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Abstract: In a large comparative study in 2004–2005, children aged 6–59 months vaccinated with live attenuated influenza vaccine (LAIV) experienced 55% fewer cases of culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) recipients. To better understand the characteristics of the breakthrough influenza illnesses, we analyzed the HA1 genetic sequence for all available samples and examined disease severity by strain and treatment group. All 48 A/H1N1 viruses were well-matched to the vaccine, whereas all 276 A/H3N2 viruses and 349 (96%) influenza B viruses were mismatched to the vaccine. The incidence of fever or lower respiratory illness did not differ by strain; however, LAIV recipients had less febrile disease and fewer lower respiratory illnesses than TIV recipients. Viruses of each influenza B lineage caused more illnesses than A/H1N1 viruses; strategies to enhance protection against multiple influenza B lineages should be pursued. [Copyright &y& Elsevier]

Abstract: Seasonal influenza vaccines, including live attenuated influenza vaccine (LAIV), contain three vaccine strains (two type A and one type B). Ideally, the hemagglutinin antigens of the recommended vaccine strains are antigenically similar to epidemic wild-type strains; in actuality, the antigenic match between circulating and vaccine strains each year can vary significantly owing to intermittent genetic reassortment and continuous antigenic drift. For influenza B, antigenic relatedness is further complicated by the existence of two distinct lineages. Consequently, the influenza B vaccine component can be of a completely different antigenic lineage from the circulating epidemic strains. Using data from nine randomized clinical trials in young children (6 months to 6 years of age), vaccine efficacy of LAIV against influenza B strains was assessed across this spectrum of antigenic relatedness. In an integrated analysis, vaccine efficacy of two doses of LAIV in vaccine-naive children was 86% against B strains of the same lineage and closely matched to the vaccine strain, 55% against strains of the same lineage but antigenically drifted from the vaccine strain, and 31% against strains of the opposite B lineage and antigenically unrelated to the vaccine strain. These data provide a more accurate assessment of the protection provided by the current trivalent vaccine and highlight the need for vaccination strategies that provide enhanced protection against both lineages of influenza B such as a quadrivalent influenza vaccine. [Copyright &y& Elsevier]

Abstract: The present study was undertaken with controls using equal doses ID and IM plus the standard full dose IM to assess the role of route of vaccine in immunogenicity of inactivated influenza vaccine. The study was a prospective, randomized, active-controlled, open label clinical trial conducted in healthy young adult outpatients to compare the effect of route (IM versus ID) on antibody responses to influenza vaccine. Volunteers received 3, 6 or 9μg of vaccine by ID or IM route; 15μg IM was also studied. Low doses of vaccine given by either route were almost as immunogenic as the standard 15μg IM dose of influenza vaccine. ID route was not superior to IM vaccine at inducing antibodies. ID vaccine induced significantly more local inflammatory response than IM vaccine. [Copyright &y& Elsevier]

Abstract: Seasonal influenza epidemics represent a substantial public health burden, causing significant morbidity and mortality. Influenza in humans can be caused by influenza type A and type B viruses, and although influenza A is responsible for the majority of seasonal influenza infections, influenza B disease is common in children and young adults, and causes seasonal epidemics every 2–4 years. Influenza strains circulating during a seasonal epidemic may be influenza type A strains A/H1N1 and A/H3N2, strains of influenza B lineages B/Victoria and B/Yamagata, or any combination of these. The morbidity and mortality burden of influenza infections means that public health agencies worldwide recommend vaccination to try and protect against seasonal epidemics. The World Health Organization (WHO) and, in the United States of America (USA), the Food and Drug Administration (FDA), recommend trivalent seasonal influenza vaccines containing the two main influenza type A strains and, due to its lesser but still important prevalence, one influenza type B strain. There is little or no cross-reactive protection between the influenza B lineages: this means that good protection against the circulating virus relies on correctly predicting the prevalent influenza B lineage in any season. This has proved to be reliant on chance, and little or no protection has been provided in the USA by the trivalent vaccines against the circulating influenza B virus in 5 of the 10 seasons between 2001 and 2010. There is, therefore, a clear need for a quadrivalent influenza vaccine, containing influenza A/H1N1, A/H3N2, and B/Victoria and B/Yamagata lineage strains, to improve protection against influenza B virus and reduce the morbidity of influenza B infection. [ABSTRACT FROM AUTHOR]

Abstract: Three pivotal trials supported the licensure of live attenuated influenza vaccine (LAIV) for children ≥2 years of age: 2 placebo-controlled studies each conducted over 2 seasons, and a 1-year trial comparing LAIV with trivalent inactivated influenza vaccine (TIV). Analyses were conducted to evaluate the safety and efficacy of LAIV in the subgroup of children ≥2 years of age from these trials. Efficacy was demonstrated compared with placebo in children aged 2–7 years in seasons with matched strains (69.2% [95% CI: 52.7, 80.4] and 94.6% [95% CI: 88.6, 97.5]), seasons with primarily mismatched strains (87% [95% CI: 77.0, 92.6]), and during late season epidemics (73.8% [95% CI: 40.4, 89.4]). Compared with TIV recipients, LAIV recipients aged 2–5 years had 52.5% (95% CI: 26.7, 68.7) and 54.4% (95% CI: 41.8, 64.5) fewer cases of influenza illness against matched and mismatched strains, respectively. No unusual or unexpected adverse reactions were noted. The adverse reactions most commonly associated with LAIV were runny nose/nasal congestion and low-grade fever. Hospitalizations and medically significant wheezing were increased in children 6–11 and 6–23 months of age who received LAIV, respectively, but were not increased in children 2–5 years of age. [Copyright &y& Elsevier]

Abstract: Background: The US Advisory Committee on Immunization Practices (ACIP) recently expanded the influenza vaccine recommendation to include children 24–59 months of age. In a large head-to-head randomized controlled trial, live attenuated influenza vaccine, trivalent (LAIV) demonstrated a 54% relative reduction in culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) among children aged 24–59 months. Objective: To evaluate the relative cost and benefit between two influenza vaccines (LAIV and TIV) for healthy children 24–59 months of age. Methods: Using patient-level data from the clinical trial supplemented with cost data from published literature, we modeled the cost-effectiveness of these two vaccines. Effectiveness was measured in quality-adjusted life years (QALY) and cases of influenza avoided. The analysis used the societal perspective. Results: Due to its higher acquisition cost, LAIV increased vaccination costs by $7.72 per child compared with TIV. However, compared with TIV, LAIV reduced the number of influenza illness cases and lowered the subsequent healthcare use of children and productivity losses of parents. The estimated offsets in direct and indirect costs saved $15.80 and $37.72 per vaccinated child, respectively. LAIV had a net total cost savings of $45.80 per child relative to TIV. One-way and probabilistic sensitivity analyses indicated that the model was robust across a wide range of relative vaccine efficacy and cost estimates. Conclusions: Due to its increased relative vaccine efficacy over TIV, LAIV reduced the burden of influenza and lowered both direct health care and societal costs among children 24–59 months of age. [Copyright &y& Elsevier]

Abstract: Early in the development of respiratory syncytial virus (RSV) vaccines severe disease occurred in children after receipt of formalin-inactivated RSV vaccine. Continuing efforts to develop an appropriately attenuated and immunogenic live RSV vaccine have given opportunities to assure that live vaccines are safe through surveillance of children after vaccination. In the present study, the rate of RSV-associated upper respiratory tract illness in 388 children was lower in RSV vaccinated children than in controls (14% versus 20% in a 6–24 month old group and 16% versus 25% in infants). Additionally, there was no evidence that vaccination predisposed to more severe lower respiratory tract illness. Thus infection with a series of live attenuated RSV vaccines did not result in enhanced disease upon infection with wild type RSV. The impact of RSV during this surveillance will inform the design of future efficacy studies with RSV vaccines. [Copyright &y& Elsevier]

A vaccine against Respiratory Syncytial Virus (RSV) is a major unmet need to prevent the significant morbidity and mortality that it causes in society. In addition to efficacy, such a vaccine must not induce adverse events, as previously occurred with a formalin-inactivated vaccine (FI-RSV). In this study, the safety, immunogenicity and efficacy of a molecularly adjuvanted adenovirus serotype 5 based RSV vaccine encoding the fusion (F) protein (Ad-RSVF) is demonstrated in cotton rats. Protective immunity to RSV was induced by Ad-RSVF when administered by an oral route as well as by intranasal and intramuscular routes. Compared to FI-RSV, the Ad-RSVF vaccine induced significantly greater neutralizing antibody responses and protection against RSV infection. Significantly, oral or intranasal immunization each induced protective multi-functional effector and memory B cell responses in the respiratory tract. This study uniquely demonstrates the capacity of an orally administered adenovirus vaccine to induce protective immunity in the respiratory tract against RSV in a pre-clinical model and supports further clinical development of this oral Ad-RSVF vaccine strategy. [ABSTRACT FROM AUTHOR]

Introduction Intentional aerosolization of Yersinia pestis may result in pneumonic plague which is highly fatal if not treated early. Methods We conducted a phase 1 randomized, double blind (within each group), placebo controlled, dose escalation trial to evaluate a plague vaccine, Flagellin/F1/V, in healthy adults aged 8 through 45 years. Vaccine was administered intramuscularly on Days 0 and 28 at a dose of 1, 3, 6 or 10 mcg. Subjects were observed for 4 h after vaccination for cytokine release syndrome. Reactogenicity and adverse events (AE) were collected for 14 and 28 days, respectively, after each vaccination. Serious AE were collected for the entire study. ELISA antibody and cytokines were measured at multiple time points. Subject’s participation lasted 13 months. Results Sixty healthy subjects were enrolled; 52% males, 100% non-Hispanic, 91.7% white and mean age 30.8 years. No severe reactogenicity events occurred; most AE were mild. No serious AE related to vaccine occurred. A dose response effect was observed to F1, V and flagellin. The peak ELISA IgG antibody titers (95% CI) after two 10 mcg doses of vaccine were 260.0 (102.6–659.0) and 983.6 (317.3–3048.8), respectively, against F1 and V antigens. The 6 mcg dose group provided similar titers. Titers were low for the placebo, 1 mcg and 3 mcg recipients. A positive antibody dose response was observed to F1, V and flagellin. Vaccine antigen specific serum IgE was not detected. There were no significant rises in serum or cellular cytokine responses and no significant IgG increase to flagellin after the second dose. Conclusion The Flagellin/F1/V vaccine exhibited a dose dependent increase in immunogenicity and was well tolerated at all doses. Antibody specific responses to F1, V and flagellin increased as dose increased. Given the results from this trial, testing higher doses of the vaccine may be merited. [ABSTRACT FROM AUTHOR]

Measurement of neutralizing antibodies against herpes simplex virus (HSV) is important for evaluation of candidate vaccines. The established plaque-reduction neutralization assay is time consuming, labor intensive, and difficult to validate and transfer. Here, we describe the characterization of a HSV-neutralization assay based on the expression of a reporter gene, β-galactosidase (β-Gal). Using previously constructed HSV-β-Gal recombinant viruses, HSV-2/Gal and HSV-1/tk12, we developed a colorimetric β-Gal-based neutralization assay that is sensitive and highly reproducible, and performed in less than 48 h. HSV-1 and HSV-2 neutralizing titers measured by the β-Gal-based neutralization assay were equivalent to those obtained by a plaque reduction neutralization assay. Intra- and inter-assay precision studies demonstrated that the β-Gal-based assay was repeatable and yielded low and acceptable variation. In addition, comparison of HSV-2 neutralizing antibody (NAb) titers measured in two independent laboratories by two unique β-Gal-based assays showed a highly significant correlation ( r = 0.9499, p < 0.0001) between the two assays. The new assay will serve as an important tool both for preclinical and clinical trials of new HSV vaccines. [ABSTRACT FROM AUTHOR]

Purpose The study aims were to determine whether inactivated influenza A/H5N1 vaccine administration elicited cell mediated immune (CMI) responses and the impact of adjuvant, vaccine dose and subject age on these responses. Methods Adults who were previously primed with either adjuvanted or unadjuvanted, inactivated, A/H5N1/Vietnam/1203/2004 (Clade 1) vaccine or unprimed (received placebo) in previous vaccine studies were randomized to receive one (primed) or two (unprimed) 15- or 90-mcg doses of inactivated, A/H5N1/Indonesia/05/05 (Clade 2) vaccine. Peripheral blood mononuclear cells (PBMCs) were collected and analyzed from a subset of vaccinees to assess CMI responses using IFN-γ and granzyme B ELISPOT assays. Cytokine measurements were performed on PBMC supernatants after stimulation with H5N1 virus. Results PBMCs were available from 177 participants; 88 and 89 received 15-mcg and 90-mcg of unadjuvanted clade 2 vaccine, respectively. Following H5N1 clade 1 stimulation, IFN-γ but not granzyme B normalized spot-forming cell numbers had statistically significant increased numbers at each of the post-vaccination timepoints compared to baseline in pooled analyses of all vaccine doses and age groups. Clade 2 stimulation resulted in statistically significant increased numbers of IFN-γ cells only 180 days following the last vaccination. Responses were similar among younger and older study participants, as were responses among those primed with alum-adjuvanted or non-adjuvanted clade 1 H5N1 vaccines. The dosage of clade 2 vaccine did not impact CMI responses among primed subjects, but responses were statistically significantly greater in unprimed recipients of the 90-mcg dosage compared to unprimed recipients of the 15-mcg dosage. IFN-γ levels in the supernatants of stimulated PBMC were strongly correlated with IFN-γ ELISPOT results. Conclusion CMI responses occur in adults administered influenza A/H5N1 inactivated influenza vaccine. [ABSTRACT FROM AUTHOR]

Background During the 2009 influenza pandemic both seasonal and 2009 pandemic vaccines were recommended. We conducted a randomized trial of monovalent 2009-H1N1 vaccine and seasonal trivalent inactivated influenza vaccine (IIV3) given sequentially or concurrently to adults. Methods Adults randomized to 4 study groups and stratified by age (18–64 and ≥65 years) received 1 dose of seasonal IIV3 or placebo and 2 doses of 2009-H1N1 vaccine or placebo in one of 4 combinations, i.e., H1N1 + Placebo/H1N1 + Placebo/ II V 3 (HP/HP/ V3 ), H1N1 + IIV3 /H1N1 + Placebo/Placebo (H V3 /HP/P), H1N1 + Placebo/H1N1 + IIV3 /Placebo (HP/H V3 /P), and IIV3 + Placebo/H1N1 + Placebo/H1N1 ( V3 P/HP/H). Intramuscular injections were given three times at 21 day intervals. Sera for antibody assays were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. Results Eight hundred-five (805) adults were enrolled. All combinations of vaccines were safe and well tolerated. In general, one dose of 2009-H1N1 and one dose of IIV3, regardless of sequence or concurrency of administration, were immunogenic in adults. There were no significant differences in geometric mean titers (GMT) or the proportions of subjects with ≥4-fold rise in antibody responses and titers ≥40 for any vaccine group or between age strata for 2009-H1N1 after the first or second dose, although the vaccine sequence affected the titers to the IIV3 antigens. Hemagglutination inhibition antibody (HAI) GMTs against 2009-H1N1 for the combined age strata 21 days after the first 2009-H1N1 dose were 190.4, 182.1, 232.9 and 157.5 for HP/HP/ V3 , H V3 /HP/P, HP/H V3 /P and V3 P/HP/H, respectively. While IIV3 GMTs were adequate they were generally lower than the 2009-H1N1 GMTs. In a subset of subjects, there was good correlation between HAI and microneutralization (MN) titers (Spearman's correlation coefficient 0.92). Conclusions All vaccine combinations were generally well tolerated. Immune responses to one dose of 2009-H1N1 were adequate regardless of the sequence of vaccination in all age groups, but the sequence affected titers to IIV3 antigens. [ABSTRACT FROM AUTHOR]

Highlights: [•] A single dose of high titer MVA vaccine was compared to 1 or 2 standard doses. [•] High dose MVA was safe and well-tolerated. [•] Median time to seroconversion was similar between the two groups. [•] ELISA and PRNT peak titers after 1 high dose were higher than 1 standard dose. [•] ELISA and PRNT peak titers after 1 high dose were inferior to 2 standard doses. [Copyright &y& Elsevier]

Highlights: [•] Reintroduction of Variola major as an agent of bioterrorism remains a concern. [•] A compressed schedule of MVA was evaluated for use in a post event scenario. [•] MVA is well tolerated when given as two standard doses at Days 0 and 28 or 0 and 7. [•] A 2nd dose of MVA at Day 28 compared to Day 7 provided greater antibody responses. [•] INF-γ expression was greatest within 2 weeks after last vaccination. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hepatitis C virus (HCV) causes chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. In animal studies, chimpanzees were protected against chronic infection following experimental challenge with either homologous or heterologous HCV genotype 1a strains which predominate in the USA and Canada. We describe the first in humans clinical trial of this prophylactic HCV vaccine. Methods: HCV E1E2 adjuvanted with MF59C.1 (an oil-in-water emulsion) was given at 3 different dosages on day 0 and weeks 4, 24 and 48 in a phase 1, placebo-controlled, dose escalation trial to healthy HCV-negative adults. Results: There was no significant difference in the proportion of subjects reporting adverse events across the groups. Following vaccination subjects developed antibodies detectable by ELISA, CD81 neutralization and VSV/HCV pseudotype neutralization. There were no significant differences between vaccine groups in the number of responders and geometric mean titers for each of the three assays. All subjects developed lymphocyte proliferation responses to E1E2 and an inverse response to increasing amounts of antigen was noted. Conclusions: The vaccine was safe and generally well-tolerated at each of the 3 dosage levels and induced antibody and lymphoproliferative responses. A larger study to further evaluate safety and immunogenicity is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Background: Development of vaccines against highly pathogenic avian influenza virus H5N1 subtypes posing a pandemic threat remains a priority. Limitations in manufacturing capacity and production time of conventional inactivated vaccines highlight the need for additional approaches. Methods: We conducted two double-blind, placebo-controlled phase 1 studies involving a total of 103 healthy adults who received two intramuscular injections of Vaxfectin®-adjuvanted plasmid DNA vaccine or placebo 21 days apart. Vaccine cohorts received either a monovalent vaccine containing an A/Vietnam/1203/04 H5 hemagglutinin-encoding plasmid or a trivalent vaccine with plasmids encoding H5, NP, and M2 proteins in doses from 0.1 to 1mg of DNA/injection. Results: All doses were well tolerated without vaccine-related serious adverse events or discontinuations. In the monovalent cohorts, hemagglutination inhibition (HI) titers of ≥40 and 4-fold rises from baseline were achieved in 47–67% of subjects and H5-specific T-cell responses in 75–100%. Trivalent cohorts had lower HI response rates (≤20%), but 72% of subjects achieved T-cell and/or antibody responses to one or more antigens. Conclusions: Vaxfectin®-adjuvanted monovalent H5 DNA vaccines were well tolerated and induced HI response rates and titers in the reported range of inactivated protein-based H5 vaccines, suggesting that adjuvanted DNA vaccines with rapid vaccine production could be useful for pandemic control. [Copyright &y& Elsevier]

Abstract: Smallpox vaccination with replication deficient vaccinia strains such as Modified Vaccinia Ankara (MVA) may induce protective immunity with improved safety and tolerability profiles compared with currently available smallpox vaccines. Ninety subjects were randomized equally to six groups in a partially blinded, randomized, controlled clinical trial. IMVAMUNE® (MVA-BN®, Bavarian Nordic A/S, Kvistgård, Denmark) vaccine or placebo was administered at Study Days 0 and 28 by subcutaneous or intramuscular injection and five groups were challenged with Dryvax® at study Day 112. Vaccination with two doses of IMVAMUNE® was safe and well tolerated compared to Dryvax®. IMVAMUNE® produced comparable cellular and humoral immune responses to one dose of Dryvax® and the immunity induced appears robust 90 days post-vaccination by evidence of attenuated primary cutaneous reaction responses following Dryvax®. IMVAMUNE® vaccination prior to Dryvax® reduced virus replication at the Dryvax® site, decreased the size of the primary cutaneous lesion, and decreased the time to healing but did not completely ameliorate the immune response. [Copyright &y& Elsevier]

Abstract: Background: This study examined the transmissibility between young children of an intranasally administered live attenuated human parainfluenza virus type 3 (HPIV3)-cp45 vaccine candidate. Methods: Eighty subjects were enrolled in playgroups among whom there was at least one infected vaccinee in close contact with a seronegative placebo recipient over 21 days without a confounding infection with wtHPIV3. Following vaccination viral cultures were obtained on nine occasions to detect shedding and transmission of HPIV3cp45. Serum antibody titers were measured before and 7 weeks after vaccination. Results: No child fulfilled the criteria for transmission of HPIV3cp45 giving a risk of transmission of 0.04 (95% CI 0.01–0.19), hence establishing that HPIV3cp45 is less infectious than wtHPIV3 and risk of transmission is not a limitation to further clinical development of this vaccine candidate. [Copyright &y& Elsevier]

Binding of antibodies to oligomeric envelope glycoprotein of R5-tropic primary isolates of human immunodeficiency virus type 1 (HIV-1) was studied by flow cytometry using sera from HIV-1 vaccine recipients and clade B and C HIV-1-infected patients, and monoclonal and polyclonal antibodies to neutralizing epitopes of HIV-1. Vaccine recipients received recombinant canarypox virus vaccine expressing HIV-1 gene products, and SF-2 recombinant gp120 subunit vaccine. Anti-gp120 neutralizing antibodies including human monoclonal antibody 2G12 and goat polyclonal anti-serum to V3 loop peptide [peptide T1-SP10MN(A)] bound to HIV-1-infected cells. Sera from vaccine recipients bound to HIV-1-infected cells, but at levels lower than did infected patient sera. [Copyright &y& Elsevier]

A recent study of inactivated influenza vaccine (IIV) in children aged 3–8 years demonstrated higher efficacy against moderate/severe influenza. A meta-analysis of all previous published randomized clinical trials of live attenuated influenza vaccine (LAIV) that collected information on illness severity in children aged 24–71 months was conducted. Moderate/severe influenza was defined as fever >39 °C, acute otitis media, or lower respiratory tract illness; other cases were classified as milder influenza. LAIV efficacy versus placebo was 95.4% [95% confidence interval: 88.5, 98.1] (year 1) and 88.5% [77.4, 94.9] (year 2) against moderate/severe influenza and 91.4% [77.9, 96.7] (year 1) and 84.2% [56.7, 94.3] (year 2) against milder influenza. The relative efficacy of LAIV versus IIV was 52.2% [31.6, 66.6] for moderate/severe influenza and 45.0% [28.6, 57.5] for milder influenza. Efficacy against all influenza illnesses, regardless of severity, is critical to prevent influenza illness and transmission in the community. [ABSTRACT FROM AUTHOR]