Peter Horby

A Long Neglected World Malaria Map: Plasmodium vivax Endemicity in 2010

Background Current understanding of the spatial epidemiology and geographical distribution of Plasmodium vivax is far less developed than that for P. falciparum, representing a barrier to rational strategies for control and elimination. Here we present the first systematic effort to map the global endemicity of this hitherto neglected parasite. Methodology and Findings We first updated to the year 2010 our earlier estimate of the geographical limits of P. vivax transmission. Within areas of stable transmission, an assembly of 9,970 geopositioned P. vivax parasite rate (PvPR) surveys collected from 1985 to 2010 were used with a spatiotemporal Bayesian model-based geostatistical approach to estimate endemicity age-standardised to the 1–99 year age range (PvPR1–99) within every 5×5 km resolution grid square. The model incorporated data on Duffy negative phenotype frequency to suppress endemicity predictions, particularly in Africa. Endemicity was predicted within a relatively narrow range throughout the endemic world, with the point estimate rarely exceeding 7% PvPR1–99. The Americas contributed 22% of the global area at risk of P. vivax transmission, but high endemic areas were generally sparsely populated and the region contributed only 6% of the 2.5 billion people at risk (PAR) globally. In Africa, Duffy negativity meant stable transmission was constrained to Madagascar and parts of the Horn, contributing 3.5% of global PAR. Central Asia was home to 82% of global PAR with important high endemic areas coinciding with dense populations particularly in India and Myanmar. South East Asia contained areas of the highest endemicity in Indonesia and Papua New Guinea and contributed 9% of global PAR. Conclusions and Significance This detailed depiction of spatially varying endemicity is intended to contribute to a much-needed paradigm shift towards geographically stratified and evidence-based planning for P. vivax control and elimination.

Nonpharmaceutical interventions for pandemic influenza, national and community measures

Recommended interventions vary by transmission pattern, pandemic phase, and disease severity.

Nonpharmaceutical interventions for pandemic influenza, international measures

Closing international borders was usually ineffective in past pandemics and would be less effective today.

Mapping the zoonotic niche of Ebola virus disease in Africa

Ebola virus disease (EVD) is a complex zoonosis that is highly virulent in humans. The largest recorded outbreak of EVD is ongoing in West Africa, outside of its previously reported and predicted niche. We assembled location data on all recorded zoonotic transmission to humans and Ebola virus infection in bats and primates (1976–2014). Using species distribution models, these occurrence data were paired with environmental covariates to predict a zoonotic transmission niche covering 22 countries across Central and West Africa. Vegetation, elevation, temperature, evapotranspiration, and suspected reservoir bat distributions define this relationship. At-risk areas are inhabited by 22 million people; however, the rarity of human outbreaks emphasises the very low probability of transmission to humans. Increasing population sizes and international connectivity by air since the first detection of EVD in 1976 suggest that the dynamics of human-to-human secondary transmission in contemporary outbreaks will be very different to those of the past. DOI: http://dx.doi.org/10.7554/eLife.04395.001

A national outbreak of multi-resistant Salmonella enterica serovar typhimurium definitive phage type (DT) 104 associated with consumption of lettuce

Between 1 August and 15 September 2000, 361 cases of Salmonella enterica serotype Typhimurium definitive phage type (DT) 104, resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides, spectinomycin and tetracycline (R-type ACSSuSpT), were identified in England and Wales residents. Molecular typing of 258 isolates of S. Typhimurium DT104 R-type ACSSuSpT showed that, although isolates were indistinguishable by pulsed-field gel electrophoresis, 67% (174/258) were characterized by a particular plasmid profile. A statistically significant association between illness and consumption of lettuce away from home was demonstrated (OR = 7.28; 95% CI=2.25-23.57; P=0.0006) in an unmatched case-control study. Environmental investigations revealed that a number of food outlets implicated in the outbreak had common suppliers of salad vegetables. No implicated foods were available for microbiological testing. An environmental audit of three farms that might have supplied salad vegetables to the implicated outlets did not reveal any unsafe agricultural practices. The complexity of the food supply chain and the lack of identifying markers on salad stuffs made tracking salad vegetables back to their origin extremely difficult in most instances. This has implications for public health since food hazard warnings and product withdrawal are contingent on accurate identification of the suspect product.

Global health security: the wider lessons from the west African Ebola virus disease epidemic

Summary The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security—its definition, meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing.

Antibody landscapes after influenza virus infection or vaccination

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals. Preemptive vaccine updates may substantially improve influenza vaccine efficacy in previously exposed individuals. [Also see Perspective by Lessler] Hills and valleys of influenza infection Each one of us may encounter several different strains of the ever-changing influenza virus during a lifetime. Scientists can now summarize such histories of infection over a lifetime of exposure. Fonville et al. visualize the interplay between protective responses and the evasive influenza virus by a technique called antibody landscape modeling (see the Perspective by Lessler). Landscapes reveal how exposure to new strains of the virus boost immune responses and indicate possibilities for optimizing future vaccination programs. Science, this issue p. 996; see also p. 919

Clinical Features of Human Influenza A (H5N1) Infection in Vietnam: 2004–2006

BACKGROUND The first cases of avian influenza A (H5N1) in humans in Vietnam were detected in early 2004, and Vietnam has reported the second highest number of cases globally. METHODS We obtained retrospective clinical data through review of medical records for laboratory confirmed cases of influenza A (H5N1) infection diagnosed in Vietnam from January 2004 through December 2006. Standard data was abstracted regarding clinical and laboratory features, treatment, and outcome. RESULTS Data were obtained for 67 (72%) of 93 cases diagnosed in Vietnam over the study period. Patients presented to the hospital after a median duration of illness of 6 days with fever (75%), cough (89%), and dyspnea (81%). Diarrhea and mucosal bleeding at presentation were more common in fatal than in nonfatal cases. Common findings were bilateral pulmonary infiltrates on chest radiograph (72%), lymphopenia (73%), and increased serum transaminase levels (aspartate aminotransferase, 69%; alanine aminotransferase, 61%). Twenty-six patients died (case fatality rate, 39%; 95% confidence interval, 27%-51%) and the most reliable predictor of a fatal outcome was the presence of both neutropenia and raised alanine aminotransferase level at admission, which correctly predicted 91% of deaths and 82% of survivals. The risk of death was higher among persons aged < or =16 years, compared with older persons (P < .001), and the risk of death was higher among patients who did not receive oseltamivir treatment (P = .048). The benefit of oseltamivir treatment remained after controlling for potential confounding by 1 measure of severity (odds ratio, 0.15; 95% confidence interval, 0.026-0.893; P = .034). CONCLUSION In cases of infection with Influenza A (H5N1), the presence of both neutropenia and raised serum transaminase levels predicts a poor outcome. Oseltamivir treatment shows benefit, but treatment with corticosteroids is associated with an increased risk of death.

Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea

BACKGROUND In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Unions Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Randomised controlled trials for Ebola: practical and ethical issues

2 months ago, when the numbers known to have died from Ebola in west Africa could still be counted in hundreds, WHO made an important statement about investigational drugs and vaccines. This crisis is so acute, WHO declared, that it is ethical to offer interventions with potential benefits but unknown efficacy and side-effects, though every effort should be made to evaluate benefits and risks and share all data generated. The need for drugs and vaccines was urgent then. With cases now rising exponentially and health systems overwhelmed, it is even greater today. Vaccine safety trials are underway in the USA and the UK, and poised to roll out to Africa soon. But treatments for those with infection are required too. Besides playing a direct part in containing the epidemic, interventions that could improve outcomes for the sick would help to rebuild the confidence of affected communities in health services, a critical step if Ebola is to be overcome. A fast-track initiative for evaluating investigational drugs was launched in September, 2014.1 But although the question of whether unproven treatments should be offered at all is now settled, the question of how they should be deployed and tested is not. Still at issue is whether such treatments should be made available only in the context of randomised controlled trials (RCTs) in which patients receive either a new intervention and conventional care, or conventional care alone or with a placebo. Advocates of this RCT approach2 state that as this experimental design will create the most robust evidence for the future, and is what regulators are used to, it is the only approach that should be considered. We disagree. While we concur that RCTs provide robust evidence, and support their use where this is ethical and practical, we do not believe that either consideration is likely to be satisfied in the context of this epidemic. The priority must be to generate data about effectiveness and safety as swiftly as possible, so that the most useful new treatments can be identified for rapid deployment. Alternative trial designs have the potential to do this more quickly, and with greatest social and ethical acceptability. The first objection to RCTs in which investigational drugs plus conventional care are compared purely with conventional care is ethical. Such randomisation is ethical when there is equipoise—when there is genuine uncertainty about whether an untested treatment has benefits or risks that exceed those of conventional care. Equipoise is a useful principle, but it can break down when conventional care offers little benefit and mortality is extremely high. This is precisely the problem with Ebola: current conventional care does not much affect clinical outcomes and mortality is as high as 70%. When conventional care means such a high probability of death, it is problematic to insist on randomising patients to it when the intervention arm holds out at least the possibility of benefit. Ethical arguments are not the same for all levels of risk. No-one insisted that western medical workers offered zMapp and other investigational products were randomised to receive the drug or conventional care plus a placebo. None of us would consent to be randomised in such circumstances. In cancers with a poor prognosis for which there are no good treatments, evidence from studies without a control group can be accepted as sufficient for deployment, and even for licensing by regulators, with fuller analysis following later. There is no need for rules to be bent or corners to be cut: the necessary procedures already exist, and are used. The second objection is practical. Even if randomisation were ethically acceptable, it might not be deliverable in the context of health-care systems, and indeed wider social order, that are breaking down as in Liberia, Guinea, and Sierra Leone. Populations who are terrified by the progress of the epidemic, and who lack trust in health-care and aid workers, and in public authorities in the aftermath of civil wars, cannot be expected to offer informed consent to such randomised trials. It is also unclear that any capacity exists to impose controlled conditions during a raging epidemic. Insisting on RCTs could even worsen the epidemic, by undermining trust in the Ebola treatment centres that are central to containing it. Randomisation is not, moreover, the only way to gather reliable information about the safety and effectiveness of potential Ebola therapies. Indeed, other methods might be more appropriate for achieving the key objective, which is to identify drug regimens that improve outcomes over existing methods of care, quickly, so that WHO can recommend their use and lives can be saved. One viable approach would be to try different treatments in parallel and at different sites, following observational studies that document mortality under standard care. This approach could effectively triage treatments into those with great benefits that should be rolled out immediately, those with no effect that should be discarded quickly, and those with promise needing follow-up in randomised trials. These trials can be designed adaptively, meaning that patient enrolment can be altered as efficacy data emerge, minimising the numbers of individuals who get ineffective treatments and increasing the numbers getting those that show benefits. This is not different from phase 2 studies as currently conducted and accepted by regulatory authorities for other diseases. It will also enable quick follow-up trials of combinations of antivirals and new treatments that have already shown evidence of activity. A different type of RCT might also become an option once more than one drug has shown efficacy—even efficacy in animal models. Then, patients could ethically be randomised to one investigational drug or another. No-one would get only standard care. We accept that RCTs can generate strong evidence in ordinary circumstances; not, however, in the midst of the worst Ebola epidemic in history. The urgent need is to establish whether new investigational drugs offer survival benefits, and thus which, if any, should be recommended by WHO to save lives. We have innovative but proven trial designs for doing exactly that. We should be using them, rather than doggedly insisting on gold standards that were developed for different settings and purposes.