Chris Green

Chimpanzee adenovirus– and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults

The RSV vaccine candidates PanAd3-RSV and MVA-RSV were safe and immunogenic in healthy adults. RSV vaccine cows infection Respiratory syncytial virus (RSV) causes a severe lower respiratory tract disease that affects both children and the elderly. Vaccines have shown promise in rodents and nonhuman primates, but it remains unclear if these models reflect human RSV infection. Now, two papers by Taylor et al. and Green et al. translate one vaccine strategy first into calves, which are natural hosts of bovine RSV, and then into humans in a phase 1 clinical trial. A prime-boost strategy protected against upper and lower respiratory tract infection and pulmonary disease induced by heterologous bovine RSV challenge in calves and demonstrated safety and immunogenicity in humans. These data support further trials to test vaccine efficacy in human patients. Respiratory syncytial virus (RSV) causes respiratory infection in annual epidemics, with infants and the elderly at particular risk of developing severe disease and death. However, despite its importance, no vaccine exists. The chimpanzee adenovirus, PanAd3-RSV, and modified vaccinia virus Ankara, MVA-RSV, are replication-defective viral vectors encoding the RSV fusion (F), nucleocapsid (N), and matrix (M2-1) proteins for the induction of humoral and cellular responses. We performed an open-label, dose escalation, phase 1 clinical trial in 42 healthy adults in which four different combinations of prime/boost vaccinations were investigated for safety and immunogenicity, including both intramuscular (IM) and intranasal (IN) administration of the adenovirus-vectored vaccine. The vaccines were safe and well tolerated, with the most common reported adverse events being mild injection site reactions. No vaccine-related serious adverse events occurred. RSV neutralizing antibody titers rose in response to IM prime with PanAd3-RSV and after IM boost for individuals primed by the IN route. Circulating anti-F immunoglobulin G (IgG) and IgA antibody-secreting cells (ASCs) were observed after the IM prime and IM boost. RSV-specific T cell responses were increased after the IM PanAd3-RSV prime and were most efficiently boosted by IM MVA-RSV. Interferon-γ (IFN-γ) secretion after boost was from both CD4+ and CD8+ T cells, without detectable T helper cell 2 (TH2) cytokines that have been previously associated with immune pathogenesis following exposure to RSV after the formalin-inactivated RSV vaccine. In conclusion, PanAd3-RSV and MVA-RSV are safe and immunogenic in healthy adults. These vaccine candidates warrant further clinical evaluation of efficacy to assess their potential to reduce the burden of RSV disease.

Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma

Background Admission of infants to hospital with bronchiolitis consumes considerable healthcare resources each winter. We report an analysis of hospital admissions in England over five decades. Methods Data were analysed from the Hospital In-Patient Enquiry (HIPE, 1968–1985), Hospital Episode Statistics (HES, 1989–2011), Oxford Record Linkage Study (ORLS, 1963–2011) and Paediatric Intensive Care Audit Network (PICANet, 2003–2012). Cases were identified using International Classification of Diseases (ICD) codes in discharge records. Bronchiolitis was given a separate code in ICD9 (used in England from 1979). Geographical variation was analysed using Local Authority area boundaries. Maternal and perinatal risk factors associated with bronchiolitis and subsequent admissions for asthma were analysed using record-linkage. Results All-England HIPE and HES data recorded 468 138 episodes of admission for bronchiolitis in infants aged <1 year between 1979 and 2011. In 2011 the estimated annual hospital admission rate was 46.1 (95% CI 45.6 to 46.6) per 1000 infants aged <1 year. Between 2004 and 2011 the rates rose by an average of 1.8% per year in the all-England HES data, whereas admission rates to paediatric intensive care changed little (1.3 to 1.6 per 1000 infants aged <1 year). A fivefold geographical variation in hospital admission rates was observed. Young maternal age, low social class, low birth weight and maternal smoking were among factors associated with an increased risk of hospital admission with bronchiolitis. Conclusions Hospital admissions for infants with bronchiolitis have increased substantially in recent years. However, cases requiring intensive care have changed little since 2004.

Adolescents need a booster of serogroup C meningococcal vaccine to protect them and maintain population control of the disease

The serogroup C meningococcal immunisation programme was reviewed during 2012 by the Department of Healths Joint Committee on Vaccination and Immunisation (JCVI), and an adolescent booster has been recommended as a result of concerns over duration of immunity in the childhood population.1 During the 1990s, a clone of Neisseria meningitidis (sequence type 11; ST11) with a serogroup C polysaccharide capsule (repeating units of the sugar, α-2-9 N acetyl neuraminic acid) swept through the UK causing outbreaks of meningococcal disease in schools and universities, generating considerable media attention and anxiety for parents and those doctors, including paediatricians, in the front line of early diagnosis. The highest rates of disease were in the first 2 years of life, presumably as a result of immunological naivety, and among adolescents and young adults (see figure 1) as a result of various well known risk factors and behaviours (smoking, bar attendance, interpersonal proximity).2 ,3 The response to this serious public health problem, with some 955 microbiologically confirmed cases in the year from mid-1998, was the development, clinical testing and licensure of three serogroup C meningococcal (MenC) conjugate vaccines.4 These vaccines contain the MenC polysaccharide, chemically conjugated to a carrier protein (either tetanus toxoid or a mutant diphtheria toxoid, CRM197). The Department of Health launched an ambitious campaign of vaccination against MenC in the autumn of 19994 with the majority of infants, children and young people from 2 months to 19 years of age receiving MenC vaccine (see table 1) in a mass vaccination campaign over the next 12 months.5 Cases of disease caused by serogroup C meningococci plummeted over the next year, and continued to fall during the ensuing decade.6 Based on the prevaccination 1998 levels of disease, the vaccine may now have prevented more than 10 000 cases (see figure 2). …

Best practice in the prevention and management of paediatric respiratory syncytial virus infection

Respiratory syncytial virus (RSV) infection is ubiquitous with almost all infants having been infected by 2 years of age and lifelong repeated infections common. It is the second largest cause of mortality, after malaria, in infants outside the neonatal period and causes up to 200,000 deaths per year worldwide. RSV results in clinical syndromes that include upper respiratory tract infections, otitis media, bronchiolitis (up to 80% of cases) and lower respiratory tract disease including pneumonia and exacerbations of asthma or viral-induced wheeze. For the purposes of this review we will focus on RSV bronchiolitis in infants in whom the greatest disease burden lies. For infants requiring hospital admission, the identification of the causative respiratory virus is used to direct cohorting or isolation and infection control procedures to minimize nosocomial transmission. Nosocomial RSV infections are associated with poorer clinical outcomes, including increased mortality, the need for mechanical ventilation and longer length of hospital stay. Numerous clinical guidelines for the management of infants with bronchiolitis have been published, although none are specific for RSV bronchiolitis. Ribavirin is the only licensed drug for the specific treatment of RSV infection but due to drug toxicity and minimal clinical benefit it has not been recommended for routine clinical use. There is currently no licensed vaccine to prevent RSV infection but passive immunoprophylaxis using a monoclonal antibody, palivizumab, reduces the risk of hospitalization due to RSV infection by 39–78% in various high-risk infants predisposed to developing severe RSV disease. The current management of RSV bronchiolitis is purely supportive, with feeding support and oxygen supplementation until the infant immune system mounts a response capable of controlling the disease. The development of a successful treatment or prophylactic agent has the potential to revolutionize the care and outcome for severe RSV infections in the world’s most vulnerable infants.

A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial

Summary Objectives Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. Methods The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. Results MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetAonPorAoff compared to 51% in the strain 44/76 FetAoffPorAoff, demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. Conclusion This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.

Understanding the Spatial Patterning of English Archaeology: Modelling Mass Data, 1500 BC to AD 1086

Variation in the density of archaeological evidence is caused by a multitude of interacting factors, some of which reinforce each other and some of which act to disguise genuine patterns of past practice. This paper initially presents a set of density models for England constructed by the members of the English Landscape and Identities (EngLaId) project and then goes on to discuss three possible explanations for the variation seen: modern affordance, variability in past usage of material culture, and past population density. The various members of the project team (with the aid of Andrew Lowerre) then provide their thoughts on the models and ideas presented from their own specific period specialist perspectives. The article is presented in this discursive format to reflect the differing opinions and approaches across an unusual multi-period project, in the spirit of multi-vocality and healthy debate.

RSV vaccine use--the missing data.

ABSTRACT Respiratory syncytial virus (RSV) infection is the most important cause of hospitalization in infants and is one of the leading global causes of infant mortality and as such its prevention through vaccination is a public health priority. While essential for the successful implementation of vaccine programs, there remains a paucity of data on the epidemiology of the virus in different settings and age groups and limited knowledge about virus transmission and the health-care costs of the disease. Such data are now needed to populate health economic models and to inform optimal approaches to disease control through vaccination.

Protocol for establishing an infant feeding database linkable with population-based administrative data: a prospective cohort study in Manitoba, Canada

Introduction Breast feeding is associated with many health benefits for mothers and infants. But despite extensive public health efforts to promote breast feeding, many mothers do not achieve their own breastfeeding goals; and, inequities in breastfeeding rates persist between high and low-income mother–infant dyads. Developing targeted programme to support breastfeeding dyads and reduce inequities between mothers of different socioeconomic status are a priority for public health practitioners and health policy decision-makers; however, many jurisdictions lack the timely and comprehensive population-level data on infant-feeding practices required to monitor trends in breastfeeding initiation and duration. This protocol describes the establishment of a population-based infant-feeding database in the Canadian province of Manitoba, providing opportunities to develop and evaluate breastfeeding support programme. Methods and analysis Routinely collected administrative health data on mothers’ infant-feeding practices will be captured during regular vaccination visits using the Teleform fax tool, which converts handwritten information to an electronic format. The infant-feeding data will be linked to the Manitoba Population Research Data Repository, a comprehensive collection of population-based information spanning health, education and social services domains. The linkage will allow us to answer research questions about infant-feeding practices and to evaluate how effective current initiatives promoting breast feeding are. Ethics and dissemination Approvals have been granted by the Health Research Ethics Board at the University of Manitoba. Our integrative knowledge translation approach will involve disseminating findings through government and community briefings, presenting at academic conferences and publishing in scientific journals.

Antibodies in lymphocyte supernatants can distinguish between neutralising antibodies induced by RSV vaccination and pre-existing antibodies induced by natural infection

INTRODUCTION Respiratory syncytial virus (RSV) is the single most important cause of severe respiratory illness in infants. There is no effective vaccine and the only effective treatment available is the monoclonal antibody palivizumab which reduces the risk of severe RSV disease in prematurely born infants. However, palivizumab is too costly to allow for wide implementation and thus treatment is restricted to supportive care. Despite extensive efforts to develop a vaccine, progress has been hindered by the difficulty in measuring and assessing immunological correlates of RSV vaccine efficacy in the presence of high levels of pre-existing RSV antibodies. METHODS Here we describe a new method for measuring the functional activity of antibodies induced by vaccination distinct from pre-existing antibodies. Antibodies in lymphocyte supernatants (ALS) from the cultured peripheral blood mononuclear cells (PBMCs) of young adults who had recently been vaccinated with a novel RSV candidate vaccine were directly assayed for virus neutralising activity. An ELISA method was used to measure antibodies in nasal and serum samples and then compared with the adapted ALS based method. RESULTS There was a wide background distribution of RSV-specific antibodies in serum and nasal samples that obscured vaccine-specific responses measured two weeks after vaccination. No RSV-specific antibodies were observed at baseline in ALS samples, but a clear vaccine-specific antibody response was observed in ALS seven days after the administration of each dose of vaccine. These vaccine-specific antibodies in ALS displayed functional activity in vitro, and quantification of this functional activity was unperturbed by pre-existing antibodies from natural exposure. The results demonstrate a promising new approach for assessing functional immune responses attributed to RSV vaccines.

Humoral and cellular immunity to RSV in infants, children and adults.

BACKGROUND Respiratory syncytial virus (RSV) causes respiratory disease throughout life. Here we report differences in naturally acquired immunity with age and presumed exposure. METHODS A longitudinal, non-interventional, observational study was performed in healthy adults (20 paediatric healthcare workers and 10 non-healthcare workers), children (10 aged 3-6 years) and infants (5 aged 2-4 months and 20 aged 6-12 months). Blood samples were analysed for RSV-neutralising antibody titre, F/Ga/Gb-specific antibody titres, F-specific IgG/IgA memory B-cell frequencies and T-cell production of IFNγ, IL-4, IL-13 and IL-17. RESULTS Serum G-specific antibody titres were significantly lower in infants and children than adults. However, serum titres of F-specific and RSV-neutralising antibody and IFNγ-producing T-cell frequencies were low or absent in the infants, but comparable between children and adults. Interestingly, F-specific memory IgA B-cells could not be detected in paediatric samples and in samples from non-healthcare workers, but recordable IgA memory B-cells were found in 9/18 paediatric healthcare workers and 2/8 non-healthcare workers at the end of the RSV season. These responses waned 4-6 months later. By contrast, F-specific IgG memory B-cells were detectable in samples from all adults without significant variation across time points. T-cells producing IL-4, IL-13 and IL-17 responses were not detectable in peripheral blood from a subset of volunteers. CONCLUSIONS Repeated RSV exposure in early life generates immune responses that are inversely related to frequency of severe disease. Induction of F-specific antibody and cellular immune responses through infant vaccination might help to accelerate the development of protective immune responses at an early age. Clinicaltrials.gov reference NCT01563692 and NCT01640652.