The Lancet Infectious Diseases
Oct 2014 Volume 14 Number 10 p899 – 1022
http://www.thelancet.com/journals/laninf/issue/current

Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial
Iman Satti PhD a, Joel Meyer DM a Stephanie A Harris BSc a, Zita-Rose Manjaly Thomas MRCP a, Kristin Griffiths PhD a, Richard D Antrobus MBChB a, Rosalind Rowland BM a, Raquel Lopez Ramon RN a, Mary Smith RN a, Sharon Sheehan FRCPath a, Henry Bettinson FRCP b, Prof Helen McShane FRCP a
Summary
Background
Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A
Methods
In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769.
Findings
Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine.
Interpretation
Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens.
Funding
The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre.

Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis
Silvia S Chiang, Faiz Ahmad Khan, Meredith B Milstein, Arielle W Tolman, Andrea Benedetti, Jeffrey R Starke, Mercedes C Becerra
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Despite treatment, childhood tuberculous meningitis has very poor outcomes. Poor prognosis and difficult early diagnosis emphasise the importance of preventive therapy for child contacts of patients with tuberculosis and low threshold for empirical treatment of tuberculous meningitis suspects. Implementation of consensus definitions, standardised reporting of data, and high-quality clinical trials are needed to clarify optimum therapy.

Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study
A/Prof Sepehr N Tabrizi PhD a b c d, Julia M L Brotherton BMed e f, Prof John M Kaldor PhD g, S Rachel Skinner PhD f, Bette Liu DPhil h, Deborah Bateson MBBS i, Kathleen McNamee MBBS j k, Maria Garefalakis MBBS l, Samuel Phillips BSc a d, Eleanor Cummins BSc a d, Michael Malloy PhD e, Prof Suzanne M Garland MD a b c d
Summary
Background
After the introduction of a quadrivalent human papillomavirus (HPV) vaccination programme in Australia in April, 2007, we measured the prevalence of vaccine-targeted and closely related HPV types with the aim of assessing direct protection, cross-protection, and herd immunity.
Methods
In this repeat cross-sectional study, we recruited women aged 18—24 years who attended Pap screening between October, 2005, and July, 2007, in three major metropolitan areas of Australia to form our prevaccine-implementation sample. For our postvaccine-implementation sample, we recruited women aged 18—24 years who attended Pap screening in the same three metropolitan areas from August, 2010, to November, 2012. We compared the crude prevalence of HPV genotypes in cervical specimens between the prevaccine and the postvaccine implementation groups, with vaccination status validated against the National HPV Vaccination Program Register. We estimated adjusted prevalence ratios using log linear regression. We estimated vaccine effectiveness both for vaccine-targeted HPV types (16, 18, 6, and 11) and non-vaccine but related HPV types (31, 33, and 45).
Findings
202 women were recruited into the prevaccine-implementation group, and 1058 were recruited into the postvaccine-implementation group. Crude prevalence of vaccine-targeted HPV genotypes was significantly lower in the postvaccine-implementation sample than in the prevaccine-implementation sample (58 [29%] of 202 vs 69 [7%] of 1058; p<0•0001). Compared with the prevaccine-implementation sample, adjusted prevalence ratios for vaccine-targeted HPV genotypes were 0•07 (95% CI 0•04—0•14; p<0•0001) in fully vaccinated women and 0•65 (0•43—0•96; p=0•03) in unvaccinated women, which suggests herd immunity. No significant declines were noted for non-vaccine-targeted HPV genotypes. However, within the postvaccine-implementation sample, adjusted vaccine effectiveness against vaccine-targeted HPV types for fully vaccinated women compared with unvaccinated women was 86% (95% CI 71—93), and was 58% (26—76) against non-vaccine-targeted but related genotypes (HPV 31, 33, and 45).
Interpretation
6 years after the initiation of the Australian HPV vaccination programme, we have detected a substantial fall in vaccine-targeted HPV genotypes in vaccinated women; a lower prevalence of vaccine-targeted types in unvaccinated women, suggesting herd immunity; and a possible indication of cross-protection against HPV types related to the vaccine-targeted types in vaccinated women.
Funding
Australian National Health and Medical Research Council and Cancer Council Victoria.

Series
Emerging respiratory tract infections
Surveillance for emerging respiratory viruses
Jaffar A Al-Tawfiq, Alimuddin Zumla, Philippe Gautret, Gregory C Gray, David S Hui, Abdullah A Al-Rabeeah, Ziad A Memish
Summary
Several new viral respiratory tract infectious diseases with epidemic potential that threaten global health security have emerged in the past 15 years. In 2003, WHO issued a worldwide alert for an unknown emerging illness, later named severe acute respiratory syndrome (SARS). The disease caused by a novel coronavirus (SARS-CoV) rapidly spread worldwide, causing more than 8000 cases and 800 deaths in more than 30 countries with a substantial economic impact. Since then, we have witnessed the emergence of several other viral respiratory pathogens including influenza viruses (avian influenza H5N1, H7N9, and H10N8; variant influenza A H3N2 virus), human adenovirus-14, and Middle East respiratory syndrome coronavirus (MERS-CoV).

Emerging respiratory tract infections
Emerging infectious diseases and pandemic potential: status quo and reducing risk of global spread
Brian McCloskey, Osman Dar, Alimuddin Zumla, David L Heymann
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Emerging infectious diseases are an important public health threat and infections with pandemic potential are a major global risk. Although much has been learned from previous events the evidence for mitigating actions is not definitive and pandemic preparedness remains a political and scientific challenge. A need exists to develop trust and effective meaningful collaboration between countries to help with rapid detection of potential pandemic infections and initiate public health actions. This collaboration should be within the framework of the International Health Regulations.