Tom Havelock

Preliminary Assessment of the Efficacy of a T-Cell–Based Influenza Vaccine, MVA-NP+M1, in Humans

A single vaccination with MVA-NP+M1 boosts T-cell responses to conserved influenza antigens in humans. Protection against influenza disease and virus shedding was demonstrated in an influenza virus challenge study.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

BACKGROUND Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING Novartis Vaccines.

ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

Evaluation of the Efficacy of ChAd63-MVA Vectored Vaccines Expressing Circumsporozoite Protein and ME-TRAP Against Controlled Human Malaria Infection in Malaria-Naive Individuals.

Background. Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope–thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy. Methods. We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP. Results. One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA ME-TRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%–79%, compared with 79%–84% for ChAd63-MVA ME-TRAP. Conclusions. ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development. Clinical Trials Registration. NCT01623557.

The Co-imaging of Gamma Camera Measurements of Aerosol Deposition and Respiratory Anatomy

The use of gamma camera imaging following the inhalation of a radiolabel has been widely used by researchers to investigate the fate of inhaled aerosols. The application of two-dimensional (2D) planar gamma scintigraphy and single-photon emission computed tomography (SPECT) to the study of inhaled aerosols is discussed in this review. Information on co-localized anatomy can be derived from other imaging techniques such as krypton ventilation scans and low- and high-resolution X-ray computed tomography (CT). Radionuclide imaging, combined with information on anatomy, is a potentially useful approach when the understanding of regional deposition within the lung is central to research objectives for following disease progression and for the evaluation of therapeutic intervention.

Assessment of novel vaccination regimens using viral vectored liver stage malaria vaccines encoding ME-TRAP

Heterologous prime-boost vaccination with viral vectors simian adenovirus 63 (ChAd63) and Modified Vaccinia Ankara (MVA) induces potent T cell and antibody responses in humans. The 8-week regimen demonstrates significant efficacy against malaria when expressing the pre-erythrocytic malaria antigen Thrombospondin-Related Adhesion Protein fused to a multiple epitope string (ME-TRAP). We tested these vaccines in 7 new 4- and 8- week interval schedules to evaluate safety and immunogenicity of multiple ChAd63 ME-TRAP priming vaccinations (denoted A), multiple MVA ME-TRAP boosts (denoted M) and alternating vectors. All regimens exhibited acceptable reactogenicity and CD8+ T cell immunogenicity was enhanced with a 4-week interval (AM) and with incorporation of additional ChAd63 ME-TRAP vaccination at 4- or 8-weeks (AAM or A_A_M). Induction of TRAP antibodies was comparable between schedules. T cell immunity against the ChAd63 hexon did not affect T cell responses to the vaccine insert, however pre-vaccination ChAd63-specific T cells correlated with reduced TRAP antibodies. Vaccine-induced antibodies against MVA did not affect TRAP antibody induction, and correlated positively with ME-TRAP-specific T cells. This study identifies potentially more effective immunisation regimens to assess in Phase IIa trials and demonstrates a degree of flexibility with the timing of vectored vaccine administration, aiding incorporation into existing vaccination programmes.

The Relationship Between Crackle Characteristics and Airway Morphology in COPD

BACKGROUND: Crackles in COPD are believed to be generated by the re-opening of collapsed airways, which result from chronic inflammation, secretions, and loss of cartilaginous support through inflammation. However, it is unclear whether crackle characteristics can be used to identify COPD. This is the first study to examine the relationship between specific added lung sounds (crackles) and measurements of conductive airways and emphysema score obtained from high-resolution computed tomography (HRCT) in vivo in humans. A predictive relationship might permit the use of lung sounds as a biomarker for COPD. METHODS: A convenience sample of 26 subjects was recruited into the study and consisted of 9 healthy non-smokers, 9 healthy smokers, and 8 subjects with mild or moderate COPD. Lung sound data were recorded using a digital stethoscope connected to a laptop computer. Airway diameter, emphysema score, and percentage of wall area were measured from HRCT scans. RESULTS: The analysis showed that there were no statistically significant differences in crackle characteristics (the number of crackles per breathing cycle and crackle 2-cycle duration) between the 3 subject groups. Both crackle 2-cycle duration and crackle number showed some significant correlation with airway parameters at some branch generations, but due to the large number of correlations performed, these were consistent with chance findings. CONCLUSIONS: Although there were some significant correlations between crackle characteristics and measurements of the conductive airways and emphysema score, the possibility that these correlations have occurred by chance cannot be ruled out. Therefore, this study provides no conclusive evidence that crackle characteristics are related to HRCT variables in COPD.

Regional assessment of lung function using thin-plate splines to align structural and functional imaging

Ventilation / perfusion (VQ) Single Photon Emission Computed Tomography (SPECT) imaging provides 3D data of the regional distribution of ventilation and perfusion throughout the lung, but interpretation of the results is difficult without reference to the underlying lung anatomy. Multi-Slice Computed Tomography (MSCT) imaging is able to provide significant anatomical detail in the lung, allowing delineation of regional features such as the lobes. The purpose of this work was to develop software tools to allow the alignment of regions delineated from the MSCT scans, with the corresponding SPECT data, to allow measurements of VQ to be made for anatomically meaningful regions. The technique developed was based on the use of thin-plate splines and the results showed that it was able to provide good alignment between the MSCT and SPECT data.

Robust similarity registration technique for volumetric shapes represented by characteristic functions

This paper proposes a novel similarity registration technique for volumetric shapes implicitly represented by characteristic functions (CFs). Here, the calculation of rotation parameters is considered as a spherical cross-correlation problem and the solution is therefore found using the standard phase correlation technique facilitated by principal components analysis (PCA). Thus, fast Fourier transform (FFT) is employed to vastly improve efficiency and robustness. Geometric moments are then used for shape scale estimation which is independent from rotation and translation parameters. It is numerically demonstrated that our registration method is able to handle shapes with various topologies and robust to noise and initial poses. Further validation of our method is performed by registering a lung database. HighlightsWe propose a similarity registration method that registers volumetric shapes.The method naturally handles shapes with topological differences.The method is validated by registering a lung database.The method can be applied to shape-based image segmentation.

A Solution to the Similarity Registration Problem of Volumetric Shapes

This paper provides a novel solution to the volumetric similarity registration problem usually encountered in statistical study of shapes and shape-based image segmentation. Here, shapes are implicitly represented by characteristic functions CFs. By mapping shapes to a spherical coordinate system, shapes to be registered are projected to unit spheres and thus, rotation and scale parameters can be conveniently calculated. Translation parameter is computed using standard phase correlation technique. The method goes through intensive tests and is shown to be fast, robust to noise and initial poses, and suitable for a variety of similarity registration problems including shapes with complex structures and various topologies.