Novel genetically-modified chimpanzee adenovirus and MVA-vectored respiratory syncytial virus vaccine safely boosts humoral and cellular immunity in healthy older adults.

OBJECTIVES: Respiratory syncytial virus (RSV) causes respiratory infection across the world, with infants and the elderly at particular risk of developing severe disease and death. The replication-defective chimpanzee adenovirus (PanAd3-RSV) and modified vaccinia virus Ankara (MVA-RSV) vaccines were shown to be safe and immunogenic in young healthy adults. Here we report an extension to this first-in-man vaccine trial to include healthy older adults aged 60-75 years. METHODS: We evaluated the safety and immunogenicity of a single dose of MVA-RSV given by intra-muscular (IM) injection (n = 6), two doses of IM PanAd3-RSV given 4-weeks apart (n = 6), IM PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), intra-nasal (IN) spray of PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), or no vaccine (n = 6). Safety measures included all adverse events within one week of vaccination and blood monitoring. Immunogenicity measures included serum antibody responses (RSV- and PanAd3-neutralising antibody titres measured by plaque-reduction neutralisation and SEAP assays, respectively), peripheral B-cell immune responses (frequencies of F-specific IgG and IgA antibody secreting cells and memory B-cells by ex vivo and cultured dual-colour ELISpot assays respectively), and peripheral RSV-specific T-cell immune responses (frequencies of IFNγ-producing T-cells by ex vivo ELISpot and CD4+/CD8+/Tfh-like cell frequencies by ICS/FACS assay). RESULTS: The vaccines were safe and well tolerated. Compared with each individual baseline immunity the mean fold-changes in serum RSV-neutralising antibody, appearance and magnitude of F-specific IgG and IgA ASCs and expansion of CD4+/CD8+ IFNγ-producing T-cells in peripheral circulation were comparable to the results seen from younger healthy adults who received the same vaccine combination and dose. There were little/no IgA memory B-cell responses in younger and older adults. Expansion of IFNγ-producing T-cells was most marked in older adults following IM prime, with balanced CD4+ and CD8+ T cell responses. The RSV-specific immune responses to vaccination did not appear to be attenuated in the presence of PanAd3 (vector) neutralising antibody. CONCLUSIONS: PanAd3-RSV and MVA-RSV was safe and immunogenic in older adults and the parallel induction of RSV-specific humoral and cellular immunity merits further assessment in providing protection from severe disease.

Non-specific immunological effects of selected routine childhood immunisations: systematic review.

OBJECTIVE:  To identify and characterise non-specific immunological effects after routine childhood vaccines against BCG, measles, diphtheria, pertussis, and tetanus. DESIGN:  Systematic review of randomised controlled trials, cohort studies, and case-control studies. DATA SOURCES:  Embase, PubMed, Cochrane library, and Trip searched between 1947 and January 2014. Publications submitted by a panel of experts in the specialty were also included. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:  All human studies reporting non-specific immunological effects after vaccination with standard childhood immunisations. Studies using recombinant vaccines, no vaccine at all, or reporting only vaccine specific outcomes were excluded. The primary aim was to systematically identify, assemble, and review all available studies and data on the possible non-specific or heterologous immunological effects of BCG; measles; mumps, measles, and rubella (MMR); diphtheria; tetanus; and pertussis vaccines. RESULTS:  The initial search yielded 11 168 references; 77 manuscripts met the inclusion criteria for data analysis. In most included studies (48%) BCG was the vaccine intervention. The final time point of outcome measurement was primarily performed (70%) between one and 12 months after vaccination. There was a high risk of bias in the included studies, with no single study rated low risk across all assessment criteria. A total of 143 different immunological variables were reported, which, in conjunction with differences in measurement units and summary statistics, created a high number of combinations thus precluding any meta-analysis. Studies that compared BCG vaccinated with unvaccinated groups showed a trend towards increased IFN-γ production in vitro in the vaccinated groups. Increases were also observed for IFN-γ measured after BCG vaccination in response to in vitro stimulation with microbial antigens from Candida albicans, tetanus toxoid, Staphylococcus aureas, lipopolysaccharide, and hepatitis B. Cohort studies of measles vaccination showed an increase in lymphoproliferation to microbial antigens from tetanus toxoid and C albicans Increases in immunogenicity to heterologous antigens were noted after diphtheria-tetanus (herpes simplex virus and polio antibody titres) and diphtheria-tetanus-pertussis (pneumococcus serotype 14 and polio neutralising responses) vaccination. CONCLUSIONS:  The papers reporting non-specific immunological effects had heterogeneous study designs and could not be conventionally meta-analysed, providing a low level of evidence quality. Some studies, such as BCG vaccine studies examining in vitro IFN-γ responses and measles vaccine studies examining lymphoproliferation to microbial antigen stimulation, showed a consistent direction of effect suggestive of non-specific immunological effects. The quality of the evidence, however, does not provide confidence in the nature, magnitude, or timing of non-specific immunological effects after vaccination with BCG, diphtheria, pertussis, tetanus, or measles containing vaccines nor the clinical importance of the findings.

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.

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

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.

Group- and genotype-specific neutralizing antibody responses against respiratory syncytial virus in infants and young children with severe pneumonia.

The effect of genetic variation on the neutralizing antibody response to respiratory syncytial virus (RSV) is poorly understood. In this study, acute- and convalescent-phase sera were evaluated against different RSV strains. The proportion of individuals with homologous seroconversion was greater than that among individuals with heterologous seroconversion among those infected with RSV group A (50% vs 12.5%; P = .0005) or RSV group B (40% vs 8%; P = .008). Seroconversion to BA genotype or non-BA genotype test viruses was similar among individuals infected with non-BA virus (35% vs 50%; P = .4) or BA virus (50% vs 65%; P = .4). The RSV neutralizing response is group specific. The BA-associated genetic change did not confer an ability to escape neutralizing responses to previous non-BA viruses.

Comparison of strain-specific antibody responses during primary and secondary infections with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants. RSV repeatedly reinfects individuals: this may be due in part to the variability of the attachment (G) glycoprotein and changes in this protein have been shown to be under positive selection. Infants experiencing their primary infection show a genotype-specific antibody response with respect to the variable regions of the G protein. A prospective study of RSV infections in a birth cohort in rural Kenya identified infants experiencing repeat infections with RSV. The serum antibody responses of these infants were investigated with respect to their anti-RSV reactions in an enzyme-linked immunosorbent assay (ELISA) and the specificity of the response to a variable region of the G protein by ELISA and immunoblotting using bacterially expressed polypeptides representative of the currently circulating strains of RSV. The results presented here confirm that the primary antibody response to the variable regions of the G protein is generally genotype-specific, but show that the response may become cross-reactive (at least within group A viruses) during secondary infections even where the secondary infection is of the same genotype as the initial infection. Also, some infants who did not mount a detectable antibody response to whole RSV antigens during their primary infection nevertheless showed genotype-specific responses to the G protein. In conclusion, the strain-specific nature of the serum antibody response to the variable regions of the G protein of RSV observed in primary infections can become cross-reactive in subsequent reinfections.