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Recent studies have shown that live attenuated influenza vaccines (LAIVs) expressing avian influenza virus hemagglutinins (HAs) prime for strong protective antibody responses to an inactivated influenza vaccine (IIV) containing the HA. To better understand this priming effect, we compared H7 HA head and stalk domain-specific B-cell responses in H7N7 LAIV-primed subjects and non-H7-primed controls after a single dose of H7N7 IIV. As previously reported, H7N7 LAIV-primed subjects but not control subjects generated strong hemagglutination-inhibiting and neutralizing antibody responses to the H7N7 IIV. Here, we found that the quantity, epitope diversity, and affinity of H7 head-specific antibodies increased rapidly in only H7N7 LAIV-primed subjects after receipt of the IIV. However, all cohorts generated a vigorous, high-affinity, stalk-specific antibody response. Consistent increases in circulating memory B-cell frequencies after receipt of the IIV reflected the specificity of high-affinity antibody production. Our findings emphasize the value of LAIVs as a vehicle for prepandemic vaccination. [ABSTRACT FROM AUTHOR]

Abstract: Background: We evaluated the safety and immunogenicity profiles of 3 novel influenza vaccine constructs consisting of the globular head of the HA1 domain of the Novel H1N1 genetically fused to the TLR5 ligand, flagellin. HA1 was fused to the C-terminus of flagellin in VAX128A, replaced the D3 domain of flagellin in VAX128B and was fused in both positions in VAX128C. Methods: In a dose escalation trial, 112 healthy subjects 18–49 and 100 adults ≥65 years old were enrolled in a double blind, placebo controlled clinical trial at two centers. Vaccines were administered IM at doses ranging from 0.5 to 20μg. VAX128C was selected for second study performed in 100 subjects 18–64 years old comparing 1.25 and 2.5μg doses. All subjects were followed for safety and sera collected pre- and post-vaccination were tested by hemagglutination-inhibition (HAI). Serum C-reactive protein and cytokine levels were also measured. Conclusions: In the first study high HAI titers and high seroconversion and seroprotection rates were observed at doses ≥2.5μg in adults 18–49. In adults ≥65 years, the vaccines doses of ≥4μg were required to induce a ≥4-fold rise in HAI titer, 50% seroconversion and 70% seroprotection. Based on safety, VAX128A was tested up to 8μg, VAX128B to 16μg and VAX128C to 20μg. Dose escalation for VAX128A was stopped at 8μg because one subject had temperature 101.6°F associated with a high CRP response, VAX128B was stopped at 16μg because of a severe AE associated with a high CRP and IL-6 response. VAX128C was not stopped before reaching the 20μg dose. In the second study VAX128C was well tolerated among 100 subjects who received 1.25 or 2.5μg. The peak GMT was 385 (95%CI 272–546), 79% (71–87%) seroconversion and 92% (84–96%) seroprotection. Discussion: Flagellin adjuvanted vaccines can be designed to minimize reactogenicity and retain immunogenicity, thereby representing a promising next generation vaccine technology. [Copyright &y& Elsevier]

Background: Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US. Methods: The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period. Results: Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval [CI] lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity. Conclusions: Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk. Trial registration: NCT00216242. [ABSTRACT FROM AUTHOR]

Previously, we evaluated 2 doses of H5N1 influenza vaccine in persons 18-64 years of age (placebo and 7.5-, 15-, 45-, or 90-µg doses), separated by 28 days. In this study, 337 participants received a third dose, 6 months thereafter. Microneutralization (MN) and hemagglutination-inhibition geometric mean titers (GMTs) of antibody declined before the third dose. Twenty-eight days after the third dose, 78%, 67%, 43%, and 31% of recipients in the 90-, 45-, 15-, and 7.5-µg-dose groups had a MN GMT ≥ 1:40, respectively. Five months later, MN GMTs were significantly greater than those after the second dose. (Trial registration: Clinical Trials.gov identifier NCT00240968.) [ABSTRACT FROM AUTHOR]

The article presents a randomized controlled trial that examined the safety, immunogenicity, and efficacy of a trivalent influenza virus hemagglutinin vaccine that was produced in insect cells using recombinant baculoviruses. The authors of the study found that the vaccine was safe and immunogenic in a healthy population of adults. They also found preliminary evidence that showed the vaccine had a protective effect against a drifted influenza A virus. The inclusion of a neuraminidase component was not required for the protective effect.

Background A pandemic H5N1 influenza outbreak would be facilitated by an absence of immunity to the avian-derived virus in the human population. Although this condition is likely in regard to hemagglutinin-mediated immunity, the neuraminidase (NA) of H5N1 viruses (avN1) and of endemic human H1N1 viruses (huN1) are classified in the same serotype. We hypothesized that an immune response to huN1 could mediate cross-protection against H5N1 influenza virus infection. Methods and Findings Mice were immunized against the NA of a contemporary human H1N1 strain by DNA vaccination. They were challenged with recombinant A/Puerto Rico/8/34 (PR8) viruses bearing huN1 (PR8-huN1) or avN1 (PR8-avN1) or with H5N1 virus A/Vietnam/1203/04. Additional naïve mice were injected with sera from vaccinated mice prior to H5N1 challenge. Also, serum specimens from humans were analyzed for reactivity with avN1. Immunization elicited a serum IgG response to huN1 and robust protection against the homologous challenge virus. Immunized mice were partially protected from lethal challenge with H5N1 virus or recombinant PR8-avN1. Sera transferred from immunized mice to naïve animals conferred similar protection against H5N1 mortality. Analysis of human sera showed that antibodies able to inhibit the sialidase activity of avN1 exist in some individuals. Conclusions These data reveal that humoral immunity elicited by huN1 can partially protect against H5N1 infection in a mammalian host. Our results suggest that a portion of the human population could have some degree of resistance to H5N1 influenza, with the possibility that this could be induced or enhanced through immunization with seasonal influenza vaccines. [ABSTRACT FROM AUTHOR]

Seasonal influenza continues to have a huge annual impact in the United States, accounting for tens of millions of illnesses, hundreds of thousands of excess hospitalizations, and tens of thousands of excess deaths. Vaccination remains the mainstay for the prevention of influenza. In the United States, 2 types of influenza vaccine are currently licensed: trivalent inactivated influenza vaccine and live attenuated influenza vaccine. Both are safe and effective in the populations for which they are approved for use. Children, adults <65 years of age, and the elderly all receive substantial health benefits from vaccination. In addition, vaccination appears to be cost-effective, if not cost saving, across the age spectrum. Despite long-standing recommendations for the routine vaccination of persons in high-priority groups, US vaccination rates remain too low across all age groups. Important issues to be addressed include improving vaccine delivery to current and expanded target groups, ensuring timely availability of adequate vaccine supply, and development of even more effective vaccines. Development of a vaccine against potentially pandemic strains is an essential part of the strategy to control and prevent a pandemic outbreak. The use of existing technologies for influenza vaccine production would be the most straightforward approach, because these technologies are commercially available and licensing would be relatively simple. Approaches currently being tested include subvirion inactivated vaccines and cold-adapted, live attenuated vaccines. Preliminary results have suggested that, for some pandemic antigens, particularly H5, subvirion inactivated vaccines are poorly immunogenic, for reasons that are not clear. Data from evaluation of live pandemic vaccines are pending. Second-generation approaches designed to provide improved immune responses at lower doses have focused on adjuvants such as alum and MF59, which are currently licensed for influenza or other vaccines. Additional experimental approaches are required to achieve the ultimate goal for seasonal and pandemic influenza prevention—namely, the ability to generate broadly cross-reactive and durable protection in humans. [ABSTRACT FROM AUTHOR]

Background: Although influenza vaccination is recommended in persons infected with HIV-1, its efficacy is unknown.Objective: To assess the immunogenicity, efficacy, and risks associated with influenza vaccination in persons infected with HIV-1.Design: Randomized, double-blind, placebo-controlled trial.Setting: Outpatient military clinic.Patients: 102 patients with HIV-1 infection.Intervention: Influenza vaccine (n = 55) or saline placebo (n = 47).Measurements: Influenza antibody titers, CD4+ cell counts, and plasma HIV-1 RNA levels at baseline, 1 month after immunization, and 3 months after immunization; viral cultures from persons presenting with respiratory illness; and respiratory symptom interview.Results: Twenty-three placebo recipients (49%) and 16 vaccine recipients (29%) reported respiratory symptoms (P = 0.04). Ten placebo recipients but no vaccine recipients had laboratory-confirmed symptomatic influenza (P < 0.001) (protective efficacy, 100% [95% CI, 73% to 100%]). No effect on plasma HIV-1 RNA levels or CD4+ cell counts was noted.Conclusion: Influenza vaccination is highly effective in HIV-1-infected persons and does not seem to be associated with substantial changes in viral load or CD4 cell count. [ABSTRACT FROM AUTHOR]

The author emphasizes the need to expand the options for addressing pandemic influenza. He cites the limitation of vaccination in preventing pandemic influenza. He discuss two reports that offer information on pandemic influenza prevention, including a randomized clinical trial involving patients who received influenza A/Shanghai/2/13 (H7N9) inactivated virus vaccine intramuscularly. He also cites the need to do further research on hemagglutinin inhibition and neutralizing antibody.

OBJECTIVES: The recombinant influenza vaccine is well established in adults >18 years of age abstract for preventing seasonal influenza disease. In this randomized controlled trial, we compared the safety and immunogenicity of the quadrivalent, recombinant influenza vaccine (RIV4) versus the inactivated influenza vaccine in children and adolescents 6 to 17 years of age. METHODS: Two age cohorts were enrolled sequentially: 159 subjects aged 9 to 17 years and, after reviewing for safety, 60 children aged 6 to 8 years. Enrollment of the younger children was halted prematurely at the onset of the influenza season. Subjects in each cohort were randomly assigned 1:1 to the RIV4 or inactivated vaccine. Hemagglutination inhibition antibody titers were obtained before and 28 days after vaccination. Tolerability and safety were monitored for 7 days and 6 months after vaccination, respectively. RESULTS: Both vaccines were well tolerated in both age groups, and long-term follow-up revealed no vaccine-related adverse events. Overall, immunogenicity (geometric mean titers and seroconversion rate differences) provided comparable antibody responses to most antigens in both vaccines in the older subjects. Low responses to the influenza B Victoria lineage in both vaccines made interpretation difficult. Immunogenicity in younger children was similar, but the truncated sample size was insufficient to support noninferiority comparisons. CONCLUSIONS: Despite low responses to influenza B lineages in both vaccines, the RIV4 provided safety and immunogenicity that were comparable to those of the licensed inactivated vaccine in pediatric subjects, which was most convincing in those aged 9 to 17 years. Future confirmatory clinical efficacy trials may be used to support the recombinant influenza vaccine as an alternative for the pediatric age group of >6 years. [ABSTRACT FROM AUTHOR]

Abstract: Periodic outbreaks of pandemic influenza have been a devastating cause of human mortality over the past century. More recently, an avian influenza strain, designated H5N1, has been identified as having the potential to cause a zoogenic pandemic in humans, and a current outbreak of a new H1N1 influenza variant hypothesized to be of swine origin is of considerable concern. In order to facilitate surveillance and the rapid assessment and comparison of vaccination efforts, a high-throughput assay is highly desirable to supplement standard methods, which require high biosafety-level facilities. In this paper, we describe the design, production, and preliminary evaluation of an antigen array incorporating a panel of hemagglutinins as a platform for the detection and rapid quantification of influenza-specific antibodies in human serum by Arrayed Imaging Reflectometry (AIR), a label-free optical biosensor. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few observational studies have evaluated the relative effectiveness of live attenuated (LAIV] and inactivated (IIV] influenza vaccines against medically attended laboratory-confirmed influenza. METHODS: We analyzed US Influenza Vaccine Effectiveness Network data from participants aged 2 to 17 years during 4 seasons (2010-2011 through 2013-2014] to compare relative effectiveness of LAIV and IIV against influenza-associated illness. Vaccine receipt was confirmed via provider/electronic medical records or immunization registry. We calculated the ratio (odds] of influenza-positive to influenza-negative participants among those age-appropriately vaccinated with either LAIV or IIV for the corresponding season. We examined relative effectiveness of LAIV and IIV by using adjusted odds ratios (ORs] and 95% confidence intervals (CIs] from logistic regression. RESULTS: Of 6819 participants aged 2 to 17 years, 2703 were age-appropriately vaccinated with LAIV (n = 637] or IIV (n = 2066], Odds of influenza were similar for LAIV and IIV recipients during 3 seasons (2010-2011 through 2012-2013]. In 2013-2014, odds of influenza were significantly higher among LAIV recipients compared with IIV recipients 2 to 8 years old (OR 5.36; 95% CI, 2.37 to 12.13], Participants vaccinated with LAIV or IIV had similar odds of illness associated with influenza A/H3N2 or B. LAIV recipients had greater odds of illness due to influenza A/HlNlpdm09 in 2010-2011 and 2013-2014. CONCLUSIONS: We observed lower effectiveness of LAIV compared with IIV against influenza A/HlNlpdm09 but not A(H3N2] or B among children and adolescents, suggesting poor performance related to the LAIV A/HlNlpdm09 viral construct. [ABSTRACT FROM AUTHOR]