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• In elderly COVID-19 inpatients, admission NEWS2 scores did not predict mortality. • Of components of NEW2 score, only systolic blood pressure predicted mortality. • A high variability in NEW2 score predicted mortality. • NEWS2 score does not consider the degree of supplemental oxygen patients require. • A more sensitive early warning score for COVID-19 is needed.

BackgroundMigration is a major global driver of population change. Certain migrants may be at increased risk of infectious diseases, including tuberculosis (TB), HIV, hepatitis B and hepatitis C, and have poorer outcomes. Early diagnosis and management of these infections can reduce morbidity, mortality and onward transmission and is supported by national guidelines. To date, screening initiatives have been sporadic and focused on individual diseases; systematic routine testing of migrant groups for multiple infections is rarely undertaken and its impact is unknown. We describe the protocol for the evaluation of acceptability, effectiveness and cost-effectiveness of an integrated approach to screening migrants for a range of infectious diseases in primary care.Methods and analysisWe will conduct a mixed-methods study which includes an observational cohort with interrupted time-series analysis before and after the introduction of routine screening of migrants for infectious diseases (latent TB, HIV, hepatitis B and hepatitis C) when first registering with primary care within Leicester, UK. We will assess trends in the monthly number and rate of testing and diagnosis for latent TB, HIV, hepatitis B and hepatitis C to determine the effect of the policy change using segmented regression analyses at monthly time-points. Concurrently, we will undertake an integrated qualitative sub-study to understand the views of migrants and healthcare professionals to the new testing policy in primary care. Finally, we will evaluate the cost-effectiveness of combined infection testing for migrants in primary care.Ethics and disseminationThe study has received HRA and NHS approvals for both the interrupted time-series analysis (16/SC/0127) and the qualitative sub-study (16/EM/0159). For the interrupted time-series analysis we will only use fully anonymised data. For the qualitative sub-study, we will gain written, informed, consent. Dissemination of the results will be through local and national meetings/conferences as well as publications in peer-reviewed journals.

Summary Clinical challenges exist in the management of hospitalized patients returning to the UK with potential Middle East respiratory syndrome coronavirus (MERS-CoV) infection, particularly with its clinical overlap with influenza, as demonstrated in this case-series and cost-analysis review of returning Hajj pilgrims. These patients were hospitalized with acute febrile respiratory illness, initially managed as potential MERS-CoV infections, but were eventually diagnosed with influenza. Additional costs were small, yet enhanced infection prevention measures created significant burdens on isolation rooms and staff time. Planning for predictable events such as Hajj is important for resource management. Here, in-house MERS-CoV diagnostic testing would have facilitated earlier diagnosis and discharge.

Syphilitic proctitis is a rare presentation of sexually transmitted infection that poses a diagnostic challenge as it mimics rectal cancer clinically, radiologically and endoscopically. We report a case of a 66-year-old male patient with a background of HIV infection presenting with obstructive bowel symptoms and initial diagnosis of rectal cancer on CT. Sigmoidoscopy and histopathology were non-diagnostic. A diagnosis of secondary syphilis was suspected after obtaining sexual history and diagnostic serology, avoiding planned surgical intervention.

Latent TB infection (LTBI) screening and treatment in HIV-positive individuals in the UK is advocated by the British HIV Association (BHIVA) and National Institute for Health and Care Excellence (NICE), although each recommends differing strategies. We undertook an evaluation of UK practice, relating the responses to the local HIV/TB disease burden. 162 of 188 (86%) UK geographical areas responded; only 93/162 (57.4%) offer LTBI testing with considerable heterogeneity in practice, and no difference in HIV/TB burden between areas offering testing and those who do not. Only 33/93 (35.5%) and 6/93 (6.5%) reported full compliance with BHIVA and NICE guidance respectively. A uniform national guideline is required.

Current influenza vaccines are limited by the need for annual immunisation, frequent antigenic updating to match the evolution of circulating influenza virus strains, and reduced efficacy in elderly persons. On 9-10 November 2009, the Initiative for Vaccine Research of the World Health Organization convened jointly with the Wellcome Trust in London, United Kingdom, the fourth meeting on 'Influenza vaccines that induce broad spectrum and long-lasting immune responses'. Presentations were made by representatives from industry, academia, governmental and non-governmental organisations. The objectives of the meeting were to update the progress of research in the field of influenza vaccine strategies able to generate cross protection against divergent influenza virus strains. Improvements in existing strategies including live attenuated influenza vaccines and adjuvantation of inactivated vaccines were summarised. Developments in novel antigen production methods, new routes of vaccine delivery and administration, and vaccine approaches based on conserved virus antigens were explored. In addition, correlates of immune protection and regulatory issues for the evaluation and approval of future novel vaccine strategies were discussed.

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 (PCONCLUSIONS: 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).

Avian influenza H9N2 viruses are considered as a pandemic threat. We assessed the safety and immunogenicity of fourteen H9N2 vaccine formulations. A randomized, phase I trial was done in 353 adults, aged 18-82 years. Subjects received two doses of A/Hong Kong/1073/99 (H9N2) whole-virus, alum-adjuvanted whole-virus, virosomal, or intradermal whole-virus vaccine at four doses (1.7, 5, 15 or 45 microg haemagglutinin). Sera were obtained before and three weeks after each vaccination (days 0, 21, and 42) for haemagglutination-inhibition (HAI) and neutralization assays. All formulations were well tolerated. Pre-vaccination sera from subjects aged below or above 40 years had baseline antibody to H9N2 in 1% and 16% of samples. Compared to intramuscular whole-virus vaccine, alum-adjuvanted vaccine was more immunogenic, intradermal vaccine was comparable, and virosomal vaccine less immunogenic. Among subjects under 40 years, two doses (45, 15, and 5 microg) of alum-adjuvanted vaccine achieved seroprotective HAI titres in 50%, 41%, and 39% respectively, and neutralization seroconversions in 83%, 82%, and 78% of recipients. Among subjects over 40 years, one dose (45, 15, and 5 microg) of alum-adjuvanted vaccine achieved seroprotective HAI titres in 50%, 25% and 0% respectively, and neutralization seroconversions in 88%, 63% and 63% of recipients. Among immunologically naive subjects under 40 years, two doses of vaccine are required and alum-adjuvanted vaccines were most immunogenic. Among immunologically primed subjects over 40 years, one dose of whole-virus or alum-adjuvanted vaccine induced immune responses; the second dose provided less additional benefit. However, no vaccine formulation satisfied all European regulatory criteria for pandemic vaccines.

Older adults (> or =65 years of age) are particularly vulnerable to influenza illness. This is due to a waning immune system that reduces their ability to respond to infection, which leads to more severe cases of disease. The majority ( approximately 90%) of influenza-related deaths occur in older adults and, in addition, catastrophic disability resulting from influenza-related hospitalization represents a significant burden in this vulnerable population. Current influenza vaccines provide benefits for older adults against influenza; however, vaccine effectiveness is lower than in younger adults. In addition, antigenic drift is also a concern, as it can impact on vaccine effectiveness due to a mismatch between the vaccine virus strain and the circulating virus strain. As such, vaccines that offer higher and broader protection against both homologous and heterologous virus strains are desirable. Approaches currently available in some countries to meet this medical need in older adults may include the use of adjuvanted vaccines. Future strategies under evaluation include the use of high-dose vaccines; novel or enhanced adjuvantation of current vaccines; use of live attenuated vaccines in combination with current vaccines; DNA vaccines; recombinant vaccines; as well as the use of different modes of delivery and alternative antigens. However, to truly evaluate the benefits that these solutions offer, further efficacy and effectiveness studies, and better correlates of protection, including a precise measurement of the T cell responses that are markers for protection, are needed. While it is clear that vaccines with greater immunogenicity are required for older adults, and that adjuvanted vaccines may offer a short-term solution, further research is required to exploit the many other new technologies.

Results for clade 1 viruses were more consistent among laboratories when a standard antibody was used., 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.

Background Oseltamivir, a specific influenza neuraminidase inhibitor, is an effective treatment for seasonal influenza. Emergence of drug-resistant influenza viruses after treatment has been reported, particularly in children in Japan, where the dosing schedule is different from that used throughout the rest of the world. We investigated the emergence of drug-resistant infection in children treated with a tiered weight-based dosing regimen. Methods We analyzed sequential clinical nasopharyngeal samples, obtained before and after tiered weight-based oseltamivir therapy, from children with acute influenza during 2005-2007. We isolated viruses, tested for drug resistance with use of a fluorescence-based neuraminidase inhibition assay, performed neuraminidase gene sequencing, and determined quantitative viral loads. Results Sixty-four children (34 with influenza A subtype H3N2, 11 with influenza A subtype H1N1, and 19 with influenza B virus) aged 1-12 years (median age, 3 years, 1 month) were enrolled. By days 4-7 after initiation of treatment, of 64 samples tested, 47 (73.4%) and 26 (40.6%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. By days 8-12 after initiation of treatment, of 53 samples tested, 18 (33.9%) and 1 (1.8%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. We found no statistically significant differences in the reduction of viral shedding or time to clearance of virus between viral subtypes. Antiviral-resistant viruses were recovered from 3 (27.3%) of 11 children with influenza A subtype H1N1, 1 (2.9%) of 34 children with influenza A subtype H3N2, and 0 (0%) of 19 children with influenza B virus, all of whom were treated with oseltamivir (P = .004). There was no evidence of prolonged illness in children infected with drug-resistant virus. Conclusions Drug resistance emerges at a higher rate in influenza A subtype H1N1 virus than in influenza A subtype H3N2 or influenza B virus after tiered weight-based oseltamivir therapy. Virological surveillance for patterns of drug resistance is essential for determination of antiviral treatment strategies and for composition of pandemic preparedness stockpiles.

Healthcare workers may be at risk during the next influenza pandemic. Priming with stockpiled vaccine may protect staff and reduce nosocomial transmission. Despite campaigns to increase seasonal influenza vaccine coverage, uptake among healthcare workers is generally low; creating uncertainty whether they would participate in pre-pandemic vaccine programmes. We conducted a cross-sectional questionnaire survey of healthcare workers in a UK hospital during, and 6 months after, a period of media reporting of an H5N1 outbreak at a commercial UK poultry farm. A total of 520 questionnaires were returned, representing 20% of frontline workforce. More respondents indicated willingness to accept stockpiled H5N1 vaccine during the period of media attention than after (166/262, 63.4% vs. 134/258, 51.9%; p = 0.009). Following multivariate analysis, factors associated with willingness to accept H5N1 vaccine included: previous seasonal vaccine (OR 6.2, 95% CI 3.0–12.8, p < 0.0001), awareness of occupational seasonal vaccine campaigns (OR 2.2, 95% CI 1.4–3.5, p = 0.001), belief that seasonal vaccine benefits themselves (OR 2.5, 95% CI 1.6–4.0, p < 0.0001) or the hospital (OR 3.6, 95% CI 2.3–5.8, p < 0.0001), belief that pandemic risk is high/moderate (OR 14.1, 95% CI 7.6–26.1, p < 0.0001) and would threaten healthcare workers (OR 2.9, 95% CI 1.8–4.5, p < 0.0001). Those who would not accept vaccine (220 respondents, 42.7%) if offered before the pandemic do not perceive pandemic influenza as a serious threat, and have concerns regarding vaccine safety. A majority of healthcare workers are amenable to accept stockpiled H5N1 vaccine if offered in advance of pandemic activity.

A study was performed to investigate the reproducibility of haemagglutinin-inhibition (HI) and virus neutralising (VN) assays for detection of anti-influenza antibody. Participants in 11 laboratories from eight countries measured antibody to egg-grown A/Japan/434/2003, cell-grown A/Japan/434/2003 and A/Panama/2007/99 (H3N2) viruses in 18 human and two post-infection ferret sera. There was significant intra-laboratory assay variability for VN compared to HI. For replicate assays within laboratories, 14/410 (3%) and 130/631 (21%) titres differed by2-fold (p0.0001), and 0/410 (0%) and 35/631 (6%) titres differed by5-fold (p0.0001) by HI and VN, respectively. Although both assays showed inter-laboratory variation, VN assays were significantly more variable than HI. Median geometric coefficients of variation (GCV) for VN assays with each virus were 256%, 323% and 359% compared to 138%, 155% and 261% with HI. A serum standard improved inter-laboratory agreement and reduced median GCVs. This study raises concern about comparability of serology results from H5N1 vaccine trials and it is proposed that an International Standard for influenza H5N1 antibody is developed.

Since the last influenza pandemic in 1968, neuraminidase (NA) inhibitors have been licensed for the treatment and prophylaxis of seasonal influenza. Continuing outbreaks of highly pathogenic avian influenza H5N1 since 2004 have focused attention on the timing of the next pandemic and preparedness plans. Although immunization is the principal means of influenza prophylaxis, a well-matched efficacious vaccine is unlikely to be widely available for several months following the emergence of the pandemic strain. NA inhibitors could be used to contain and eliminate an emerging pandemic virus at source. If unsuccessful, they could still play a crucial role in reducing the medical impact of pandemic influenza as it spreads through countries. Accordingly, many authorities are creating stockpiles of NA inhibitors. However, the use of stockpiled drugs for treatment or prophylaxis, the rapid delivery to newly diagnosed cases and unknown characteristics of an emergent pandemic strain pose significant challenges to determining optimal use of stockpiles.

PUBLISHED, Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-?g doses of hemagglutinin from each virus strain with either 3, 10, or 30 ?g of heat-labile Escherichia coli enterotoxin (LTK63) and 990 ?g of a supramolecular biovector; one intranasally vaccinated group was given 7.5-?g doses of hemagglutinin with 30 ?g of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 ?g hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union (EU) were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 ?g LTK63 with the biovector, occurring in 7/15 (47%; P = 0.0103), 8/15 (53%; P = 0.0362), and 14/15 (93%; P = 0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 ?g LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P = 0.0491) and B/Guandong (P = 0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated., This study was supported by European Union (EU) grant QLRT-1999-00070

Avian H5N1 influenza viruses currently circulating in southeast Asia could potentially cause the next pandemic. However, currently licensed human vaccines are subtype-specific and do not protect against these H5N1 viruses. We aimed to develop an influenza vaccine and assessed its immunogenicity and efficacy to confer protection in BALB/c mice.We developed an egg-independent strategy to combat the avian influenza virus, because the virus is highly lethal to chickens and the maintenance of a constant supply of embryonated eggs would be difficult in a pandemic. We used a replication-incompetent, human adenoviral-vector-based, haemagglutinin subtype 5 influenza vaccine (HAd-H5HA), which induces both humoral and cell-mediated immune responses against avian H5N1 influenza viruses isolated from people.Immunisation of mice with HAd-H5HA provided effective protection from H5N1 disease, death, and primary viral replication (p0.0001) against antigenically distinct strains of H5N1 influenza viruses. Unlike the recombinant H5HA vaccine, which is based on a traditional subunit vaccine approach, HAd-H5HA vaccine induced a three-fold to eight-fold increase in HA-518-epitope-specific interferon-gamma-secreting CD8 T cells (p=0.01).Our findings highlight the potential of an Ad-vector-based delivery system, which is both egg-independent and adjuvant-independent and offers stockpiling options for the development of a pandemic influenza vaccine.

Antigenically well-matched vaccines against highly pathogenic avian influenza H5N1 viruses are urgently required. Human serum samples after immunization with MF59 or nonadjuvanted A/duck/Singapore/97 (H5N3) vaccine were tested for antibody to 1997-2004 human H5N1 viruses. Antibody responses to 3 doses of nonadjuvanted vaccine were poor and were higher after MF59-adjuvanted vaccine, with seroconversion rates to A/HongKong/156/97, A/HongKong/213/03, A/Thailand/16/04, and A/Vietnam/1203/04 of 100% (P < .0001), 100% (P < .0001), 71% (P = .0004), and 43% (P = .0128) in 14 subjects, respectively, compared with 27%, 27%, 0%, and 0% in 11 who received nonadjuvanted vaccine. These findings have implications for the rational design of pandemic vaccines against influenza H5.

Influenza is an infectious respiratory pathogen causing annual outbreaks and infrequent pandemics, resulting in significant morbidity, mortality and burdens on the delivery of health care. The geographical spread of highly pathogenic avian influenza (HPAI) H5N1 among poultry and wild bird populations is unprecedented. Growing numbers of sporadic avian influenza infections are occurring in humans, increasing the threat of the next influenza pandemic. Vaccines are the principle means of combating influenza, and a number of studies with H5N1 vaccine candidates are underway. Antiviral agents can be used to treat influenza infection and can be taken as chemoprophylaxis during influenza outbreaks. Oseltamivir has been stockpiled as part of influenza pandemic preparedness planning; however, the emergence of drug resistance may limit its clinical use.

Summary Sporadic human infection with avian influenza viruses has raised concern that reassortment between human and avian subtypes could generate viruses of pandemic potential. Vaccination is the principal means to combat the impact of influenza. During an influenza pandemic the immune status of the population would differ from that which exists during interpandemic periods. An emerging pandemic virus will create a surge in worldwide vaccine demand and new approaches in immunisation strategies may be needed to ensure optimum protection of unprimed individuals when vaccine antigen may be limited. The manufacture of vaccines from pathogenic avian influenza viruses by traditional methods is not feasible for safety reasons as well as technical issues. Strategies adopted to overcome these issues include the use of reverse genetic systems to generate reassortant strains, the use of baculovirusexpressed haemagglutinin or related non-pathogenic avian influenza strains, and the use of adjuvants to enhance immunogenicity. In clinical trials, conventional surfaceantigen influenza virus vaccines produced from avian viruses have proved poorly immunogenic in immunologically naive populations. Adjuvanted or whole-virus preparations may improve immunogenicity and allow sparing of antigen.

Background . Dengue occurs in many tourist destinations, and is increasingly imported by returning travellers. We review the epidemiology and clinical features of confirmed dengue in returning travellers presenting to a UK regional infectious diseases unit. Methods . A retrospective, case-record review of febrile returning travellers, admitted to Leicester Royal Infirmary during 2000–2002. The presenting clinical features of patients with positive dengue serology were compared to those who had negative serological tests. Results . Dengue, including two cases of dengue haemorrhagic fever (DHF) and 1 shock syndrome, was diagnosed in 16 of approximately 250 (6.4%) hospitalised returning travellers. 10/16 (62.5%) patients returned from Asia. There was no difference in symptoms between those with or without serological evidence of dengue. Dengue was associated with thrombocytopenia ( p =0.001), leucopenia ( p =0.03) and elevated alanine transminase ( p =0.01). Following multivariate analysis, dengue was associated with first time travel to an endemic area (odds ratio 10.9, 95% CI 1.21–99.9), early onset of symptoms after return (OR 1.91, 95% CI 1.07–3.43), duration of time overseas (OR 1.08, 95% CI 1.01–1.15) and thrombocytopenia (OR 29.4, 95% CI 1.8–494). Conclusions . Dengue is an important cause of illness in hospitalised febrile returning travellers. It should be considered in first-time travellers, with thrombocytopenia and negative malaria films who present with symptoms soon after return.

In 1997, influenza A/Hong Kong/97 (H5N1) emerged as a potential human threat. In 1999, a randomised study comparing two doses of MF59-adjuvanted and non-adjuvanted influenza A/Duck/Singapore/97 (H5N3) surface-antigen vaccine found non-adjuvanted vaccine was poorly immunogenic. Addition of MF59 significantly boosted antibody to H5N1 to levels associated with protection. At 16 months, we undertook a follow-up study to assess the effect of H5N3 revaccination. Geometric mean titres (GMTs) of antibody by haemagglutination-inhibition (HI), microneutralisation (MN) and single radial haemolysis (SRH) indicated that protective antibody titres did not exist at 16 months after two-dose priming. Twenty-one days after revaccination, there was significant boosting of antibody compared to GMTs achieved 21 days after two-dose priming in the original study (P

During normal interpandemic influenza seasons, immune responses to vaccines are quite predictable and meet the licensing criteria of the European Union (EU) Committee for Proprietary Medicinal Products (CPMP). In a pandemic situation, large sections, if not all of the community will be immunologically naïve and therefore new immunisation strategies will be needed. In 1976 and 1977 H1N1 vaccines were prepared and tested clinically. To stimulate 'protective' antibody responses, two doses of vaccine were needed in people below the age of 24 years (no previous experience of H1N1 virus), whereas one conventional dose was adequate in older people. In 1997, the highly pathogenic avian influenza H5N1 virus caused widespread concern when it infected man, with lethal effects. Due to safety concerns it was necessary to adopt new strategies for vaccine development and one such strategy was to produce vaccine from an avirulent H5N3 virus, A/Duck/Singapore-Q/F119-2/97. Clinical trials of a subunit vaccine prepared from A/Duck/Sing/97 virus revealed that even two doses of twice the normal vaccine concentration (i.e. 30 micro g haemagglutinin) were poorly immunogenic, whereas an H5N3 vaccine adjuvanted with microfluidised emulsion (MF) 59 stimulated antibody levels that complied with CPMP criteria after two half strength doses (i.e. 7.5 micro g haemagglutinin).

Summary Background In 1997, pathogenic avian influenza A/Hong Kong/97 (H5N1) viruses emerged as a pandemic threat to human beings. A non-pathogenic variant, influenza A/Duck/Singapore/97 (H5N3), was identified as a leading vaccine candidate. We did an observer-blind, phase I, randomised trial in healthy volunteers to assess safety, tolerability, and antigenicity of MF59-adjuvanted and non-adjuvanted vaccines. Methods 32 participants were randomly assigned MF59, and 33 non-adjuvanted vaccine. Two doses were given 3 weeks apart, of 7·5, 15, or 30 μg haemagglutinin surface-antigen influenza A H5N3 vaccine. Antibody responses were measured by haemagglutination inhibition, micro-neutralisation, and single radial haemolysis (SRH). The primary outcome was geometric mean antibody titre 21 days after vaccination. Findings The A/Duck/SIngapore vaccines were safe and well tolerated. Antibody response to non-adjuvanted vaccine was poor, the best response occurring after two 30 μg doses: one, four, four, and one person of eleven seroconverted by haemagglutination inhibition, microneutralisation, H5N3 SRH, and H5N1 SRH, respectively. The geometric mean titres of antibody, and seroconversion rates, were significantly higher after MF59 adjuvanted vaccine. Two 7·5 μg doses of MF59 adjuvanted vaccine gave the highest seroconversion rates: haemagglutination inhibition, six of ten; microneutralisation, eight often; H5N3 SRH, ten often; H5N1 SRH, nine of ten. Geometric mean titre of antibody to the pathogenic virus, A/Hong Kong/489/97 (H5N1), was about half that to A/Duck/Singapore virus. Interpretation Non-adjuvanted A/Duck/Singapore/97 (H5N3) vaccines are poorly immunogenic and doses of 7·5–30 μg haemagglutinin alone are unlikely to give protection from A/Hong Kong/97 (H5N1) virus. Addition of MF59 to A/Duck/Singapore/97 vaccines boost the antibody response to protection levels. Our findings have implications for development and assessment of vaccines for future pandemics.

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

Background In December 2009, the World Health Organization (WHO) issued updated guidelines on the prevention of H1N1 influenza virus in healthcare settings. In 2010, the WHO pandemic influenza alert level was still at phase 6. Aim To study the practice of infection control measures during the 2009 influenza H1N1 pandemic among healthcare workers (HCWs) in three countries. Methods A standardized, self-administered anonymous questionnaire survey was conducted in 2010 among doctors, nurses and allied HCWs in 120 hospital-based clinical departments in Hong Kong, Singapore and the UK. Questions were asked on demographics; previous experience and perceived severity of influenza; infection control practices; uptake of seasonal influenza vaccination and H1N1 vaccination. Multiple logistic regression was used to test the independent association with different factors. Findings A total of 2100 HCWs in the three countries participated. They reported high compliance (>80%) with infection control procedures regarded as standard for droplet-transmitted infections including wearing and changing gloves, and washing hands before and after patient contact. However, the reported use of masks with indirect or direct patient contact (surgical or N95 as required by their hospital) varied considerably (96.4% and 70.4% for Hong Kong; 82.3% and 87.7% for Singapore; 25.3% and 62.0% for the UK). Reported compliance was associated with job title, number of patient contacts and perceived severity of pandemics. There was no association between the uptake for seasonal or 2009 H1N1 vaccines and compliance. Conclusions Compliance with infection control measures for pandemic influenza appears to vary widely depending on the setting.

Haemagglutination-inhibition (HI) and virus neutralisation (VN) assays are used to evaluate immunogenicity of pandemic H1N1 vaccines; however these bioassays are poorly standardised leading to inter-laboratory variation. A candidate International Standard (IS) for antibody to H1N1 pdm virus (09/194) was prepared from pooled sera of subjects who had either recovered from H1N1 pdm infection or who had been immunised with an adjuvanted subunit vaccine prepared from reassortant virus NYMC X-179A (derived from A/California/7/2009 virus). Ten laboratories from seven countries tested the candidate IS, 09/194 and a panel of human sera by HI and VN using the A/California/7/2009 virus (six laboratories) and/or the reassortant virus NYMC X-179A (ten laboratories). As expected, the inter-laboratory variability for HI and VN assay results was high. For results of antibody tests to NYMC X-179A, the % geometric coefficient of variation (%GCV) for 09/194 between laboratories was 83% for HI and 192% for VN. For tests of all sera, the median %GCV ranged from 95 to 345% for HI (80-fold variation) and 204 to 383% for VN (109-fold variation), but for the titres relative to 09/194 the median %GCV was much reduced (HI 34-231%; VN 44-214%). For tests of antibody to the A/California/7/2009 wild type virus there were similar reductions in %GCV when 09/194 was used. These results suggest that 09/194 will be of use to standardise assays of antibody to A/California/7/2009 vaccine and 09/194 has now been established by WHO as an IS for antibody to A/California/7/2009 with an assigned potency of 1300 IU per ml.

The aim of this study was to identify the common barriers and facilitators for acceptance of pandemic influenza vaccination across different countries. This study utilized a standardized, anonymous, self-completed questionnaire-based survey recording the demographics and professional practice, previous experience and perceived risk and severity of influenza, infection control practices, information of H1N1 vaccination, acceptance of the H1N1 vaccination and reasons of their choices and opinions on mandatory vaccination. Hospital-based doctors, nurses and allied healthcare workers in Hong Kong (HK), Singapore (SG) and Leicester, United Kingdom (UK) were recruited. A total of 6318 (HK: 5743, SG: 300, UK: 275) questionnaires were distributed, with response rates of 27.1% (HK), 94.7% (SG) and 94.5% (UK). The uptake rates for monovalent 2009 pandemic H1N1 vaccine were 13.5% (HK), 36.2% (SG) and 41.3% (UK). The single common factor associated with vaccine acceptance across all sites was having seasonal influenza vaccination in 2009. In UK and HK, overestimation of side effect reduced vaccination acceptance; and fear of side effect was a significant barrier in all sites. In HK, healthcare workers with more patient contact were more reluctant to accept vaccination. Drivers for vaccination in UK and HK were concern about catching the infection and following advice from health authority. Only a small proportion of respondents agreed with mandatory pandemic influenza vaccination (HK: 25% and UK: 42%), except in Singapore where 75.3% were in agreement. Few respondents (

Summary Introduction Enteric fever is an increasingly common diagnosis in returning travellers in the UK. Methods We performed a retrospective descriptive study of culture-confirmed cases of enteric fever admitted to University Hospitals Leicester, UK between January 1999 and April 2009. Results 100 cases of enteric fever were identified in adults ( n = 76) and children ( n = 24). The median age of adult subjects was 38 (range 18–71) and 55% were male. Of the 61 adult cases with notes available, 60 (98.3%) were of Asian ethnicity and 56 (92%) had a recent travel history, principally to the Indian Subcontinent. Symptoms included fever (100%), headache (62%), diarrhoea (59%) and abdominal pain (44%). Common examination findings included pyrexia and mild generalized abdominal tenderness. Mild hyponatraemia, transaminitis and a normal white cell count were commonly identified. Reduced ciprofloxacin sensitivity was common and increased over the study period. Median fever clearance time was 6 days, and treatment failure occurred in 20% of cases. Relapse occurred in 2 patients. Complications were unusual, and one patient died. Discussion Patients with enteric fever presented with a non-specific febrile illness within one month after returning from travel, and most had an uncomplicated clinical course. Increasing ciprofloxacin insensitivity was the likely explanation for a high treatment failure rate and this agent can no longer recommended as empirical treatment.

Proactive priming before the next pandemic could induce immune memory responses to novel influenza antigens. In an open-label study, we analyzed B cell memory and antibody responses of 54 adults who received 2 7.5-μg doses of MF59-adjuvanted A/Vietnam/1194/2004 clade 1 (H5N1) vaccine. Twenty-four subjects had been previously primed with MF59-adjuvanted or plain clade 0-like A/duck/Singapore/1997 (H5N3) vaccine during 1999–2001. The prevaccination frequency of circulating memory B cells reactive to A/Vietnam/1194/2004 was low in both primed and unprimed individuals. However, at day 21 after boosting, MF59-adjuvanted primed subjects displayed a higher frequency of H5N1-specific memory B cells than plain-primed or unprimed subjects. The immune memory was rapidly mobilized by a single vaccine administration and resulted in high titers of neutralizing antibodies to antigenically diverse clade 0, 1, and 2 H5N1 viruses already at day 7. In general, postvaccination antibody titers were significantly higher in primed subjects than in unprimed subjects. Subjects primed with MF59-adjuvanted vaccine responded significantly better than those primed with plain vaccine, most notably in early induction and duration of cross-reacting antibody responses. After 6 months, high titers of cross-reactive antibody remained detectable among MF59-primed subjects. We conclude that distant priming with clade 0-like H5N3 induces a pool of cross-reactive memory B cells that can be boosted rapidly years afterward by a mismatched MF59-adjuvanted vaccine to generate high titers of cross-reactive neutralizing antibodies rapidly. These results suggest that pre-pandemic vaccination strategies should be considered.

The authors report on an open-label study of an MF59-adjuvanted vaccine against avian influenza. The findings indicate that priming subjects with H5 antigen induces a rapidly mobilized, long-lastin...

Background Specific anti-influenza drugs are available for the management of seasonal influenza. Objectives To evaluate European recommendations and guidelines for the use of antiviral drugs in treatment and prevention of seasonal influenza. Design Guidelines issued between January 2003 and September 2007 were scored using the AGREE appraisal instrument and evaluated. Results Guidelines were obtained from France, Germany, Italy, Netherlands, Poland, Portugal, Sweden and the UK. Most guidelines recommend neuraminidase inhibitors over M2 inhibitors, but three countries were unclear or suggested M2 inhibitor use in some circumstances. Clinical diagnosis of patients eligible for treatment during periods of influenza activity is acceptable except in Poland where virological confirmation is required. Guidelines recommend antiviral use in patients at high risk of complications, except in Germany where there is a strong recommendation to treat all patients. Post-exposure prophylaxis for household contacts is recommended in Sweden and Germany, but not other countries. Only UK guidelines are regularly updated. All scored fairly poorly by the AGREE instrument. French, Polish, Swedish and UK guidelines were recommended. Conclusion Major variations exist in recommendations for treatment and prevention of seasonal influenza. Development of Pan-European guidance should be considered. Updating is important to reflect emerging patterns of antiviral resistance.

Influenza is an important epidemic and pandemic illness associated with serious morbidity and mortality in unprotected communities. Patients at increased risk of infection are those with pre-existing cardiopulmonary disease including asthma. The influenza virus has the ability to produce antigenic changes posing problems for vaccine development. Influenza vaccines have been available for over 50 years. Despite the continuing global threat posed by infection and recommendations in many countries that immunisation should be widely given, uptake rates are variable and often poor. It has been demonstrated that infection with influenza and other respiratory viral pathogens can produce exacerbations of asthma throughout the age groups. Despite this, vaccine uptake rates in asthmatic populations are quite low. Poor uptake rates are attributed to a number of factors and we review the evidence for the widely held view that influenza vaccination produces exacerbations of chronic airflow obstruction including asthma. Observational studies have found conflicting results: some post immunisation changes in bronchial hyperreactivity and increased requirements of bronchodilator therapy have been in some, but not all, studies. Placebo-controlled trials have not demonstrated any clinical deterioration although one study showed a small reduction in peak expiratory flow rate. Intranasal administration of cold-adapted live vaccines and new nucleic acid vaccines are briefly considered. Live adapted vaccines have been shown to be effective in influenza immunoprophylaxis and limited data on their use in patients with asthma suggest that they can be administered safely. In conclusion, based up on current studies and evidence, it seems likely that influenza infection produces morbidity in patients with asthma but that any potential adverse effects of influenza immunisation are outweighed by the benefits in this population. However, placebo-controlled trials are few and only small numbers of asthmatic patients have been investigated.

Avian influenza (H5N1) was first associated with human respiratory disease in Hong Kong in 1997. In 2004 the virus re-emerged among poultry and migratory birds in Asia and has spread into Europe and Africa, raising concerns that an H5 pandemic is imminent.

Because of the time required to identify and produce an antigenically well-matched pandemic vaccine, vaccines that offer broader cross-reactive immunity and protection are desirable. We have compared a live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) based on a related H5 hemagglutinin (HA) from a nonpathogenic avian influenza virus, A/Duck/Pottsdam/1042-6/86 (H5N2), for the ability to induce cross-reactive immunity and/or cross-protective efficacy against a contemporary highly pathogenic H5N1 viruses. Both LAIV and IIV provided cross-protection from systemic infection, severe disease, and death following lethal challenges with antigenically distinct A/Vietnam/1203/2004 (VN/1203) virus. Substantial levels of serum anti-VN/1203 HA IgG were detected in mice that received either IIV or LAIV, while nasal wash anti-VN/1203 HA IgA was detected in mice that received LAIV. Formulation of IIV with alum adjuvant augmented neutralizing antibody responses and protective efficacy. These results demonstrated that vaccination of mice with H5 IIV or LAIV induced a high degree of cross-protection from illness and death following lethal challenges with a heterologous H5N1 virus.