Chapter Controlled Human Infection with Bordetella pertussis.

Bordetella pertussis, a slow-growing Gram-negative coccobacillus and the causative agent of whooping cough, is one of the leading causes of vaccine-preventable death and morbidity globally. A state of asymptomatic human carriage has not yet been demonstrated by population studies but is likely to be an important reservoir for community transmission of infection. Such a carriage state may be a target for future vaccine strategies. This chapter presents a short summary of the characteristics of B. pertussis, which should be taken into account when developing a human challenge model and any future experimental medicine interventions. Three studies involving deliberate infection with B. pertussis have been described to date. The first of these was a scientifically and ethically unacceptable paediatric challenge study involving four children in 1930. The second was an investigation of a putative live vaccine using a genetically modified and attenuated strain of B. pertussis. Finally, a systematically constructed human challenge model using a wild-type, potentially pathogenic strain has been established. The latter study has demonstrated that deliberate induction of asymptomatic colonisation in humans is safe and immunogenic, with colonised participants exhibiting seroconversion to pertussis antigens. It has also shown nasal wash to be a more sensitive method of detecting the presence of B. pertussis than either pernasal swab or throat swab, and that B. pertussis carriage can be cleared effectively with Azithromycin. The development of this wild-type B. pertussis human challenge model will allow the investigation of host-pathogen and facilitate future vaccine development.

Exploring the acceptability of controlled human infection with SARSCoV2-a public consultation.

Rapid development of an effective vaccine for SARSCoV2 is a global priority. A controlled human infection model (CHIM) would accelerate the efficacy assessment of candidate vaccines. This strategy would require deliberate exposure of volunteers to SARSCoV2 with no currently available treatment and a small but definite risk of serious illness or death. This raises complex questions about the social and ethical acceptability of risk to individuals, given the potential benefit to the wider population, and as such, a study cannot be done without public involvement. We conducted a structured public consultation with 57 individuals aged 20-40 years to understand public attitudes to a CHIM, and pre-requisites for enrolment. The overall response to this strategy was positive, and many would volunteer altruistically. Carefully controlled infection is viewed as safer than natural exposure to wild virus. The prolonged social isolation required for the proposed CHIM is considered an obstacle but not insurmountable, with reasonable compensation and supportive care. Given the significant level of public interest, a CHIM should be done as open science with regular, controlled dissemination of information into the public domain. Importantly, there was a strong view that the final decision whether to conduct a CHIM should be in the hands of qualified and experienced clinician-scientists and the authorities.

International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia

The most recent European guidelines and task force reports on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) were published almost 10 years ago. Since then, further randomised clinical trials of HAP and VAP have been conducted and new information has become available. Studies of epidemiology, diagnosis, empiric treatment, response to treatment, new antibiotics or new forms of antibiotic administration and disease prevention have changed old paradigms. In addition, important differences between approaches in Europe and the USA have become apparent.The European Respiratory Society launched a project to develop new international guidelines for HAP and VAP. Other European societies, including the European Society of Intensive Care Medicine and the European Society of Clinical Microbiology and Infectious Diseases, were invited to participate and appointed their representatives. The Latin American Thoracic Association was also invited.A total of 15 experts and two methodologists made up the panel. Three experts from the USA were also invited (Michael S. Niederman, Marin Kollef and Richard Wunderink).Applying the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology, the panel selected seven PICO (population-intervention-comparison-outcome) questions that generated a series of recommendations for HAP/VAP diagnosis, treatment and prevention.(AU)

The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults.

Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis. Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults. A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system. Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients.

Effect of ethnicity on care pathway and outcomes in patients hospitalized with influenza A(H1N1)pdm09 in the UK.

Data were extracted from the case records of UK patients admitted with laboratory-confirmed influenza A(H1N1)pdm09. White and non-White patients were characterized by age, sex, socioeconomic status, pandemic wave and indicators of pre-morbid health status. Logistic regression examined differences by ethnicity in patient characteristics, care pathway and clinical outcomes; multivariable models controlled for potential confounders. Whites (n = 630) and non-Whites (n = 510) differed by age, socioeconomic status, pandemic wave of admission, pregnancy, recorded obesity, previous and current smoking, and presence of chronic obstructive pulmonary disease. After adjustment for a priori confounders non-Whites were less likely to have received pre-admission antibiotics [adjusted odds ratio (aOR) 0·43, 95% confidence interval (CI) 0·28-0·68, P < 0·001) but more likely to receive antiviral drugs as in-patients (aOR 1·53, 95% CI 1·08-2·18, P = 0·018). However, there were no significant differences by ethnicity in delayed admission, severity at presentation for admission, or likelihood of severe outcome.

MBL2 deficiency is associated with higher genomic bacterial loads during meningococcemia in young children.

Mannose binding lectin (MBL2) is a soluble pattern recognition receptor that is key to generating innate immune responses to invasive infection, including against the cardinal Gram-negative bacterium Neisseria meningitidis. Individuals homozygous or heterozygous for any of three variant alleles of MBL2 (O/O or A/O genotypes) have deficient concentrations of MBL2 in circulating blood, but previous studies linking MBL deficiency to susceptibility to meningococcal disease have not revealed a consistent association. We genotyped 741 patients with microbiologically-proven meningococcal disease and correlated MBL2 genotype with plasma bacterial load of N. meningitidis with blood samples taken during hospital admission. We show that individuals with genotypes compatible with MBL2 deficiency have higher measurable levels of bacterial plasma genomic load with the greatest effect seen in children <2 years of age. However, the overall impact of this is minor, because there was no evidence that such genotypes are more common in children with meningococcal disease compared with uninfected cohorts. The findings suggest that MBL2 supports innate immune defence against meningococcal disease in the early months of life, before acquired immunity is sufficiently robust for effective natural protection.

Neisseria meningitidis; clones, carriage, and disease.

Neisseria meningitidis, the cause of meningococcal disease, has been the subject of sophisticated molecular epidemiological investigation as a consequence of the significant public health threat posed by this organism. The use of multilocus sequence typing and whole genome sequencing classifies the organism into clonal complexes. Extensive phenotypic, genotypic and epidemiological information is available on the PubMLST website. The human nasopharynx is the sole ecological niche of this species, and carrier isolates show extensive genetic diversity as compared with hyperinvasive lineages. Horizontal gene exchange and recombinant events within the meningococcal genome during residence in the human nasopharynx result in antigenic diversity even within clonal complexes, so that individual clones may express, for example, more than one capsular polysaccharide (serogroup). Successful clones are capable of wide global dissemination, and may be associated with explosive epidemics of invasive disease.

The Nyhus-Wantz lectureship: etiology, herniosis, diverticulosis coli, and cancer.

The Nyhus-Wantz Lectureship honors two giants who represent the few who formed a new surgical specialty: herniology. My topics are etiology, herniosis, diverticulosis coli, and cancer. Hippocrates blamed wear and tear for herniation. Russell's (Lancet 1:1519-1523, 1902) explanation was congenital peritoneal "buds" extending down to the pelvis. Harrison (Arch Surg 4:680-689, 1922) attributed herniae to transversalis fascial degradation. Keith (Lancet 2(17):1398-1399, 1906) concluded that pathology was involved, even though Russell (Lancet 1:1519-1523, 1902) had denied it. Nevertheless, the congenital theory prevailed. According to McVay (Christopher's textbook of surgery, W.B. Saunders, Philadelphia, 1960, p. 159), defects arise in normal musculo-aponeurotic structures. Research showed that atrophy was caused by damaged fibroblasts producing less collagen, which was abnormal (having a reduced I/III ratio). The disease was systemic, later named herniosis. Nicotine addiction increased the incidence of herniation by an inflammatory process named metastatic emphysema. In 1948, Saint's Triad, an aggregation of hiatus hernia (later, any primary hernia), gallstones, and diverticulosis coli, was introduced. This association occurred eight times more often than expected, with herniosis appearing to be its cause, abetted by high blood cholesterol causing gallstones. In 2006, Krones et al. (Int J Colorectal Dis 21:18-24, 2006) provided evidence that colon cancer is accompanied by a reduction in diverticula. Klinge et al. (Hernia 8(4):300-301, 2004) showed that these entities require different extracellular matrices (ECMs). Ghajar and Bissell (Histochem Cell Biol 130:1105-1118, 2008) pointed out that the ECM, which comprises 80% of the breast, influences its epithelial genetic expression, likewise with other organs (kidney, skin, lung, colon, and ovaries). Recently, a fundamental change in our understanding of cancer growth and metastasis has taken place. Whereas the degradation of connective tissue was thought to encourage invasion, eliciting concern for the herniated, now, investigators report the reverse, a reactive vascularized stroma resembling wound healing with an increase in fibroblasts and collagen I. Words such as desmoplasia, fibrosis, and stiffening abound. In conclusion, degradation of the ECM may be why herniosis appears to be hostile to the development of cancer throughout the body. Studies are needed of patients with and without a history of hernia to determine their incidence of cancer. Data from smokers should be separated, since they carry their own high risk of malignancy.

Serum antibody kinetics following nasal or parenteral challenge with meningococcal polysaccharide in healthy adults.

Limited data are available on the kinetics of meningococcal serogroup C (MenC)-specific antibody responses following parenteral or nasal challenge in those who have received prior MenC vaccination (polysaccharide or conjugate). Young adults who had previously received either meningococcal A/C polysaccharide (MACP) or MenC conjugate (MCC) vaccine or naïve subjects were challenged with MACP via one of two routes, nasal or parenteral. Blood samples were taken prevaccination and on days 1 to 4 and day 10 postvaccination. MenC serum bactericidal antibody (SBA) and MenC-specific IgG were measured. Following parenteral challenge, MenC SBA and IgG responses were seen to occur between 4 and 7 days postchallenge. A lower proportion of subjects responded following nasal challenge, with naïve subjects showing little change in SBA geometric mean titer (GMT) and IgG geometric mean concentration (GMC) over the 10 days following challenge. Increases in SBA GMTs were seen between 4 and 7 days after nasal challenge in those who had received prior MCC and between 7 and 10 days in those who had received prior MACP, and the responses in the prior-MACP group were of lower magnitude than the responses of the prior-MCC group. The data presented here indicate that, following MCC vaccination, memory has been induced at the mucosal level, and these subjects were able to respond with increases in SBA levels. These results demonstrate that the speed of response (primary or secondary) to challenge with MenC polysaccharide via the nasal or parenteral route does not differ and support concerns that immunological memory alone is too slow to provide protection.

Crucial steps in the evolution of the preperitoneal approaches to the groin: an historical review.

Preperitoneal approaches to the repair of primary, bilateral, recurrent, inguinal, and femoral herniae, the most common abdominal protrusions, now dominate techniques of repair. The purpose of this review is to outline crucial steps which have led to this result. Abernethy (Surgical cases and remarks. Of the operation for the aneurysm. Cadell and Davies (Strand), London, pp. 149-176, 1797) introduced an operation to treat aneurysms of the external iliac artery, which was endorsed by Cooper (The anatomy and surgical treatment of abdominal hernia. Longman and Co, London, 1804). Bogros (Essai sur l'anatomie chirurgical de la region iliac et description d'un nouveau procede pour faire la ligature des arteries epigastric et iliaque externe. Th. Paris, no. 153. A Paris, de l'imprimerie de Didot le Jeune, imprimeur de la Faculte de Medicine, rue des Macons, Sorbonne no. 13, 1823) described his preperitoneal space which continues into the suprapubic space of Retzius. Annandale (Edinb Med J 21:1087-1091, 1876) initiated anterior preperitoneal repair. Cheatle (Br Med J 2:68-69, 1920, Br Med J 2:1025-1026, 1921) demonstrated the median posterior preperitoneal approach, resurrected by Henry (Lancet 1:531-533, 1936). McEvedy (Ann R Coll Surg Engl 7:484-496, 1950) modified the Cheatle-Henry procedure by using a unilateral oblique incision in the rectus sheath and underlying transversalis fascia with medial retraction of the rectus muscle. Estrin et al. (Surg Gynecol Obstet 116:547-550, 1963) reinforced this repair with prostheses attached to Cooper's ligament, thereby, eliminating tension. Anterior prosthetic preperitoneal repair was introduced by Usher et al. (Am Surg 24:969-974, 1958) using polyethylene and, later, polypropylene meshes which were not slit, since the spermatic cord was lateralized. Stoppa et al., beginning in 1965, performed giant prosthetic reinforcement of the visceral sac, covering Fruchaud's myopectineal orifice preperitoneally with extensive overlap. They used a posterior approach to avoid scarring in recurrent cases and to allow the exposure of large, bilateral, inguinal, and femoral sacs (Rev Med Picardie 1:46-46, 1972). Wantz (Surg Gynecol Obstet, 169:408-417, 1989) proposed a unilateral version. Gilbert (Am J Surg 163:331-335, 1992) described the anterior preperitoneal sutureless repair of groin herniation. He employed a two-layered prosthesis, the upper resting on the transversalis fascia, the lower in the space of Bogros. They were connected by a plug passed through the internal inguinal ring. Kugel (Am J Surg 178:298-302, 1999) described his anterior preperitoneal prosthetic repair of groin herniation through an abdominal gridiron incision. Laparoscopic repair of groin protrusions began in 1982 (Ger; Ann R Coll Surg Engl 64:342-344, 1982). In 1992, Arregui et al. (Surg Laparosc Endosc 2:53-58, 1992) and Dion and Morin (Can J Surg 35:209-212, 1992) reported on their transabdominal preperitoneal (TAPP) approach. To avoid intraperitoneal complications, Dulucq (Cahiers Chir 79:15-16, 1991) recommended a totally extraperitoneal (TEP) approach. These techniques incur fewer recurrences than open techniques and diminish postoperative pain. However, the operating time is longer, they are more expensive, and special skills are needed. In addition, general anesthesia is required. Thus, late in the 18th century, surgeons began incising the groin to treat aneurysms there. This experience led to the discovery of the preperitoneal space of Bogros, which, in the 1870 s, was employed for the anterior repair of groin herniation. The posterior preperitoneal approach became established in the 1920s-1960s, along with the use of prostheses. Laparoscopy was applied near the end of the century.

Virus shedding and environmental deposition of novel A (H1N1) pandemic influenza virus: interim findings.

BACKGROUND: The relative importance of different routes of influenza transmission, including the role of bioaerosols, and ability of masks and/or hand hygiene to prevent transmission, remains poorly understood. Current evidence suggests that infectious virus is not typically released from adults after 5 days of illness, however, little is known about the extent to which virus is deposited by infected individuals into the environment and whether deposited virus has the ability to infect new hosts. Further information about the deposition of viable influenza virus in the immediate vicinity of patients with pandemic influenza is fundamental to our understanding of the routes and mechanisms of transmission. OBJECTIVES: To collect data on patients infected with pandemic H1N1 2009 (swine flu). Primary objectives were to correlate the amount of virus detected in a patient's nose with that recovered from his/her immediate environment, and with symptom duration and severity. Secondary objectives were to describe virus shedding and duration according to major patient characteristics: adults versus children, and those with mild illness (community patients) versus those with more severe disease (hospitalised patients). METHODS: Adults and children, both in hospital and from the community, who had symptoms of pandemic H1N1 infection, were enrolled and visited every day during follow-up for a maximum of 12 days. Symptom data was collected and samples were taken, including nose swabs and swabs from surfaces and objects around patients. Samples of air were obtained using validated sampling equipment. The samples were tested for the presence of pandemic H1N1 virus, using polymerase chain reaction (PCR) to detect virus genome and an immunofluorescence technique to detect viable virus. RESULTS: Forty-three subjects were followed up, and 19 of them were subsequently proven to be infected with pandemic H1N1 virus. The median duration of virus shedding from the 19 infected cases was 6 days when detection was performed by PCR, and 3 days when detection was performed by a culture technique. Over 30% of cases remained potentially infectious for at least 5 days. Only 0.5% of all community and none of the hospital swabs taken revealed virus on surfaces. Five subjects had samples of the air around them collected and virus was detected by PCR from four; some of the air particles in which virus was detected were small enough to be inhaled and deposited deep in the lungs. LIMITATION: Small number of subjects recruited. CONCLUSIONS: The finding that over 30% of infected individuals have infectious virus in their noses for 5 days or more has infection control implications. The data suggest that contact transmission of pandemic influenza via fomites may be less important than previously thought, but transmission via bioaerosols at short range may be possible, meaning that high-level personal protective equipment may be needed by health-care workers when attending patients with pandemic influenza. Further work is being undertaken to consolidate these findings, as they have important potential implications for the protection of health-care workers and the formulation of advice to households, nationally and internationally.

Clinical efficacy of moxifloxacin versus comparator therapies for community-acquired pneumonia caused by Legionella spp.

The aim of this study was to compare outcomes for patients with community-acquired pneumonia (CAP) caused by Legionella spp. following treatment with moxifloxacin or a range of comparator antimicrobial agents. Data were pooled from four sequential I.V./P.O. trials of moxifloxacin in the treatment of CAP. Comparators were ceftriaxone +/- erythromycin, amoxicillin/clavulanate +/- clarithromycin, trovafloxacin, levofloxacin, or ceftriaxone + levofloxacin. Legionella infection was diagnosed by culture, urine antigen testing and/or serology. Clinical success rates for the efficacy-valid (per protocol) populations were recorded at the test-of-cure visit (5-30 days post-therapy). Severity of CAP was determined using the modified American Thoracic Society criteria.Of 1786 efficacy-valid patients, 33 (1.8%) had documented infection with Legionella spp. (moxifloxacin: n=13; comparator: n=20). Of these, 30 cases were identified by serology and/or urine antigen detection and 3 by respiratory culture. The success rate of moxifloxacin vs. comparator therapy was 92.3% vs. 80.0% for the I.V./P.O. trials.Sequential (I.V./P.O.) moxifloxacin demonstrated clinical efficacy that was at least as good as that of comparator treatments for the treatment of CAP due to Legionella.

Risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May-September 2009).

BACKGROUND: During the first wave of pandemic H1N1 influenza in 2009, most cases outside North America occurred in the UK. The clinical characteristics of UK patients hospitalised with pandemic H1N1 infection and risk factors for severe outcome are described. METHODS: A case note-based investigation was performed of patients admitted with confirmed pandemic H1N1 infection. RESULTS: From 27 April to 30 September 2009, 631 cases from 55 hospitals were investigated. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged > or = 65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physician-recorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically-confirmed pneumonia and a raised C-reactive protein (CRP) level (> or = 100 mg/l). 59% of all in-hospital deaths occurred in previously healthy people. CONCLUSIONS: Pandemic H1N1 infection causes disease requiring hospitalisation of previously fit individuals as well as those with underlying conditions. An abnormal chest x-ray or a raised CRP level, especially in patients who are recorded as obese or who have pulmonary conditions other than asthma or COPD, indicate a potentially serious outcome. These findings support the use of pandemic vaccine in pregnant women, children <5 years of age and those with chronic lung disease.

Cytokine production by activated T cells in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency. It is characterized by hypogammaglobulinemia, increased susceptibility to recurrent infections, autoimmunity, and malignancies. OBJECTIVES: To determine whether patients with CVID have cytokine production defects after T-cell activation and to assess whether or not these are correlated with markers of severe disease. METHODS: Twenty-seven patients with CVID and 17 healthy volunteers were investigated. Peripheral blood mononuclear cells were cultured under standard conditions in the presence and absence of phytohemagglutinin. Subsequent cell proliferation and cytokine release were measured and compared between stimulated and unstimulated cells. RESULTS: A general enhancement in cytokine production was observed in both CVID patients and controls after stimulation. However, we detected a lower production of interferon-gamma in CVID patients than in controls (P = .026). A production defect for at least 1 cytokine was observed in 12 patients. Ten of these failed to generate protective titers in response to the polysaccharide vaccine, and the frequency of bronchiectasis in this group of patients was 91.7%. Cytokine release correlated strongly with cell proliferation. CONCLUSIONS: This study indicates that some CVID patients have T-cell proliferation and secretory defects and that these may be associated with severe manifestations of disease. Screening for such defects could permit more effective monitoring and therapeutic strategies for CVID patients.

Systemic hernial disease protects against cancer: an hypothesis.

Research by herniologists from around the world has shown that abdominal defects, in the adult, are not caused by wear and tear but systemic hernial disease (herniosis), a disorder of connective tissue which affects the extracellular matrix (ECM). Wound healing may be affected, leading to recurrences after hernia repair or primary incisional herniation. Women with genitourinary prolapse show signs of herniosis in the pelvis. Diverticulosis coli, commonly seen in the elderly, like hernia, was once attributed to stress and strain from constipation. It is now suspected that herniosis weakens the colonic ECM, allowing the mucosa to form diverticula by herniating alongside the vasa recta. Remarkably, clinical studies of Saint's triad extending over the past 60 years have repeatedly demonstrated a highly significant relationship between colonic diverticula and abdominal herniae. Krones et al. (Int J Colorectal Dis 21:18-24, 2006) reported that diverticula and cancer are rarely coincident in the colon, despite aging. Their data indicate that the two pathologies arise in different ECMs. Klinge et al. (Int J Colorectal Dis 22:515-520, 2007), quoting Paget (Lancet 1:571-573, 1889), "Tumor cells can like seeds only grow if they fall on congenial soil," suggested that certain genes prevent stromal malignancy by influencing the microenvironment to stop epithelia from becoming cancerous. Thus, damage to the colonic ECM from hernial disease is conducive to diverticulosis, but hostile for cancer. Hernial disease being systemic, a similar ECM should be present throughout the body. Coincident diverticulosis and herniae support this hypothesis. Its validation requires further research involving the lifetime risk of cancer in patients with and without hernia. Since smoking causes both herniation and cancer, data from indulgers will have to be analyzed separately from abstainers.

A randomised, partially observer blind, multicentre, head-to-head comparison of a two-dose regimen of Baxter and GlaxoSmithKline H1N1 pandemic vaccines, administered 21 days apart.

OBJECTIVES: To evaluate the immunogenicity of a two-dose schedule of Baxter cell-cultured, non-adjuvanted, whole-virion H1N1 vaccine, and GlaxoSmithKline AS03(A)-adjuvanted split-virion H1N1 vaccine with respect to the EU Committee for Medicinal Products for Human Use (CHMP) and the US Food and Drug Administration (FDA) licensing criteria. DESIGN: An age-stratified, randomised, observer-blind, parallel-group, multicentre controlled trial was carried out in volunteers aged ≥ 18-44, ≥ 45-64 and ≥ 65 years. SETTING: Three teaching hospitals in the UK (Leicester Royal Infirmary, Leicester; Nottingham City Hospital, Nottingham; and Royal Hallamshire Hospital, Sheffield). PARTICIPANTS: Three hundred and forty-seven subjects were identified and randomised to AS03(A)-adjuvanted split-virion H1N1 vaccine or whole-virion (WV) vaccine in age groups [≥ 18-44 years (n = 140), ≥ 45-64 years (n = 136) and ≥ 65 years (n = 71)]. INTERVENTIONS: Vaccine was administered by intramuscular injection into the deltoid muscle of the non-dominant arm. One hundred and seventy-five randomised subjects were allocated AS03(A)-adjuvanted split H1N1 vaccine; one hundred and sixty-nine subjects had a second dose of the same vaccine 21 days later. One hundred and seventy-two subjects were allocated WV vaccine; one hundred and seventy-one subjects had a second dose of the same vaccine 21 days later. Serum samples for antibody measurements were collected on days 0 (before the first vaccination), 7, 14, 21 (before the second vaccination), 28, 35, 42 and 180. Subjects were observed for local and systemic reactions for 30 minutes after each injection, and for the next 7 days they recorded, in self-completed diaries, the severity of solicited local (pain, bruising, erythema and swelling) and systemic symptoms (chills, malaise, muscle aches, nausea and headache), oral temperature and use of analgesic medications. MAIN OUTCOME MEASURES: Vaccine immunogenicity using the CHMP and the FDA licensing criteria. Antibody titres were measured using haemagglutination inhibition (HI) and microneutralisation (MN) assays at baseline and 7, 14 and 21 days after each vaccination and at day 180. The three immunogenicity criteria end points were the seroprotection rate, the seroconversion rate and the mean-fold titre elevation. RESULTS: Both vaccine doses were given in 340 subjects (98%). Data from 680 (99%) of 687 issued diary cards were returned. Sera were obtained from 340 (98.0%), 333 (96.0%), 341 (98.3%), 331 (95.4%), 329 (94.8%) and 332 (95.7%) subjects on days 7, 14, 21, 28, 35 and 42, respectively. Three hundred and forty-six and 345 subjects were included in the safety and immunogenicity analyses, respectively. Prevaccination antibody was detected by HI (titre ≥ 1 : 8) and MN (titre ≥ 1 : 10) in 14% and 31% of subjects, respectively. Among the 298 (85.9%) subjects without baseline antibody on HI assay, a titre of ≥ 1 : 40 (seroprotection) was achieved after a single dose of AS03(A)-adjuvanted vaccine and WV vaccine by day 21 in 93.0% and 65.5%, respectively, of subjects between 18 and 44 years, 76.4% and 36.1% of subjects between 45 and 64 years, and 53.1% and 30.0% of subjects ≥ 65 years. Among all 347 subjects, a titre of ≥ 1 : 40 was achieved after a single dose of AS03(A)-adjuvanted vaccine and WV vaccine by day 21 in 94.0% and 71.4%, respectively, of subjects between 18 and 44 years, 77.3% and 38.8% of subjects between 45 and 64 years, and 51.4% and 32.4% of subjects ≥ 65 years. The age-adjusted odds ratio (OR) for adjuvanted compared with WV vaccine, in terms of seroprotection, was 4.42 [95% confidence interval (CI) 2.63 to 7.44, p < 0.001]. On day 42, among subjects without baseline antibody on HI assay, a titre of ≥ 1 : 40 was achieved after the second dose of AS03(A)-adjuvanted vaccine and WV vaccine by 100% and 67.9%, respectively, of subjects between 18 and 44 years, 89.3% and 41% of subjects between 45 and 64 years, and 76.5% and 34.5% of subjects ≥ 65 years. Among all 347 subjects, a titre of ≥ 1 : 40 was achieved on day 42 after the second dose of AS03(A)-adjuvanted vaccine and WV vaccine in 100% and 73.1%, respectively, of subjects between 18 and 44 years, 90.8% and 43.9% of subjects between 45 and 64 years, and 75.7% and 36.4% of subjects ≥ 65 years. The age-adjusted OR for adjuvanted vaccine compared with WV vaccine, in terms of seroprotection, was 11.21 (95% CI 5.80 to 21.64, p < 0.001). Age-related decline in antibody response occurred after both doses of both vaccines. WV vaccine was associated with fewer local and systemic reactions and lower immune responses than was AS03(A)-adjuvanted vaccine. The most frequent solicited local event was pain, reported by 28% and 76% of subjects after either dose of WV or adjuvanted vaccine, respectively (OR 7.71, 95% CI 4.48 to 13.24, p < 0.0001). The most common systemic event was myalgia, reported by 24% and 49% of subjects after either dose of WV or adjuvanted vaccine (OR 2.99, 95% CI 1.86 to 4.80, p < 0.0001). CONCLUSIONS: AS03(A)-adjuvanted 2009 H1N1 vaccine is more immunogenic and provides greater antigen-sparing capacity than WV 2009 H1N1 vaccine. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92328241. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 14, No. 55. See the HTA programme website for further project information.

Wristwatch use and hospital-acquired infection.

The wrists and hands of hospital-based healthcare workers (HCWs) were sampled for bacterial contamination in two consecutive cross-sectional cohort studies of wristwatch wearers and non-wristwatch wearers. In the first study (N=100), wrists were sampled by skin swabs and hands by direct plate inoculation. In the second study (N=155) wrists were sampled after each HCW removed the watch immediately prior to sampling. Staphylococcus aureus was found on the hands of 25% of wristwatch wearers and 22.9% of non-wristwatch wearers in the first study. Watch wearers had higher counts of bacteria on their wrist (P<0.001) but not on their hands. In the second study, removal of the watch prior to sampling resulted in increased counts of bacteria on both hands as well as on the watch wrist compared with non-watch wearers (P<0.001). In conclusion, wearing a wristwatch results in an increase in bacterial contamination of the wrist but excess hand contamination does not occur unless the watch is manipulated.