA) and neuraminidase (NA) genes from the H9N2 avian influenza virus A/chicken/Hong Kong/G9/97 (G9) and six internal genes from A/Puerto Rico/8/34 (PR8) by genetic reassortment, for evaluation as a potential vaccine candidate in humans. Pathogenicity studies showed that the G9/PR8 reassortant was not highly pathogenic for mice or chickens. Two doses of a formalin-inactivated G9/PR8 virus vaccine induced hemagglutination inhibiting antibodies and conferred complete protection against challenge with G9 and the antigenically distinct H9N2 A/Hong Kong/1073/99 (G1-like) virus in a mouse model. These results indicate that the high growth G9/PR8 reassortant has properties that are desirable in a vaccine seed virus and is suitable for evaluation in humans for use in the event of an H9 pandemic. [Copyright &y& Elsevier]