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Background: The 2022/23 influenza season in the United Kingdom saw the return of influenza to prepandemic levels following two seasons with low influenza activity. The early season was dominated by A(H3N2), with cocirculation of A(H1N1), reaching a peak late December 2022, while influenza B circulated at low levels during the latter part of the season. From September to March 2022/23, influenza vaccines were offered, free of charge, to all aged 2-13 (and 14-15 in Scotland and Wales), adults up to 49 years of age with clinical risk conditions and adults aged 50 and above across the mainland United Kingdom., Methods: End-of-season adjusted vaccine effectiveness (VE) estimates against sentinel primary-care attendance for influenza-like illness, where influenza infection was laboratory confirmed, were calculated using the test negative design, adjusting for potential confounders., Methods: Results In the mainland United Kingdom, end-of-season VE against all laboratory-confirmed influenza for all those > 65 years of age, most of whom received adjuvanted quadrivalent vaccines, was 30% (95% CI: -6% to 54%). VE for those aged 18-64, who largely received cell-based vaccines, was 47% (95% CI: 37%-56%). Overall VE for 2-17 year olds, predominantly receiving live attenuated vaccines, was 66% (95% CI: 53%-76%)., Conclusion: The paper provides evidence of moderate influenza VE in 2022/23., (© 2024 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: We report 2023/2024 season interim influenza vaccine effectiveness for three studies, namely, primary care in Great Britain, hospital settings in Scotland and hospital settings in England., Methods: A test negative design was used to estimate vaccine effectiveness., Results: Estimated vaccine effectiveness against all influenzas ranged from 63% (95% confidence interval 46 to 75%) to 65% (41 to 79%) among children aged 2-17, from 36% (20 to 49%) to 55% (43 to 65%) among adults 18-64 and from 40% (29 to 50%) to 55% (32 to 70%) among adults aged 65 and over., Conclusions: During a period of co-circulation of influenza A(H1N1)pdm09 and A(H3N2) in the United Kingdom, evidence for effectiveness of the influenza vaccine in both children and adults was found., (© 2024 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: Prepandemic sentinel surveillance focused on improved management of winter pressures, with influenza-like illness (ILI) being the key clinical indicator. The World Health Organization (WHO) global standards for influenza surveillance include monitoring acute respiratory infection (ARI) and ILI. The WHO's mosaic framework recommends that the surveillance strategies of countries include the virological monitoring of respiratory viruses with pandemic potential such as influenza. The Oxford-Royal College of General Practitioner Research and Surveillance Centre (RSC) in collaboration with the UK Health Security Agency (UKHSA) has provided sentinel surveillance since 1967, including virology since 1993., Objective: We aim to describe the RSC's plans for sentinel surveillance in the 2023-2024 season and evaluate these plans against the WHO mosaic framework., Methods: Our approach, which includes patient and public involvement, contributes to surveillance objectives across all 3 domains of the mosaic framework. We will generate an ARI phenotype to enable reporting of this indicator in addition to ILI. These data will support UKHSA's sentinel surveillance, including vaccine effectiveness and burden of disease studies. The panel of virology tests analyzed in UKHSA's reference laboratory will remain unchanged, with additional plans for point-of-care testing, pneumococcus testing, and asymptomatic screening. Our sampling framework for serological surveillance will provide greater representativeness and more samples from younger people. We will create a biomedical resource that enables linkage between clinical data held in the RSC and virology data, including sequencing data, held by the UKHSA. We describe the governance framework for the RSC., Results: We are co-designing our communication about data sharing and sampling, contextualized by the mosaic framework, with national and general practice patient and public involvement groups. We present our ARI digital phenotype and the key data RSC network members are requested to include in computerized medical records. We will share data with the UKHSA to report vaccine effectiveness for COVID-19 and influenza, assess the disease burden of respiratory syncytial virus, and perform syndromic surveillance. Virological surveillance will include COVID-19, influenza, respiratory syncytial virus, and other common respiratory viruses. We plan to pilot point-of-care testing for group A streptococcus, urine tests for pneumococcus, and asymptomatic testing. We will integrate test requests and results with the laboratory-computerized medical record system. A biomedical resource will enable research linking clinical data to virology data. The legal basis for the RSC's pseudonymized data extract is The Health Service (Control of Patient Information) Regulations 2002, and all nonsurveillance uses require research ethics approval., Conclusions: The RSC extended its surveillance activities to meet more but not all of the mosaic framework's objectives. We have introduced an ARI indicator. We seek to expand our surveillance scope and could do more around transmissibility and the benefits and risks of nonvaccine therapies., (©Xinchun Gu, Conall Watson, Utkarsh Agrawal, Heather Whitaker, William H. Elson, Sneha Anand, Ray Borrow, Anna Buckingham, Elizabeth Button, Lottie Curtis, Dominic Dunn, Alex J. Elliot, Filipa Ferreira, Rosalind Goudie, Uy Hoang, Katja Hoschler, Gavin Jamie, Debasish Kar, Beatrix Kele, Meredith Leston, Ezra Linley, Jack Macartney, Gemma L Marsden, Cecilia Okusi, Omid Parvizi, Catherine Quinot, Praveen Sebastianpillai, Vanashree Sexton, Gillian Smith, Timea Suli, Nicholas P B Thomas, Catherine Thompson, Daniel Todkill, Rashmi Wimalaratna, Matthew Inada-Kim, Nick Andrews, Victoria Tzortziou-Brown, Rachel Byford, Maria Zambon, Jamie Lopez-Bernal, Simon de Lusignan. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 03.04.2024.)

We present England 2021/22 end-of-season adjusted vaccine effectiveness (aVE) against laboratory confirmed influenza related emergency care use in children aged 1-17 and in adults aged 50+, and serological findings in vaccinated vs unvaccinated adults by hemagglutination inhibition assay. Influenza vaccination has been routinely offered to all children aged 2-10 years and adults aged 65 years + in England. In 2021/22, the offer was extended to children to age 15 years, and adults aged 50-64 years. Influenza activity rose during the latter half of the 2021/22 season, while remaining comparatively low due to COVID-19 pandemic control measures. Influenza A(H3N2) strains predominated. A test negative design was used to estimate aVE by vaccine type. Cases and controls were identified within a sentinel laboratory surveillance system. Vaccine histories were obtained from the National Immunisation Management Service (NIMS), an influenza and COVID-19 vaccine registry. These were linked to emergency department presentations (excluding accidents) with respiratory swabbing ≤ 14 days before or ≤ 7 days after presentation. Amongst adults, 423 positive and 32,917 negative samples were eligible for inclusion, and 145 positive and 6,438 negative samples among children. Those admitted to hospital were further identified. In serology against the circulating A(H3N2) A/Bangladesh/4005/2020-like strain, 61 % of current season adult vaccinees had titres ≥ 1:40 compared to 17 % of those unvaccinated in 2020/21 or 2021/22 (p < 0.001). We found good protection from influenza vaccination against influenza requiring emergency care in children (72.7 % [95 % CI 52.7, 84.3 %]) and modest effectiveness in adults (26.1 % [95 % CI 4.5, 42.8 %]). Adult VE was higher for A(H1N1) (81 % [95 % CI 50, 93 %]) than A(H3N2) (33 % [95 % CI 6, 53 %]). Consistent protection was observable across preschool, primary and secondary school aged children. Imperfect test specificity combined with very low prevalence may have biased estimates towards null. With limited influenza circulation, the study could not determine differences by vaccine types., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: This trial explored the psychological and immunological effects of two brief interventions, targeting improving positive mood, administered to older adults immediately prior to influenza vaccination. The primary aim was to examine whether the interventions resulted in greater positive mood compared to usual care, and if so, which was superior. Secondary outcomes included antibody responses to vaccination and feasibility of collecting clinical outcome data (e.g., respiratory infections)., Method: Six hundred and fifty-four older adults (65-85 years) participated in a three-arm, parallel, randomized controlled trial between September 2019 and May 2020. Immediately prior to receiving an adjuvanted trivalent influenza vaccine (Fluad, Seqirus UK Ltd), participants viewed one of two brief (15-min) video-based positive mood interventions (one fixed content, one allowing participant choice) or received usual care. State affect was measured immediately prior to, and following, intervention exposure or usual care. Antibody responses were measured prevaccination and 4 weeks postvaccination. Clinical outcomes were extracted from primary care records for 6 months following vaccination., Results: Both interventions were equally effective at improving mood prior to vaccination compared to usual care. Antibody responses were highly robust with postvaccination seroprotection rates of > 88% observed for all vaccine strains. Antibody responses did not significantly differ between groups. Clinical outcome data were feasible to collect., Conclusions: Brief psychological interventions can improve mood prior to vaccination. However, altering antibody responses to highly immunogenic adjuvanted vaccines may require more targeted or prolonged interventions. The provision of choice did not notably enhance the interventions impact on mood or antibody outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Compared to intramuscular vaccines, nasally administered vaccines have the advantage of inducing local mucosal immune responses that may block infection and interrupt transmission of respiratory pathogens. Live attenuated influenza vaccine (LAIV) is effective in preventing influenza in children, but a correlate of protection for LAIV remains unclear. Studying young adult volunteers, we observe that LAIV induces distinct, compartmentalized, antibody responses in the mucosa and blood. Seeking immunologic correlates of these distinct antibody responses we find associations with mucosal IL-33 release in the first 8 hours post-inoculation and divergent CD8 + and circulating T follicular helper (cTfh) T cell responses 7 days post-inoculation. Mucosal antibodies are induced separately from blood antibodies, are associated with distinct immune responses early post-inoculation, and may provide a correlate of protection for mucosal vaccination. This study was registered as NCT04110366 and reports primary (mucosal antibody) and secondary (blood antibody, and nasal viral load and cytokine) endpoint data., (© 2023. The Author(s).)

Introduction: The haemagglutination inhibition assay (HAI) and the virus microneutralisation assay (MN) are long-established methods for quantifying antibodies against influenza viruses. Despite their widespread use, both assays require standardisation to improve inter-laboratory agreement in testing. The FLUCOP consortium aims to develop a toolbox of standardised serology assays for seasonal influenza. Building upon previous collaborative studies to harmonise the HAI, in this study the FLUCOP consortium carried out a head-to-head comparison of harmonised HAI and MN protocols to better understand the relationship between HAI and MN titres, and the impact of assay harmonisation and standardisation on inter-laboratory variability and agreement between these methods., Methods: In this paper, we present two large international collaborative studies testing harmonised HAI and MN protocols across 10 participating laboratories. In the first, we expanded on previously published work, carrying out HAI testing using egg and cell isolated and propagated wild-type (WT) viruses in addition to high-growth reassortants typically used influenza vaccines strains using HAI. In the second we tested two MN protocols: an overnight ELISA-based format and a 3-5 day format, using reassortant viruses and a WT H3N2 cell isolated virus. As serum panels tested in both studies included many overlapping samples, we were able to look at the correlation of HAI and MN titres across different methods and for different influenza subtypes., Results: We showed that the overnight ELISA and 3-5 day MN formats are not comparable, with titre ratios varying across the dynamic range of the assay. However, the ELISA MN and HAI are comparable, and a conversion factor could possibly be calculated. In both studies, the impact of normalising using a study standard was investigated, and we showed that for almost every strain and assay format tested, normalisation significantly reduced inter-laboratory variation, supporting the continued development of antibody standards for seasonal influenza viruses. Normalisation had no impact on the correlation between overnight ELISA and 3-5 day MN formats., Competing Interests: LZ and CC are employed by Sanofi Pasteur. TO and DF are employees of the GSK group of companies. GP is employed by Seqirus. EM is Chief Scientific Officer of VisMederi srl and VisMederi Research srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Waldock, Remarque, Zheng, Ho, Hoschler, Neumann, Sediri-Schön, Trombetta, Montomoli, Marchi, Lapini, Zhou, Lartey, Cox, Facchini, Castrucci, Friel, Ollinger, Caillet, Music, Palladino, Engelhardt and the FLUCOP consortium.)

In this short review, we summarized the results obtained with an assay to detect influenza virus-specific antibodies that mediate ADCC, which was developed and evaluated within the framework of the IMI-funded project "FLUCOP". HA-specific ADCC mediating antibodies were detected in serum samples from children and adults pre- and post-vaccination with monovalent, trivalent, or quadrivalent seasonal influenza vaccines, or following infection with H1N1pdm09 virus. Additionally, using chimeric influenza HA proteins, the presence of HA-stalk-specific ADCC mediating antibodies after vaccination and natural infection with H1N1pdm09 virus was demonstrated. With serum samples obtained from children that experienced a primary infection with an influenza B virus, we showed that primary infection induces HA-specific ADCC-mediating antibodies that cross-reacted with HA from influenza B viruses from the heterologous lineage. These cross-reactive antibodies were found to be directed to the HA stalk region. Antibodies directed to the influenza B virus HA head mediated low levels of ADCC. Finally, vaccination with a recombinant modified vaccinia virus Ankara expressing the HA gene of a clade 1 A(H5N1) highly pathogenic avian influenza virus led to the induction of ADCC-mediating antibodies, which cross-reacted with H5 viruses of antigenically distinct clades. Taken together, it is clear that virus-specific antibodies induced by infection or vaccination have immunological functionalities in addition to neutralization. These functionalities could contribute to protective immunity. The functional profiling of vaccine-induced antibodies may provide further insight into the effector functions of virus-specific antibodies and their contribution to virus-specific immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Vries, Hoschler and Rimmelzwaan.)

Current vaccination strategies against influenza focus on generating an antibody response against the viral haemagglutination surface protein, however there is increasing interest in neuraminidase (NA) as a target for vaccine development. A critical tool for development of vaccines that target NA or include an NA component is available validated serology assays for quantifying anti-NA antibodies. Additionally serology assays have a critical role in defining correlates of protection in vaccine development and licensure. Standardisation of these assays is important for consistent and accurate results. In this study we first validated a harmonized enzyme-linked lectin assay (ELLA)- Neuraminidase Inhibition (NI) SOP for N1 influenza antigen and demonstrated the assay was precise, linear, specific and robust within classical acceptance criteria for neutralization assays for vaccine testing. Secondly we tested this SOP with NA from influenza B viruses and showed the assay performed consistently with both influenza A and B antigens. Third, we demonstrated that recombinant NA (rNA) could be used as a source of antigen in ELLA-NI. In addition to validating a harmonized SOP we finally demonstrated a clear improvement in inter-laboratory agreement across several studies by using a calibrator. Importantly we showed that the use of a calibrator significantly improved agreement when using different sources of antigen in ELLA-NI, namely reverse genetics viruses and recombinant NA. We provide a freely available and detailed harmonized SOP for ELLA-NI. Our results add to the growing body of evidence in support of developing biological standards for influenza serology., Competing Interests: TO, DF, and SG were employed by the GSK group of companies. EM was employed by the company VisMederi srl in Italy. PA and SW were employed by the company Abbott. M-CB and SC were employed by Sanofi Pasteur. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bernard, Waldock, Commandeur, Strauß, Trombetta, Marchi, Zhou, van de Witte, van Amsterdam, Ho, Hoschler, Lugovtsev, Weir, Montomoli, Cox, Engelhardt, Friel, Wagner, Ollinger, Germain and Sediri-Schön.)

Background: The effect of the Toll-like receptor 7 agonist imiquimod before intradermal (ID) or intramuscular (IM) influenza vaccine in immunocompromised hosts is unknown., Methods: In this open-label randomized controlled trial, kidney transplant recipients (KT) and people living with HIV (PLWH) were randomized to receive IM trivalent inactivated influenza vaccine alone (IM), IM vaccine after topical imiquimod (imi+IM) or ID vaccine after topical imiquimod (imi+ID). Immunogenicity was assessed by hemagglutination inhibition assay. The primary outcome was vaccine response, defined as seroconversion to at least one viral strain at day 21., Results: Seventy patients (35 KT and 35 PLWH) received IM (24), imi+IM (22), or imi+ID (24) vaccine. Vaccine response was 61% (14/23) with IM, 59% (13/22) with imi+IM, and 65% (15/23) with imi+ID vaccine (P = 0.909). Vaccine response was associated with HIV infection compared to kidney transplantation (adjusted-OR 3.74, 95% CI 1.25 - 11.23, P = 0.019), but not with imiquimod application nor ID injection. After vaccination, seroprotection to all viral strains was 79% (19/24) with IM, 68% (15/22) with imi+IM, and 70% (16/23) with imi+ID (P = 0.657). We did not observe any vaccine-related severe adverse event., Conclusions: In our study, topical imiquimod did not improve the immunogenicity of influenza vaccine in KT and in PLWH., Competing Interests: Declaration of Competing Interest OM reports grants from Lophius Biosciences, personal fees from MSD, personal fees from Gilead, outside the submitted work. MC reports grants from Gilead, MSD and Viiv, outside the submitted work paid to his institution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The 2009 pandemic H1N1 (A(H1N1)pdm09) influenza A virus (IAV) has replaced the previous seasonal H1N1 strain in humans and continues to circulate worldwide. The comparative performance of inactivated A(H1N1)pdm09 influenza vaccines remains of considerable interest. The objective of this study was to evaluate the efficacy of two licensed A(H1N1)pdm09 inactivated vaccines (AS03B adjuvanted split virion Pandemrix from GlaxoSmithKline and referred here as (V1) and non-adjuvanted whole virion Celvapan from Baxter and referred here as (V2)) in ferrets as a pre-clinical model for human disease intervention., Methods: Naïve ferrets were divided into two groups (V1 and V2) and immunised intramuscularly with two different A/California/07/2009-derived inactivated vaccines, V1 administered in a single dose and V2 administered in 2 doses separated by 21 days. Six weeks after the first immunisation, vaccinated animals and a non-vaccinated control (NVC) group were intra-nasally challenged with 10 6.5 TCID 50 of the isolate A/England/195/2009 A(H1N1)pdm09 with 99.1% amino acid identity to the vaccine strain. Clinical signs, lung histopathology, viral quantification and antibody responses were evaluated., Results and Conclusions: Results revealed important qualitative differences in the performance of both inactivated vaccines in relation to protection against challenge with a comparable virus in a naive animal (ferret) model of human disease. Vaccine V1 limited and controlled viral shedding and reduced lower respiratory tract infection. In contrast, vaccine V2 did not control infection and animals showed sustained viral shedding and delayed lower respiratory infection, resulting in pulmonary lesions, suggesting lower efficacy of V2 vaccine., (© 2020 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: The UK introduced quadrivalent live attenuated influenza vaccine (qLAIV) for children in 2013/2014. The impact of annual vaccination on effectiveness and immunogenicity is being assessed., Method: A phase III/IV open-label study of the immunogenicity of annual vaccination with qLAIV (Fluenz™) was conducted over three consecutive years (2014/15-2016/17) in 254, 249 and 162 children respectively. Serum responses to vaccine components were measured by Haemagglutination Inhibition (HAI) and anti-A(H1N1)pdm09 Neuraminidase (NAI) assays, stratified according to previous receipt of AS03 B -adjuvanted A(H1N1)pdm09 pandemic vaccine in 2009/10. Antibody levels to the A(H1N1)pdm09 and H3N2 vaccine components in oral fluids (OF) were explored using an ELISA., Findings: More paired pre- and post-vaccination oral fluids (96%) than paired sera (87%) were obtained. Geometric mean titre rises using HAI assays were limited, with maximum rises seen in year one for both influenza B strains when 39% and 43% of subjects seroconverted (95% confidence interval 33-46% and 36-50%, respectively) and year two for influenza H3N2, when 40% (33-46%) individuals seroconverted. Prior pandemic vaccine receipt resulted in higher pre- and post-vaccination A(H1N1)pdm09 HAI titres and lower pre-and post-vaccination NAI (N1 neuraminidase) titres in all three years. OF results were congruent with HAI results; assay specificity compared to HAI was 88.1 and 71.6 percent, and sensitivity was 86.4 and 74.8 percent respectively for A(H1N1)pdm09 and H3N2., Conclusion: In all three study years, vaccination with qLAIV resulted in poor antibody responses. However, OFs are an alternative specimen type that allows self sampling, can easily be obtained from children, and their analysis leads to similar conclusions as classic serology by HAI. Their suitability for seroprevalence studies should be investigated. We demonstrated a sustained effect from prior receipt of the AS03 B -adjuvanted A(H1N1)pdm09 vaccine, even after repeat vaccination with qLAIV indicating that early exposure to influenza antigens has a significant long lasting effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Background: Despite annual immunization, solid organ transplant (SOT) patients remain at increased risk for severe influenza infection because of suboptimal vaccine immunogenicity. We aimed to compare the CD4+ and CD8+ T-cell responses of the high-dose (HD) and the standard-dose (SD) trivalent inactivated vaccine., Methods: We collected peripheral blood mononuclear cells pre- and postimmunization from 60 patients enrolled in a randomized trial of HD versus SD vaccine (30 HD; 30 SD) during the 2016-2017 influenza season., Results: The HD vaccine elicited significantly greater monofunctional and polyfunctional CD4+ and CD8+ T-cell responses against influenza A/H1N1, A/H3N2, and B. For example, median vaccine-elicited influenza-specific polyfunctional CD4+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza A/H1N1 (1193 vs 0 per 106 CD4+ T cells; P = .003), A/H3N2 (1154 vs 51; P = .008), and B (1102 vs 0; P = .001). Likewise, vaccine-elicited influenza-specific polyfunctional CD8+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza B (367 vs 0; P = .002)., Conclusions: Our study provides novel evidence that HD vaccine elicits greater cellular responses compared with the SD vaccine in SOT recipients, which provides support to preferentially consider use of HD vaccination in the SOT setting., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Traditionally, immune response to influenza vaccines has been measured using the haemagglutination inhibition (HAI) assay. A broader repertoire of techniques including the sensitive viral microneutralization (VMN) assay is now recommended by the European Medicines Agency (EMA). Comparing HAI and VMN, we determined immune response to a trivalent 2015-2016 seasonal inactivated influenza vaccine (SIIV) administered to 28 recipients of allogeneic haematopoietic stem cell transplant (HSCT). Vaccination was within the first-year post-transplant at a median of 78.5 (24-363) days. The proportion of patients with baseline and post-vaccination HAI titres ≥ 1:40 were 28.6% and 25% for A(H1N1)pdm09, 14.3% at both timepoints for A(H3N2), and 32.1% and 25% for B(Phuket). Pre and Post-vaccination geometric mean titres(GMT) were higher by VMN than HAI for A(H1N1)pdm09 and A(H3N2), but lower for B(Phuket)(p=<0.05). Geometric mean ratios(GMR) of baseline and post-vaccination titres were similar by HAI and VMN(p > 0.05) for all components. A single seroconversion to A(H1N1) was detected by ELISA-VMN. None of patient age, lymphocyte count, days from transplant to vaccination, donor type, or graft-versus-host disease (GVHD) or immunosuppressive therapy (IST) at vaccination correlated with baseline or post-vaccination titres by either assay. This absence of seroresponse to SIIV in the first-year post HSCT highlights the need for novel immunogenic vaccination formulations and schedules in this high-risk population., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Background: The annual standard-dose (SD) influenza vaccine has suboptimal immunogenicity in solid organ transplant recipients (SOTRs). Influenza vaccine that contains higher doses of antigens may lead to greater immunogenicity in this population., Methods: We conducted a randomized, double-blind trial to compare the safety and immunogenicity of the 2016-2017 high-dose (HD; FluzoneHD, Sanofi) vs SD (Fluviral, GSK) influenza vaccine in adult SOTRs. Preimmunization and 4-week postimmunization sera underwent strain-specific hemagglutination inhibition assay., Results: We enrolled 172 patients who received study vaccine, and 161 (84 HD; 77 SD) were eligible for analysis. Seroconversion to at least 1 of 3 vaccine antigens was present in 78.6% vs 55.8% in HD vs SD vaccine groups (P < .001), respectively. Seroconversions to A/ H1N1, A/H3N2, and B strains were 40.5% vs 20.5%, 57.1% vs 32.5%, and 58.3% vs 41.6% in HD vs SD vaccine groups (P = .006, P = .002, P = .028, respectively). Post-immunization geometric mean titers of A/H1N1, A/H3N2, and B strains were significantly higher in the HD group (P = .007, P = .002, P = .033). Independent factors associated with seroconversion to at least 1 vaccine strain were the use of HD vaccine (odds ratio [OR], 3.23; 95% confidence interval [CI], 1.56-6.67) and use of mycophenolate doses <2 g daily (OR, 2.76; 95% CI, 1.12-6.76)., Conclusions: HD vaccine demonstrated significantly better immunogenicity than SD vaccine in adult transplant recipients and may be the preferred influenza vaccine for this population., Clinical Trials Registration: NCT03139565.

We need greater understanding of the mechanisms underlying protection against influenza virus to develop more effective vaccines. To do this, we need better, more reproducible methods of sampling the nasal mucosa. The aim of the current study was to compare levels of influenza virus A subtype-specific IgA collected using three different methods of nasal sampling. Samples were collected from healthy adult volunteers before and after LAIV immunization by nasal wash, flocked swabs and Synthetic Absorptive Matrix (SAM) strips. Influenza A virus subtype-specific IgA levels were measured by haemagglutinin binding ELISA or haemagglutinin binding microarray and the functional response was assessed by microneutralization. Nasosorption using SAM strips lead to the recovery of a more concentrated sample of material, with a significantly higher level of total and influenza H1-specific IgA. However, an equivalent percentage of specific IgA was observed with all sampling methods when normalized to the total IgA. Responses measured using a recently developed antibody microarray platform, which allows evaluation of binding to multiple influenza strains simultaneously with small sample volumes, were compared to ELISA. There was a good correlation between ELISA and microarray values. Material recovered from SAM strips was weakly neutralizing when used in an in vitro assay, with a modest correlation between the level of IgA measured by ELISA and neutralization, but a greater correlation between microarray-measured IgA and neutralizing activity. In conclusion we have tested three different methods of nasal sampling and show that flocked swabs and novel SAM strips are appropriate alternatives to traditional nasal washes for assessment of mucosal influenza humoral immunity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We analyzed the impact of the anti-T-cell agents basiliximab and antithymocyte globulins (ATG) on antibody and cell-mediated immune responses after influenza vaccination in solid-organ transplant recipients., Methods: 71 kidney and heart transplant recipients (basiliximab [n=43] and ATG [n=28]) received the trivalent influenza vaccine. Antibody responses were measured at baseline and 6 weeks post-vaccination by hemagglutination inhibition assay; T-cell responses were measured by IFN-γ ELISpot assays and intracellular cytokine staining (ICS); and influenza-specific memory B-cell (MBC) responses were evaluated using ELISpot., Results: Median time of vaccination from transplantation was 29 months (IQR 8-73). Post-vaccination seroconversion rates were 26.8% for H1N1, 34.1% for H3N2 and 4.9% for influenza B in the basiliximab group and 35.7% for H1N1, 42.9% for H3N2 and 14.3% for influenza B in the ATG group (p=0.44, p=0.61, and p=0.21, respectively). The number of influenza-specific IFN-γ-producing cells increased significantly after vaccination (from 35 to 67.5 SFC/10(6) PBMC, p=0.0007), but no differences between treatment groups were observed (p=0.88). Median number of IgG-MBC did not increase after vaccination (H1N1, p=0.94; H3N2 p=0.34; B, p=0.79), irrespective of the type of anti-T-cell therapy., Conclusions: After influenza vaccination, a significant increase in antibody and T-cell immune responses but not in MBC responses was observed in transplant recipients. Immune responses were not significantly different between groups that received basiliximab or ATG., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Influenza vaccine containing an oil-in-water emulsion adjuvant (MF-59) may lead to greater immunogenicity in organ transplant recipients. However, alloimmunization may be a concern with adjuvanted vaccines., Methods: We conducted a randomized trial comparing the safety and immunogenicity of adjuvanted versus nonadjuvanted influenza vaccine in adult kidney transplant patients. Patients were randomized 1:1 to receive 2012 to 2013 influenza vaccine with or without MF59 adjuvant. Preimmunization and postimmunization sera underwent strain-specific hemagglutination inhibition assay. HLA alloantibody was determined by Luminex single-antigen bead assay., Results: We randomized 68 patients and 60 (29 nonadjuvanted; 31 adjuvanted) had complete samples available at follow-up. Seroconversion to at least 1 of 3 influenza antigens was present in 71.0% versus 55.2% in adjuvanted versus nonadjuvanted vaccine respectively (P = 0.21). Geometric mean titers and seroprotection rates were similar between groups. Seroconversion rates were especially low in those on MMF of 2 g or greater daily (44.4% vs 71.4%; P = 0.047). In the subgroup of patients 18 to 64 years old, seroconversion was significantly greater with adjuvanted vaccine (odds ratio, 6.10; 95% confidence interval, 1.25-28.6). There were no increases in HLA alloantibodies in patients who received adjuvanted vaccine., Conclusions: Adjuvanted vaccine was safe and had similar immunogenicity to standard vaccine in the overall transplant cohort but did show a potential immunogenicity benefit for the 18 to 64 years age group.

Healthcare workers are at increased risk of influenza infection through direct patient care, particularly during the early stages of a pandemic. Although influenza vaccination is widely recommended in Healthcare workers, data on long-term immunogenicity of vaccination in healthcare workers are lacking. The present study was designed to assess the persistence of the humoral response after pandemic vaccination as well as the impact of repeated annual vaccination in healthcare workers (n=24). Pandemic influenza vaccination resulted in a significant increase in haemagglutination inhibition (HI) antibody titers with 93-100% of subjects achieving protective titers 21-days post each of the three annual vaccinations. Seroprotective antibodies measured by HI, microneutralization and single radial hemolysis assays were present in 77-94% of healthcare workers 6 months post-vaccination. Repeated vaccination resulted in an increased duration of seroprotective antibodies with seroprotective titers increasing from 35-62% 12 months after 2009 pandemic vaccination to 50-75% 12 months after 2010 vaccination. Furthermore, repeated annual vaccination augmented the avidity of influenza-specific IgG antibodies. In conclusion, we have shown that A(H1N1)pdm09 vaccination induces high seroprotective titers that persist for at least 6 months. We demonstrate that repeated vaccination is beneficial to healthcare workers and results in further avidity maturation of vaccine-induced antibodies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Methods: Highly pathogenic avian influenza (HPAI) viruses constitute a pandemic threat and the development of effective vaccines is a global priority. Sixty adults were recruited into a randomized clinical trial and were intramuscularly immunized with two virosomal vaccine H5N1 (NIBRG-14) doses (21 days apart) of 30 μg HA alone or 1.5, 7.5 or 30 μg HA adjuvanted with Matrix M. The kinetics and longevity of the serological responses against NIBRG-14 were determined by haemagglutination inhibition (HI), single radial haemolysis (SRH), microneutralization (MN) and ELISA assays. The cross-H5 clade responses in sera were determined by HI and the antibody-secreting (ASC) cell ELISPOT assays. The protective efficacy of the vaccine against homologous HPAI challenge was evaluated in ferrets., Results: The serological responses against the homologous and cross-reactive strains generally peaked one week after the second dose, and formulation with Matrix M augmented the responses. The NIBRG-14-specific seroprotection rates fell significantly by six months and were low against cross-reactive strains although the adjuvant appeared to prolong the longevity of the protective responses in some subjects. By 12 months post-vaccination, nearly all vaccinees had NIBRG-14-specific antibody titres below the protective thresholds. The Matrix M adjuvant was shown to greatly improve ASC and serum IgG responses following vaccination. In a HPAI ferret challenge model, the vaccine protected the animals from febrile responses, severe weight loss and local and systemic spread of the virus., Conclusion: Our findings show that the Matrix M-adjuvanted virosomal H5N1 vaccine is a promising pre-pandemic vaccine candidate., Trial Registration: ClinicalTrials.gov NCT00868218.

Background: We report on a follow-up clinical and serological investigation of 274 children who received seasonal influenza vaccine (trivalent inactivated vaccine [TIV]) 1 year after receipt of either AS03(B)-adjuvanted subunit or whole virus monovalent A(H1N1)pdm09 vaccine and describe the antibody responses to the H3N2 A/Perth/16/2009 and B/Brisbane/60/2008 components of TIV., Methods: Vaccine responses were analyzed using hemagglutination inhibition (HAI) assays. In children aged <3 years, previous receipt of adjuvanted vaccine resulted in higher HAI antibody responses to H3N2 and B strains compared with nonadjuvanted vaccine (fold change 16.8 vs 4.3 for H3N2 and 7.0 vs 1.6 for B). In children aged >3 years, responses to the H3 and B components of TIV were similar between vaccine groups. Sera taken before and after the pandemic vaccine were also analyzed by HAI using A/Perth/16/2009 virus. This analysis showed that 11.1% of children receiving the AS03(B)-adjuvanted vaccine but only 1.4% in the nonadjuvanted group had a 4-fold rise to A/Perth/16/2009., Conclusion: AS03B-adjuvanted A(H1N1)pdm09 influenza vaccine generates a cross-reactive antibody response to H3N2 in children and enhances responses to heterologous subtypes in children aged <3 years 1 year later.

Current seasonal influenza vaccines have reduced immunogenicity and are of suboptimal efficacy in older adults. We have previously shown that the novel candidate vaccine MVA-NP+M1 is able to boost memory T cell responses in adults aged 50-85 years. Preclinical studies have demonstrated that viral vectored vaccines can act as adjuvants when coadministered with protein-based vaccines. We have conducted a phase I clinical trial to compare the coadministration of seasonal influenza vaccine and MVA-NP+M1 with seasonal influenza vaccine alone in adults aged 50 years and above. This combination of vaccines was safe and well tolerated. T cell responses to internal influenza proteins were boosted to significantly higher levels in the group receiving MVA-NP+M1 compared with the group receiving seasonal influenza vaccine alone. Rates of seroprotection and seroconversion against the three vaccine strains were similar in both groups; however, there was a significant increase in the geometric mean titer ratio for the H3N2 component of seasonal influenza vaccine in the coadministration group. While some vaccine combinations result in immune interference, the coadministration of MVA-NP+M1 alongside seasonal influenza vaccine is shown here to increase some influenza strain-specific antibody responses and boost memory T cells capable of recognizing a range of influenza A subtypes.

T cellular responses play a significant role in mediating protective immune responses against influenza in humans. In the current study, we evaluated the ability of a candidate virosomal H5N1 vaccine adjuvanted with Matrix M(TM) to induce CD4(+) and CD8(+) T cell responses in a phase 1 clinical trial. We vaccinated 60 healthy adult volunteers (at days 0 and 21) with 30 μg haemagglutinin (HA) alone or 1.5, 7.5, or 30 μg HA formulated with Matrix M(TM). To evaluate the T cellular responses, lymphocytes were stimulated in vitro with homologous (A/Vietnam/1194/2004 [H5N1]) and heterologous H5N1 (A/Anhui/1/05 or A/Bar-headed Goose/Qinghai/1A/05) antigens. The antigen-specific cytokine responses were measured by intracellular cytokine staining and by multiplex (Luminex) assays. An increase in CD4(+) Th1 and Th2 cytokines was detected 21 days after the first vaccine dose. No increase in Th cytokine responses was observed after the second dose, although it is possible that the cytokine levels peaked earlier than sampling point at day 42. Formulation with the Matrix M(TM) adjuvant augmented both the homologous and cross-reactive cytokine response. Antigen-specific CD8(+) T cell responses were detected only in a few vaccinated individuals. The concentrations of Th1 and to a lesser extent, Th2 cytokines at 21 days post-vaccination correlated moderately with subsequent days 35 and 180 serological responses as measured by the microneutralisation, haemagglutination inhibition, and single radial hemolysis assays. Results presented here show that the virosomal H5N1 vaccine induced balanced Th1/Th2 cytokine responses and that Matrix M(TM) is a promising adjuvant for future development of candidate pandemic influenza vaccines.

Objectives: Booster vaccination against 2009 H1N1 influenza virus was recommended for rheumatologic patients under immunosuppressive therapy during the 2009/2010 H1N1 pandemic. In this study we assessed whether B cell depletion with rituximab influences of the antiviral immune response in 2009 H1N1 influenza virus-vaccinated patients., Methods: Influenza virus-specific immune responses were analysed after the first and a booster vaccination with pandemrixTM in sixteen consecutive rituximab-treated patients with different rheumatic autoimmune disorders. Antibody titers were determined by a haemagglutination-inhibition assay and virus-specific T cell responses were evaluated by a flow cytometry-based intracellular cytokine-secretion assay. Patients showing clinical symptoms of influenza infection were excluded from this study., Results: Two out of seven patients with low (<10%) and four out of nine with normal (>10%) B cells developed significant antibody responses after the first vaccination. Booster vaccination led to an antibody response in one additional patient. After the first vaccination, virus-specific CD4+ and CD8+ T cell responses were significantly lower in patients with low B cells than in those with normal B cells. Of importance, the booster vaccination stimulated the antiviral T cell response only in patients with low B cells., Conclusions: In the absence of a significant effect of booster vaccinations against 2009 H1N1 influenza virus on the humoral immune response in B cell-depleted patients with autoimmune rheumatic diseases, enhanced antiviral T cell responses in patients with low B cells indicate that T cells, maybe, compensate for the impaired humoral immunity in these patients.

Annual influenza vaccine is recommended for organ transplant recipients, but immunogenicity is known to be suboptimal. Islet transplant recipients receive immunosuppressive therapy, but there are no data on the immunogenicity of influenza vaccine in this population. In this prospective cohort study, adult islet transplant recipients at least 3 months posttransplant were enrolled. All patients received the 2010-2011 seasonal influenza vaccine. Serum was obtained pre- and postvaccination to determine humoral response to each of the three influenza strains included in the vaccine. Adverse effects of vaccine were also noted. A total of 61 islet transplant recipients were enrolled and completed the study protocol. The median time from last transplant was 1.9 years (range 0.26-11.4 years), and most patients had undergone multiple prior islet transplant procedures (90.2%). Overall immunogenicity of the vaccine was poor. Seroconversion rates to H1N1, H3N2, and B antigens were 34.4%, 29.5%, and 9.8%, respectively. In the subset not seroprotected at baseline, a protective antibody titer postvaccination was achieved in 58.6%, 41.9%, and 34.5% of patients, respectively. Patients within the first year of transplant were significantly less likely to seroconvert to at least one antigen (23.5% vs. 54.5%; p = 0.029). Alemtuzumab recipients trended toward lower seroconversion rates (25% vs. 51%; p = 0.11). No vaccine-related safety concerns were identified. Seasonal influenza vaccine had suboptimal immunogenicity in islet transplant recipients especially those who were less than 1 year posttransplant or had received alemtuzumab induction. Novel strategies for protection in this group of patients need further study.

In England, during pandemic 2009 H1N1, vaccine efficacy and immunogenicity population studies in priority groups were rolled out in parallel to evaluate the pandemic vaccination programme. This provided a unique opportunity to compare immunogenicity and clinical protection in the same population and thus provide insights into the correlates of protection for the pandemic H1N1 2009 vaccine in risk groups. While clinical protection from AS03-adjuvanted pandemic 2009 H1N1 vaccine was high in those aged <25 years and pregnant women, effectiveness in older adults with chronic conditions has been found to be surprisingly poor. Here we present results from the immunogenicity study derived from the same population. Individuals from priority groups eligible for pandemic vaccination attending participating general practices were recruited. Pre and post-vaccination blood samples were collected and HI antibody testing to assess immune response to vaccination performed. The final cohort consisted of 610 individuals: 60 healthy children aged <5 years; 32 healthy pregnant women; 518 individuals from risk groups. Seroconversion rate in healthy children aged <5 years (87%, 95% CI: 75% to 94%) was higher than that of risk groups combined (65%, 95% CI: 61% to 69%) (p<0.001). Multivariable analysis of risk groups showed that the size of response in those who did seroconvert was lower in those who received the 2009/10 seasonal TIV (Fold effect: 0.52, 0.35 to 0.78). Predicted immunological boosting from higher pre-vaccine titres after 2009 pandemic H1N1 vaccination only occurred in children (seroconversion rate = 92%) and not in individuals aged 10 to 39 from risk groups (seroconversion rate = 74%). The lack of clinical protection identified in the same population in older adults from risk groups could be attributed to these lower seroresponses. Current immunogenicity licensing criteria for pandemic influenza vaccine may not correlate with clinical protection in individuals with chronic disease or immunocompromised.

Introduction: Illness and death from influenza increase during pregnancy. In the United Kingdom pregnant women were targeted in a national programme for vaccination during the H1N1 2009-10 pandemic., Methods: In this study, pregnant women were recruited in labour from November 9, 2009 to March 10, 2010. Pandemic vaccination status was determined. Venous cord blood collected at delivery was evaluated for transplacental transfer of antibodies by measurement of haemagglutination inhibition and microneutralization titres., Results: Samples were collected from 77 vaccinated and 27 unvaccinated women. Seroprotection (HI titre ≥1:40) was detected in 58 (75.3%, 95% CI 64.2-84.4) cord blood samples from vaccinated women and 5 (18.5%, 95% CI 6.3-38.1) from unvaccinated women (P<0.0001). There was evidence of transplacental seroprotection 8 days after maternal immunization (77.9%, 95 CI 66.2-87.1), maintained in most cases for at least 16 weeks., Discussion: Immunization of pregnant women with AS03(A)-adjuvanted vaccine is followed by transplacental transfer of passive immunity at titres consistent with clinical protection in three-quarters of new-born infants. The findings support national and international pandemic H1N1 2009 recommendations for immunization during pregnancy.

Background: The influence of anti-T-cell therapy in the immunogenicity of the influenza vaccine in kidney transplant recipients remains unclear., Methods: During the 2010 to 2011 influenza season, we evaluated the immune response to the inactivated trivalent influenza vaccine in kidney transplant recipients having received Thymoglobulin or basiliximab as induction therapy. A hemagglutination inhibition assay was used to assess the immunogenicity of the vaccine. The primary outcome was geometric mean titers of hemagglutination inhibition after influenza vaccination., Results: Sixty patients (Thymoglobulin n=22 and basiliximab n=38) were included. Patients in the Thymoglobulin group were older (P=0.16), showed higher creatinine levels (P=0.16) and had more frequently received a previous transplant (P=0.02). There were no significant differences in geometric mean titers for any of the three viral strains between groups (P=0.69 for H1N1, P=0.56 for H3N2, and P=0.7 for B strain). Seroconversion to at least one viral strain was seen in 15 (68%) of 22 patients in the Thymoglobulin group and 28 (73%) of 38 in the basiliximab group (P=0.77). In patients vaccinated during the first year after receiving anti-T-cell therapy (n=25), there was a trend toward lower vaccine responses in the Thymoglobulin group. Patients who received Thymoglobulin showed lower CD4(+) cell counts and lower levels of IgM, at an average of 16.2 months after transplantation. A multivariate analysis showed that only the absence of mycophenolate was associated with a better vaccine response (odds ratio=9.47; 95% confidence interval, 1.03-86.9; P=0.047)., Conclusion: No significant differences were seen in immunogenicity of the influenza vaccine in kidney transplant recipients having received either Thymoglobulin or basiliximab.

Background: Vaccination is the best measure to protect the population against a potential influenza H5N1 pandemic, but 2 doses of vaccine are needed to elicit protective immune responses. An immunological marker for H5N1 vaccine effectiveness is needed for early identification of the best vaccine candidate., Methods: We conducted a phase I clinical trial of a virosomal H5N1 vaccine adjuvanted with Matrix M. Sixty adult volunteers were vaccinated intramuscularly with 2 doses of either 30 μg hemagglutinin (HA) alone or with 1.5, 7.5, or 30 μg HA and Matrix M adjuvant (50 μg). The humoral response was measured by the hemagglutination inhibition (HI), microneutralization (MN), and single radial hemolysis (SRH) assays, and the CD4(+) T-helper 1 (Th1)-cell response was measured by intracellular staining for the cytokines interleukin 2, interferon γ, and tumor necrosis factor α., Results: The adjuvanted vaccine effectively induced CD4(+) Th1-cell responses, and the frequency of influenza-specific Th1 cells after the first vaccine dose predicted subsequent HI, MN, and SRH seroprotective responses after the second vaccination., Conclusions: These results support early identification of Th1-cell responses as a predictive biomarker for an efficient vaccine response, which could have great implications for early identification of persons with low or no response to vaccine when evaluating future pandemic influenza vaccines.

Background: We investigated antibody persistence in children 1 year after 2 doses of either an AS03(B)-adjuvanted split-virion or nonadjuvanted whole-virion monovalent pandemic influenza vaccine and assessed the immunogenicity and reactogenicity of a subsequent dose of trivalent influenza vaccine (TIV)., Methods: Children previously immunized at age 6 months to 12 years in the original study were invited to participate. After a blood sample was obtained to assess persistence of antibody against swine influenza A/H1N1(2009) pandemic influenza, children received 1 dose of 2010/2011 TIV, reactogenicity data were collected for 7 days, and another blood sample was obtained 21 days after vaccination., Results: Of 323 children recruited, 302 received TIV. Antibody persistence (defined as microneutralization [MN] titer ≥1:40) 1 year after initial vaccination was significantly higher in the AS03(B)-adjuvanted compared with the whole-virion vaccine group, 100% (95% confidence interval [CI], 94.1%-100%) vs 32.4% (95% CI, 21.5%-44.8%) in children immunized <3 years old and 96.9% (95% CI, 91.3%-99.4%) vs 65.9% (95% CI, 55.3%-75.5%) in those 3-12 years old at immunization, respectively (P < .001 for both groups). All children receiving TIV had post-vaccination MN titers ≥1:40. Although TIV was well tolerated in all groups, reactogenicity in children <5 years old was slightly greater in those who originally received AS03(B)-adjuvanted vaccine., Conclusions: This study provides serological evidence that 2 doses of AS03(B)-adjuvanted pandemic influenza vaccine may be sufficient to maintain protection across 2 influenza seasons. Administration of TIV to children who previously received 2 doses of either pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain.

The avian influenza H5 virus epizootic continues to cause zoonosis with human fatalities, highlighting the continued need for pandemic preparedness against this subtype. This study evaluated the tolerability and immunogenicity of a Matrix M™ adjuvanted virosomal H5N1 vaccine in a phase I clinical trial. Sixty healthy adults were vaccinated intramuscularly with two doses of influenza H5N1 (NIBRG-14) virosomal vaccine alone (30 μg haemagglutinin (HA)) or 1.5, 7.5 or 30 μg HA formulated with 50 μg Matrix M™ adjuvant. The antibody response was analysed by haemagglutination inhibition (HI), microneutralisation (MN) and single radial haemolysis (SRH) assays. The vaccine was well tolerated in all groups but injection site pain was more frequently observed in the Matrix M™ adjuvanted groups. The vaccine elicited homologous and heterologous H5N1-specific antibody responses and the Matrix M™ adjuvanted formulations met all the EU regulatory criteria. In conclusion, Matrix M™ adjuvant was well tolerated and augmented the antibody response allowing considerable dose sparing down to 1.5 μg HA., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In 2009, 943 children aged 6 months to 10 years were randomised to receive two doses of an oil-in water AS03B-adjuvanted split virion or a non-adjuvanted whole virion H1N1 (2009) vaccine. The large numbers allowed investigation of possible predictors of immune response and reactogenicity. We used regression analysis to examine the effect of variables including past receipt of seasonal vaccine, antipyretics post-vaccination, interval between doses and pre-existing antibodies to H1N1 (2009) on immunogenicity. We also examined the relationship between immunogenicity and reactogenicity and whether prior infection or underlying conditions affected reactogenicity. For both vaccines, haemagglutination-inhibition titres were 60% higher in children with fever ≥38 °C after vaccination and 29% lower in those previously given seasonal vaccine. Early use of antipyretics did not affect immunogenicity. Post-vaccination titres were higher with longer intervals between doses and in those with evidence of prior infection, but reactogenicity in the latter was unaffected. In the adjuvanted vaccine group, reactions were more common in children with atopy. Both vaccines were safe and immunogenic in those with prior infection. Reduction in the interval between doses for earlier protection would be at the cost of reduced immunogenicity. The effect of seasonal vaccine on immunogenicity merits further investigation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: In October 2009, the United Kingdom Department of Health recommended vaccination of high-risk groups, including children with HIV, with a novel, oil-in-water AS03(B) adjuvanted Influenza A (H1N1) vaccine (Pandemrix). There were no published data available regarding the immunogenicity of this vaccine in such children., Objectives: This study evaluated the immunogenicity of the adjuvanted Influenza A (H1N1) vaccine in HIV-infected children immunised according to national recommendations and assessed the impact of vaccination on individual CD4 counts and HIV viral loads., Methods: HIV-infected children attending outpatient appointments between 01 November and 31 December 2009 were offered two doses of H1N1 vaccine three weeks apart and a blood test before and 3 weeks after the second dose of vaccine. Serum antibody responses were determined by a haemagglutination inhibition (HAI) assay using standard methods., Results: Of the 39 children recruited for vaccination, 31 (median age 11.2, range 3.0-17.9 years) received both doses of vaccine and provided pre- and post-vaccination blood samples. Eight children (26%) had baseline HAI titres ≥ 1:32. After vaccination, 29 children (94%, 95% CI, 78.6-99.2%) had HAI titres ≥ 1:32 (seroprotection), of whom 27 (87.1%, 95% CI, 70.1-96.4%) had also had a four-fold rise in titres (seroconversion). In the univariate analysis, post-vaccination geometric mean titres (GMTs) were higher among the 21 children receiving highly active anti-retroviral therapy compared with the 10 treatment-naïve children (GMT 406 [95% CI 218-757] vs. 128 [49-336]; P=0.035), but this was no longer statistically significant when adjusted for prevaccine GMTs. There was no significant impact of vaccination on CD4+ T cell count or HIV viral load., Conclusion: The AS03(B)-adjuvanted pandemic Influenza A (H1N1) vaccine is highly immunogenic and appears to be safe in HIV-infected children., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies., Design and Methods: We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49., Results: By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P<0.001), 46% of allogeneic stem cell transplant recipients (P<0.001) and 85% of patients with chronic myeloid leukemia (P=0.086). After a second dose, seroprotection rates increased to 68%, (P=0.008), 73%, (P=0.031), and 95% (P=0.5) in patients with B-cell malignancies, after allogeneic stem cell transplantation and with chronic myeloid leukemia, respectively. On the other hand, T-cell responses to H1N1 vaccine were not significantly different between patients and controls., Conclusions: These data demonstrate the efficacy of H1N1 vaccine in most patients with hematologic malignancies and support the recommendation for the administration of two doses of vaccine in immunocompromised patients. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in such patients in the future.

Background: Effective antigen-sparing vaccines are needed to confront pandemic influenza. Whole-virion and oil-in-water adjuvanted vaccines are the most effective formulations against H5N1 avian influenza. We assessed the safety and immunogenicity in adults in the UK of pandemic H1N1 whole-virion vaccine and oil-in-water adjuvanted vaccine purchased by the UK government in 2009., Methods: In our randomised, observer-blind, parallel-group, controlled trial, healthy adults aged 18-44 years, 45-64 years, and 65 years and older (from Oct 19, to Nov 12, 2009) received two doses of vaccine given 21 days apart: either 7·5 μg of haemagglutinin formulated as whole-virion vaccine, or 3·75 μg of haemagglutinin formulated as split-virion vaccine with AS03(A) oil-in-water adjuvant. Assignment was by a computer-generated code, with random permuted blocks of two, four, and six. All participants and investigators were unaware of vaccine assignments. The trial was done at three hospitals in the UK. We measured antibody titres with a haemagglutination-inhibition assay at baseline; 7, 14, and 21 days after each vaccination; and at 6 months after the first dose. Primary outcome was vaccine immunogenicity of the full analysis set by the EU Committee of Human Medicinal Products licensing criteria. This study is registered with ISRCTN, number ISRCTN92328241., Findings: At day 0, baseline antibody (titre ≥1/8) was detected in 44 (13%) of 347 participants. Sera from 95% to 98% of participants were assessed for immunogenicity on days 7, 14, 21, 28, 35, and 42, and at 6 months. On day 21 after one dose of adjuvanted AS03(A) or whole-virion vaccine, 63 (94%, 95 CI 85·4-98·4) of 67 and 50 (71%, 59·4-81·6) of 70 participants aged 18-44 years, 51 (77%, 65·3-86·7) of 66 and 26 (39%, 27·1-51·5) of 67 aged 45-64 years, and 19 (51%, 34·4-68·1) of 37 and 11 (32%, 17·4-50·5) of 34 aged 65 years or older had titres of 1:40 or greater. On day 42 (21 days after the second dose), 64 (100%, 94·4-100) of 64 and 49 (73%, 60·9-83·2) of 67 participants aged 18-44 years, 59 (91%, 81·0-96·5) of 65 and 29 (43·9%, 31·7-56·7) of 66 aged 45-64 years, and 28 (76%, 58·8-88·2) of 37 and 12 (36%, 20·4-54·9) of 33 aged 65 years or older had titres of 1/40 or greater. At 6 months, 62 (98%, 91·5-100) of 63 and 54 (78%, 66·7-87·3) of 69 participants aged 18-44 years, 54 (82%, 70·4-90·2) of 66 and 37 (55%, 42·6-67·4) of 67 aged 45-64 years, and 21 (57%, 39·5-72·9) of 37 and 10 (29%, 15·1-47·5) of 34 aged 65 years or older had titres of 1/40 or greater. There were no vaccine-related serious adverse events. Whole-virion vaccine was associated with fewer local and systemic reactions than adjuvanted vaccine., Interpretation: AS03(A)-adjuvanted vaccine was more immunogenic against pandemic influenza A H1N1 virus than whole-virion vaccine and offers greater antigen-sparing capacity. A two-dose strategy should be considered for older people., Funding: Department of Health, National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Few data are available regarding the immunogenicity and safety of the pandemic influenza vaccine in immunocompromised patients. We evaluated the humoral response to the influenza A H1N1/09 vaccine in solid-organ transplant (SOT) recipients, in patients with human immunodeficiency virus (HIV) infection, and in healthy individuals., Methods: Patients scheduled to receive the pandemic influenza vaccine were invited to participate. All participants received the influenza A H1N1/09 AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin. SOT recipients and HIV-infected patients received 2 doses at 3-week intervals, whereas control subjects received 1 dose. Blood samples were taken at day 0, day 21, and day 49 after vaccination. Antibody responses were measured with the hemagglutination inhibition assay (HIA) and a microneutralization assay., Results: Twenty-nine SOT recipients, 30 HIV-infected patients, and 30 healthy individuals were included in the study. Seroconversion measured by HIA was observed in 15 (52%) of 29 SOT recipients both at day 21 and day 49; in 23 (77%) of 30 at day 21 and 26 (87%) of 30 at day 49 in HIV-infected patients, and in 20 (67%) of 30 at day 21 and in 23 (77%) of 30 at day 49 in control subjects (P = .12 at day 21 and P = .009 at day 49, between groups). Geometric means of antibody titers were not significantly different between groups at day 21 or at day 49., Conclusions: Influenza A H1N1/09 vaccine elicited a similar antibody response in HIV-infected individuals and in control subjects, whereas SOT recipients had an overall lower response. A second dose of the vaccine only moderately improved vaccine immunogenicity in HIV-infected patients.

Background: Children with cancer have an increased susceptibility to influenza infection. The objective of this study was to assess the immunogenicity of pandemic (H1N1) 2009 vaccine in children with cancer., Methods: Children were recruited from the Royal Marsden Hospital, England, during November 2009. The vaccination schedule consisted of 2 doses of an AS03(B)-adjuvanted vaccine given at days 0 and 21. Serological analysis was performed on blood samples obtained at day 0 and day 42. The primary immunological end point was the seroconversion rate, which was defined as the proportion of subjects with an individual 4-fold increase in hemagglutination inhibition titer and a postvaccination hemagglutination inhibition titer ≥1:32., Results: Fifty-four children with a median age of 6.3 years (range, 1.4-16.6 years) were vaccinated and had samples taken for serological analysis. Twenty-four (44.4%) of 54 children demonstrated seroconversion. Seroconversion rates were 33.3% (9 of 27) among children with acute lymphoblastic leukemia, 36.4% (4 of 11) among those with lymphoma or other leukemias, 66.7% (6 of 9) among those with brain tumors, and 71.4% (5 of 7) among those with other solid tumors. Seroconversion occurred in 4 (28.6%) of 14 children receiving acute lymphoblastic leukemia maintenance therapy. Univariate analysis showed significantly higher responses among children with solid tumors, compared with those with hematological malignancies (11 [68.8%] of 16 vs 13 [34.2%] of 38; P = .03), and among those not receiving treatment, compared with those receiving treatment (7 [87.5%] of 8 vs 17 [37.0%] of 46; P = .02). Multivariable analysis showed that age, cancer type, and lymphopenia did not influence seroconversion rates., Conclusion: These data suggest that this AS03(B)-adjuvanted pandemic (H1N1) 2009 vaccine can induce limited but useful protective immune responses in children with cancer.

Background: The 2009 pandemic influenza A (H1N1) virus has emerged to cause the first pandemic of the 21st century. Development of effective vaccines is a public health priority., Methods: We conducted a single-center study, involving 176 adults, 18 to 50 years of age, to test the monovalent influenza A/California/2009 (H1N1) surface-antigen vaccine, in both MF59-adjuvanted and nonadjuvanted forms. Subjects were randomly assigned to receive two intramuscular injections of vaccine containing 7.5 microg of hemagglutinin on day 0 in each arm or one injection on day 0 and the other on day 7, 14, or 21; or two 3.75-microg doses of MF59-adjuvanted vaccine, or 7.5 or 15 microg of nonadjuvanted vaccine, administered 21 days apart. Antibody responses were measured by means of hemagglutination-inhibition assay and a microneutralization assay on days 0, 14, 21, and 42 after injection of the first dose., Results: The most frequent local and systemic reactions were pain at the injection site and muscle aches, noted in 70% and 42% of subjects, respectively; reactions were more common with the MF59-adjuvanted vaccine than with nonadjuvanted vaccine. Three subjects reported fever, with a temperature of 38 degrees C or higher, after either dose. Antibody titers, expressed as geometric means, were higher at day 21 among subjects who had received one dose of MF59-adjuvanted vaccine than among those who had received one dose of nonadjuvanted vaccine (P<0.001 by the microneutralization assay). By day 21, hemagglutination-inhibition and microneutralization antibody titers of 1:40 or more were seen in 77 to 96% and 92 to 100% of subjects receiving MF59-adjuvanted vaccine, respectively, and in 63 to 72% and 67 to 76% of those receiving nonadjuvanted vaccine, respectively. By day 42, after two doses of vaccine, hemagglutination-inhibition and microneutralization antibody titers of 1:40 or more were seen in 92 to 100% and 100% of recipients of MF59-adjuvanted vaccine, respectively, and in 74 to 79% and 78 to 83% of recipients of nonadjuvanted vaccine, respectively., Conclusions: Monovalent 2009 influenza A (H1N1) MF59-adjuvanted vaccine generates antibody responses likely to be associated with protection after a single dose is administered. (ClinicalTrials.gov number, NCT00943358)., (Copyright 2009 Massachusetts Medical Society)

Hemagglutination-inhibition (HI) and neutralization are used to evaluate vaccines against influenza virus A (H5N1); however, poor standardization leads to interlaboratory variation of results. A candidate antibody standard (07/150) was prepared from pooled plasma of persons given clade 1 A/Vietnam/1194/2004 vaccine. To test human and sheep antiserum, 15 laboratories used HI and neutralization and reassortant A/Vietnam/1194/2004, A/turkey/Turkey/1/2005 (clade 2.2), and A/Anhui/1/2005 (clade 2.3.4) viruses. Interlaboratory variation was observed for both assays, but when titers were expressed relative to 07/150, overall percentage geometric coefficient of variation for A/Vietnam/1194/2004 was reduced from 125% to 61% for HI and from 183% to 81% for neutralization. Lack of reduced variability to clade 2 antigens suggested the need for clade-specific standards. Sheep antiserum as a standard did not reliably reduce variability. The World Health Organization has established 07/150 as an international standard for antibody to clade 1 subtype H5 and has an assigned potency of 1,000 IU/ampoule.