[Show abstract][Hide abstract] ABSTRACT: Middle East Respiratory Syndrome (MERS) is a highly lethal pulmonary infection caused by a previously unidentified coronavirus (CoV), likely transmitted to humans by infected camels. There is no licensed vaccine or antiviral for MERS, therefore new prophylactic and therapeutic strategies to combat human infections are needed. In this study, we describe, for the first time, to our knowledge, the isolation of a potent MERS-CoV-neutralizing antibody from memory B cells of an infected individual. The antibody, named LCA60, binds to a novel site on the spike protein and potently neutralizes infection of multiple MERS-CoV isolates by interfering with the binding to the cellular receptor CD26. Importantly, using mice transduced with adenovirus expressing human CD26 and infected with MERS-CoV, we show that LCA60 can effectively protect in both prophylactic and postexposure settings. This antibody can be used for prophylaxis, for postexposure prophylaxis of individuals at risk, or for the treatment of human cases of MERS-CoV infection. The fact that it took only 4 mo from the initial screening of B cells derived from a convalescent patient for the development of a stable chinese hamster ovary (CHO) cell line producing neutralizing antibodies at more than 5 g/L provides an example of a rapid pathway toward the generation of effective antiviral therapies against emerging viruses.
Proceedings of the National Academy of Sciences 07/2015; DOI:10.1073/pnas.1510199112 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We determined complete viral genome sequences from three British healthcare workers infected with Ebola virus (EBOV) in Sierra Leone, directly from clinical samples. These sequences closely resemble those previously observed in the current Ebola virus disease outbreak in West Africa, with glycoprotein and polymerase genes showing the most sequence variation. Our data indicate that current PCR diagnostic assays remain suitable for detection of EBOV in this epidemic and provide confidence for their continued use in diagnosis.
Eurosurveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 05/2015; 20(20):21. · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A high proportion of influenza infections are asymptomatic. Animal and human challenge studies and observational studies suggest T cells protect against disease among those infected, but the impact of T cell immunity at the population level is unknown.
To investigate whether naturally pre-existing T cell responses targeting highly conserved internal influenza proteins could provide cross-protective immunity against pandemic and seasonal influenza.
We quantified influenza A(H3N2) virus specific T cells in a population cohort during seasonal and pandemic periods between 2006-2010. Follow-up included paired serology, symptom reporting and PCR investigation of symptomatic cases.
1414 unvaccinated individuals had baseline T cell measurements: (1703 participant observation sets). T cell responses to A(H3N2) virus nucleoprotein (NP) dominated and strongly cross-reacted with A(H1N1)pdm09 NP (p<0.001) in participants lacking antibody to A(H1N1)pdm09. Comparison of paired pre- and post-season sera (1431 sets) showed 205 (14%) had evidence of infection based on four-fold influenza antibody titre rises. The presence of NP specific T cells before exposure to virus correlated with less symptomatic, PCR-positive influenza A (overall adjusted odds ratio 0.27 (95% Confidence Interval, 0.11-0.68), p=0.005, during pandemic (p=0.047) and seasonal periods (p=0.049)). Protection was independent of baseline antibodies. Influenza specific T cell responses were detected in 43% indicating a substantial population impact.
Naturally occurring cross-protective T cell immunity protects against symptomatic PCR-confirmed disease in those with evidence of infection and helps to explain why many infections do not cause symptoms. Vaccines stimulating T cells may provide important cross-protective immunity.
American Journal of Respiratory and Critical Care Medicine 04/2015; 191(12). DOI:10.1164/rccm.201411-1988OC · 11.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The influenza season 2014/15 started in Europe in week 50 2014 with influenza A(H3N2) viruses predominating. The majority of the A(H3N2) viruses characterised antigenically and/or genetically differ from the northern hemisphere vaccine component which may result in reduced vaccine effectiveness for the season. We therefore anticipate that this season may be more severe than the 2013/14 season. Treating influenza with antivirals in addition to prevention with vaccination will be important.
Eurosurveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 01/2015; 20(4):1-5. · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study we used the screening method to estimate the effectiveness of seasonal influenza vaccination during pregnancy in preventing influenza virus infection and influenza-related hospitalisation in infants under six months, in England in the 2013/14 season. Seasonal influenza vaccination in pregnancy was 71% (95% CI: 24–89%) effective in preventing infant influenza virus infection and 64% (95% CI: 6–86%) effective in preventing infant influenza hospitalisation, and should be recommended in pregnancy.
Eurosurveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 11/2014; 19(45). DOI:10.2807/1560-7917.ES2014.19.45.20959 · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cases of severe influenza may occur during seasonal epidemics, following sporadic zoonotic influenza A transmission from animal reservoirs or on a massive scale with the unpredictable emergence of a new pandemic influenza strain. Clinical experience identifies unmet medical need for additional therapies for influenza, in particular to treat severely unwell adults and children. During and following the pandemic of 2009, a wealth of data from hospitalized cases of influenza from many different countries accumulated and are now starting to emerge. Observational clinical data provide information about the efficacy of existing antiviral drugs in severely ill patients. The development pipeline for new therapies contains several promising agents which are focussed on a range of viral targets, and opens the possibility of combination antiviral therapy for the first time, which may be especially useful in clinically challenging cases. Advances in immunological methods and recombinant protein engineering support the potential for use of immunomodulating therapies as adjuncts in treatment of severe influenza.
Current Opinion in Infectious Diseases 10/2014; 27(6). DOI:10.1097/QCO.0000000000000113 · 5.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and thirdwave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in thirdwave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of thirdwave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves.
Journal of Virology 09/2014; 88(22). DOI:10.1128/JVI.01636-14 · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During the first year of enhanced MERS coronavirus surveillance in England, 77 persons traveling from the Middle East had acute respiratory illness and were tested for the virus. Infection was confirmed in 2 travelers with acute respiratory distress syndrome and 2 of their contacts. Patients with less severe manifestations tested negative.
[Show abstract][Hide abstract] ABSTRACT: Background Subnational variation of 2009 pandemic influenza activity in England has been reported; however, little work has been published
on this topic for seasonal influenza. If variation is present, this knowledge may assist with both identifying the onset of
influenza epidemics, informing community antiviral prescription and local health planning.
Journal of Public Health 08/2014; 37(2). DOI:10.1093/pubmed/fdu046 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: SUMMARY General Practitioner consultation rates for influenza-like illness (ILI) are monitored through several geographically distinct schemes in the UK, providing early warning to government and health services of community circulation and intensity of activity each winter. Following on from the 2009 pandemic, there has been a harmonization initiative to allow comparison across the distinct existing surveillance schemes each season. The moving epidemic method (MEM), proposed by the European Centre for Disease Prevention and Control for standardizing reporting of ILI rates, was piloted in 2011/12 and 2012/13 along with the previously proposed UK method of empirical percentiles. The MEM resulted in thresholds that were lower than traditional thresholds but more appropriate as indicators of the start of influenza virus circulation. The intensity of the influenza season assessed with the MEM was similar to that reported through the percentile approach. The MEM pre-epidemic threshold has now been adopted for reporting by each country of the UK. Further work will continue to assess intensity of activity and apply standardized methods to other influenza-related data sources.
Epidemiology and Infection 07/2014; 143(01):1-12. DOI:10.1017/S0950268814001757 · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effectiveness of the 2012/13 trivalent seasonal
influenza vaccine (TIV) was assessed using a testnegative
case–control study of patients consulting
primary care with influenza-like illness in the United
Kingdom. Strain characterisation was undertaken on
selected isolates. Vaccine effectiveness (VE) against
confirmed influenza A(H3N2), A(H1N1) and B virus
infection, adjusted for age, sex, surveillance scheme
(i.e. setting) and month of sample collection was 26%
(95% confidence interval (CI): -4 to 48), 73% (95%
CI: 37 to 89) and 51% (95% CI: 34 to 63) respectively.
There was an indication, although not significant, that
VE declined by time since vaccination for influenza
A(H3N2) (VE 50% within three months, 2% after three
months, p=0.25). For influenza A(H3N2) this is the second
season of low VE, contributing to the World Health
Organization (WHO) recommendation that the 2013/14
influenza vaccine strain composition be changed to an
A(H3N2) virus antigenically like cell-propagated prototype
2012/13 vaccine strain (A/Victoria/361/2011).
The lower VE seen for type B is consistent with antigenic
drift away from the 2012/13 vaccine strain. The
majority of influenza B viruses analysed belong to the
genetic clade 2 and were antigenically distinguishable
from the 2012/13 vaccine virus B/Wisconsin/1/2010
clade 3. These findings supported the change to the
WHO recommended influenza B vaccine component for 2013/14
Eurosurveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 07/2014; 19(27). DOI:10.2807/1560-7917.ES2014.19.27.20851 · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Emerging H7N9 influenza virus infections in Asia have once more spurred the development of effective pre-pandemic H7 vaccines. However, many vaccines based on avian influenza viruses - including H7 - are poorly immunogenic as measured by traditional correlates of protection. Here we re-evaluated sera from an H7N1 human vaccine trial performed in 2006. We examined cross-reactive antibody responses to divergent H7 strains including H7N9, dissected the antibody response into head versus stalk reactive antibodies, and tested the in vivo potency of these human sera in a passive transfer H7N9 challenge experiment in mice. Although only a low percentage of vaccinees induced neutralizing antibody responses against the homologous vaccine strain and also H7N9, we detected strong cross-reactivity to divergent H7 HAs in a large proportion of the cohort using a quantitative ELISA method. Furthermore, H7N1 vaccination induced antibodies to both the head and the stalk domain of the HA which is in sharp contrast to seasonal inactivated vaccines. Finally, we were able to show that both, neutralizing but also non-neutralizing antibodies improved in vivo virus clearance in a passive transfer H7N9 challenge mouse model.
[Show abstract][Hide abstract] ABSTRACT: Background: Influenza H5N1 virus constitutes a pandemic threat and development of effective H5N1 vaccines is a global priority. Anti-influenza antibodies directed towards the haemagglutinin (HA) define a correlate of protection. Both antibody concentration and avidity may be important for virus neutralization and resolving influenza disease. Methods: We conducted a phase I clinical trial of a virosomal H5N1 vaccine adjuvanted with the immunostimulating complex Matrix M™. Sixty adults were intramuscularly immunized with two vaccine doses (21 days apart) of 30 μg HA alone or 1.5, 7.5 or 30 μg HA adjuvanted with Matrix M™. Serum H5 HA1-specific antibodies and virus neutralization were determined at days 0, 21, 42, 180 and 360 and long-term memory B cells at day 360 post-vaccination. The binding of the HA specific antibodies was measured by avidity NaSCN-elution ELISA and surface plasmon resonance (SPR). Results: The H5 HA1-specific IgG response peaked after the second dose (day 42), was dominated by IgG1 and IgG3 and was highest in the adjuvanted vaccine groups. IgG titres correlated significantly with virus neutralization at all time points (Spearman r≥ 0.66, p< 0.0001). By elution ELISA, serum antibody avidity was highest at days 180 and 360 post vaccination and did not correlate with virus neutralization. Long-lasting H5 HA1-specific memory B cells produced high IgG antibody avidity similar to serum IgG. Conclusions: Maturation of serum antibody avidity continued up to day 360 after influenza H5N1 vaccination. Virus neutralization correlated with serum H5 HA1-specific IgG antibody concentrations and not antibody avidity.
[Show abstract][Hide abstract] ABSTRACT: Mass gatherings are regarded as potential risks for transmission of infectious diseases, and might compromise the health system of countries in which they are hosted. The evidence for increased transmission of infectious diseases at international sporting mass gatherings that attract many visitors from all over the world is not clear, and the evidence base for public health surveillance, epidemiology, and response at events such as the Olympics is small. However, infectious diseases are a recognised risk, and public health planning is, and should remain, a crucial part of the overall planning of sporting events. In this Series paper, we set out the planning and the surveillance systems that were used to monitor public health risks during the London 2012 Olympic and Paralympic Games in the summer of 2012, and draw attention to the public health issues—infectious diseases and chemical, radiation, and environmental hazards—that arose. Although the absolute risk of health-protection problems, including infectious diseases, at sporting mass gatherings is small, the need for reassurance of the absence of problems is higher than has previously been considered; this could challenge conventional public health surveillance systems. Recognition of the limitations of health-surveillance systems needs to be part of the planning for future sporting events.
The Lancet 06/2014; 383(9934). DOI:10.1016/S0140-6736(13)62342-9 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Western industrialised nations face a large increase in the number of older people. People over the age of 60 years account for almost half of the 16.8 million hospital admissions in England from 2009 to 2010. During 2009-10, respiratory infections accounted for approximately 1 in 30 hospital admissions and 1 in 20 of the 51.5 million bed-days.