Editorial: Flu papers warrant full publication

Volume 482 Number 7386 pp439-562  23 February 2012

Flu papers warrant full publication
Nature 482, 439 (23 February 2012)
Published online  22 February 2012

Although more debate is needed, the benefits of publishing sensitive data outweigh the risks that have so far been made public.

“No one should presume to know all the ways in which influenza virus could be misused, and the motivations for doing so, but the consequences could be catastrophic.  There are many scenarios to consider, ranging from mad lone scientists, desperate despots and members of millennial doomsday cults to nation states wanting mutually assured destruction options, bioterrorists or a single person’s random acts of craziness.   These are low-probability events, but they could introduce a new evolutionary H5N1 seed into the environment that seems not to exist in nature. This might not cause a pandemic instantly, but it could start the virus on a new path for pandemic evolution.”

That is the rationale provided by Paul Keim, acting chair of the US National Science Advisory Board for Biosecurity (NSABB), in response to questions posed by Nature (P. S. Keim Nature 482, 156–157; 2012) about the NSABB’s recommendation that recent work on the transmissibility in mammals of artificial strains of avian H5N1 influenza virus should not be published in full. The work was conducted in ferrets — generally considered the best animal models for human transmission — and shows that avian H5N1 viruses have a greater potential to evolve into transmissible forms in mammals, including humans, than had been thought. The work is reported in two papers accepted but not yet published in Nature and Science.

Last week, a group of flu and public-health experts gathered at the World Health Organization (WHO) headquarters in Geneva, Switzerland, to discuss the matter (see go.nature.com/uyr1uu). And it was clear at the meeting that the above opening quote expresses the only rationale that attendees had received.

To its credit and that of the US government, the NSABB is the only body in the world set up to review these issues in a systematic fashion. It includes ex-officio representatives of all relevant government departments (including intelligence and security agencies), as well as independent researchers. The NSABB’s guidance was an important first step in public consideration of the impacts and potential regulation of such research. The second step was last week’s meeting at the WHO — again, like the NSABB, a body empowered only to make recommendations.

Some context is important in considering the issues surrounding publication. In 2003, Nature and many other journals met to establish editorial procedures for considering papers that have public-health and scientific benefits but that might also have biosecurity risks (see Nature 421, 771; 2003). The statement that emerged from that meeting envisaged the possibility that a journal would reject a paper if it was clear that the risks of publication outweighed the benefits. Nature accordingly used independent advisers in considering the submission of the latest paper, and most of the advisers recommended publication in full. This is also the first paper submitted to any Nature journal for which recommendations have been made against publication on biosecurity grounds.

Rather than simply reject the papers, given also the NSABB’s opinion, both Nature and Science decided to investigate another option: to publish a redacted version omitting key methods and data. But a condition of such an approach was that a method should exist for distributing a full version to those in need of the results for public-health reasons and those capable of pursuing the science. Both journals accordingly prepared full and redacted versions.

“There is already a substantial immediate risk to humans.”

Those at the WHO meeting, under conditions of strict security, examined both versions of the two papers. It had already been said in blogs and news coverage that, because the methods used are not novel, and because one of the papers had been presented at an open meeting, redaction would be pointless. As one WHO participant said: “It was only when I’d seen both versions that I realized how ineffective redaction would be.” What was also concluded was that a system for distributing the full paper only to selected individuals would be impossible to set up on any relevant timescale.

But what also became clear, partly from unpublished data, was that not only does the mammalian transmissibility threat seem greater than previously thought, but also that current avian viruses have some of the mutations identified in the new work. In other words, there is already a substantial immediate risk to humans. The meeting also concluded that the new data are of value for surveillance, and that the results should be built on to explore the mechanisms underlying transmissibility and the high fatality rate observed in humans infected by H5N1.

Given the inadequacy of redaction, and the immediate risks to global public health, the biosecurity objections expressed above seem too general and hypothetical to justify obstructing publication and further research. Moreover, with regard to the NSABB’s recommendations and the recommendations of the WHO meeting (see go.nature.com/ky2skc), neither of the discussions that preceded them were sufficiently inclusive of the security, societal and research interests at stake.

Therefore, further discussion is essential. That must include a review of the safety regimes (lab equipment, buildings and practices) in which future work should be conducted. The two laboratories in which the latest research originated are categorized as ‘BSL-3 enhanced’ (see Nature 480, 421–422; 2011), a classification that, although rigorous in these cases, is not well defined in general. The Public Health Agency of Canada has deemed the highest level of BSL-4 to be required (see page 447). Safety-standards committees in the United States and Europe are currently assessing required safety levels, and may report within a few weeks.

As was agreed by the journals and the lead authors at the meeting, publication of the papers must wait at least for the outcome of those discussions. There may yet be regulatory or legal obstacles to publication, or biosecurity or biosafety risks sufficient to outweigh the health risks. Otherwise, it is Nature’s view that the papers should ultimately be published in full.

Comparative Coverage: Supplementary and Universally Recommended Immunizations in Children at 24 Months of Age

The Pediatric Infectious Disease Journal
March 2012 – Volume 31 – Issue 3  pp: 217-286,e52-e58,A11-A12

Original Studies
Comparative Coverage of Supplementary and Universally Recommended Immunizations in Children at 24 Months of Age
Hug, Salome; Weibel, Daniel; Delaporte, Elisabeth; Gervaix, Alain; Heininger, Ulrich
Pediatric Infectious Disease Journal. 31(3):217-220, March 2012.
doi: 10.1097/INF.0b013e31823cbaa5

Background: The introduction of pneumococcal and meningococcal group C conjugate vaccinations as supplementary (a new category in Swiss immunization recommendations) to universally recommended vaccinations in 2006 prompted this study to investigate their acceptance.

Methods: The study was performed in 24-month-old healthy children born in the Geneva or Basel areas in Switzerland between January and April 2007. After informed consent had been obtained from caregivers (for this particular study in Basel and in general for providing immunization data in Geneva on an ongoing basis), all universally recommended and supplementary vaccinations administered by ≤24 months of age were analyzed for completeness and timeliness according to set definitions. Sample size calculations and standard statistical tests were applied for comparative data analyses.

Results: Of 592 children at the age of 12 months, 94% and 73% had received complete diphtheria-tetanus-pertussis component combination and pneumococcal conjugate vaccinations, respectively. At the age of 24 months, coverage rates for complete booster doses were 77% and 70%, respectively. Rates for MMR doses 1 and 2 at 24 months were 92% and 72%, respectively, and the rate for meningococcal conjugate vaccine (single dose) was 62%. On an average, coverage rates were similar in the 2 study regions except those for pneumococcal conjugate and second dose of MMR, which were approximately 10% higher in Geneva.

Conclusions: Compliance with supplementary vaccinations was lower than that with universally recommended vaccinations. This can be explained by the recent introduction of supplementary vaccinations or by the public perception that they are less important than universal vaccinations.

Changing Epidemiology of Invasive Pneumococcal Disease in the 7-valent Conjugate Vaccine Era

The Pediatric Infectious Disease Journal
March 2012 – Volume 31 – Issue 3  pp: 217-286,e52-e58,A11-A12

Original Studies
The Changing Epidemiology of Invasive Pneumococcal Disease at a Tertiary Children’s Hospital Through the 7-valent Pneumococcal Conjugate Vaccine Era: A Case for Continuous Surveillance
Ampofo, Krow; Pavia, Andrew T.; Stockmann, Chris; Hersh, Adam L.; Bender, Jeffrey M.; Blaschke, Anne J.; Weng, Hsin Yi Cindy; Korgenski, Kent E.; Daly, Judy; Mason, Edward O.; Byington, Carrie L.
Pediatric Infectious Disease Journal. 31(3):228-234, March 2012.
doi: 10.1097/INF.0b013e31823dcc72

Background: In 2000, a 7-valent pneumococcal conjugate vaccine (PCV7) was licensed for use among US children. Many sites have since reported changes in invasive pneumococcal disease (IPD). We recognized an opportunity to describe the changes in epidemiology, clinical syndromes, and serotype distribution during a 14-year period including 4 years before vaccine introduction and spanning the entire PCV7 era.

Methods: Cases were defined as children <18 years of age who were cared for at Primary Children’s Medical Center for culture-confirmed IPD. We defined the prevaccine period as the time frame spanning from 1997 to 2000 and the postvaccine period from 2001 to 2010. Demographics, clinical data, and outcomes were collected through electronic query and chart review. Streptococcus pneumoniae serotyping was performed using the capsular swelling method.

Results: The median age of children with IPD increased from 19 months during the prevaccine period to 27 months during postvaccine period (P = 0.02), with a larger proportion of IPD among children older than 5 years. The proportion of IPD associated with pneumonia increased substantially from 29% to 50% (P < 0.001). This increase was primarily attributable to an increase in complicated pneumonia (17% to 33%, P < 0.001). Nonvaccine serotypes 7F, 19A, 22F, and 3 emerged as the dominant serotypes in the postvaccine period. In children with IPD who were younger than 5 years, for whom vaccine is recommended, 67% of the cases were caused by serotypes in 13-valent PCV during 2005 to 2010.

Conclusions: After PCV7 was introduced, significant changes in IPD were noted. One-third of IPD occurred in children older than 5 years, who were outside the age-group for which PCV is recommended. Continued surveillance is warranted to identify further evolution of the epidemiology, clinical syndromes, and serotype distribution of S. pneumoniae after 13-valent PCV licensure.

Rotavirus vaccine and intussusception among infants

The Pediatric Infectious Disease Journal
March 2012 – Volume 31 – Issue 3  pp: 217-286,e52-e58,A11-A12

Vaccine Reports
Incidence of Intussusception Among Infants in a Large Commercially Insured Population in the United States
Mona Eng, Patricia; Mast, T. Christopher; Loughlin, Jeanne; Clifford, C. Robin; Wong, Judy; Seeger, John D.
Pediatric Infectious Disease Journal. 31(3):287-291, March 2012.
doi: 10.1097/INF.0b013e31824213b1

Background: To estimate the incidence of intussusception among infants treated in inpatient and emergency department settings during the period preceding the US launch of second-generation rotavirus vaccines.

Methods: From a large US health insurance claims database, we sampled 100,000 infants aged 1 to 3 months at first diphtheria-tetanus-acellular pertussis vaccination between 2001 and 2005. Potential intussusception cases were identified on the basis of claims and were confirmed by medical record review. Incidence rates (IRs) and 95% confidence intervals (CIs) were estimated based on follow-up from first diphtheria-tetanus-acellular pertussis dose to up to 1 year of age, and within 21, 30, and 60 days after each dose.

Results: The IR of intussusception in the first year of life was 0.33/1000 person-years based on 22 confirmed cases (95% CI: 0.21–0.50/1000 person-years). The age-specific incidence peaked among infants aged 5 months (IR: 0.82/1000 person-years; 95% CI: 0.30–1.78/1000 person-years). During the 21, 30, and 60 days following any dose, the incidence per 1000 person-years was 0.27, 0.24, and 0.33, respectively.

Conclusion: The rates described in this study can serve as a benchmark for comparison with incidences observed after the introduction of the second-generation rotavirus vaccines.

Postmarketing Evaluation of the Short-term Safety of the Pentavalent Rotavirus Vaccine
Loughlin, Jeanne; Mast, T. Christopher; Doherty, Michael C.; Wang, Florence T.; Wong, Judy; Seeger, John D.
Pediatric Infectious Disease Journal. 31(3):292-296, March 2012.
doi: 10.1097/INF.0b013e3182421390

Background: A pentavalent rotavirus vaccine (RV5) demonstrated efficacy and safety in a large clinical trial before US licensure in 2006. The primary objective of this observational study was to assess the occurrence of intussusception (IS) among infants who received RV5 in routine use. Secondary objectives assessed the occurrence of Kawasaki disease (KD) and general safety.

Methods: We identified and followed infants with a health insurance claim for RV5 during the first 2 years of RV5 availability. Concurrent and historical cohorts receiving diphtheria-tetanus-acellular pertussis (DTaP) vaccine were used as comparators; the historical DTaP cohort informed sequential monitoring boundaries for IS and KD. Medical records from potential IS and KD cases were reviewed to confirm outcomes. General safety was evaluated across a wide range of outcomes using prespecified criteria. Incidence rates for outcomes along with relative risks and 95% confidence intervals (CIs) were estimated.

Results: The 85,397 RV5 and 62,820 DTaP recipients contributed 17,433 and 12,339 person-years, resulting in 6 and 5 confirmed cases of IS, respectively, within 30 days following any dose. The relative risk of IS was 0.8 (95% confidence interval: 0.22–3.52). The number of IS or KD cases did not cross the monitoring boundaries. The general safety evaluation did not identify any specific diagnoses or patterns of diagnoses that might suggest other safety concerns.

Conclusion: RV5 was not associated with an increased risk of IS, KD, or any other recognized health outcome.

Mobile Phone Text Messaging: Malaria Control in Africa

PLoS Medicine
(Accessed 26 February 2012)

Mobile Phone Text Messaging: Tool for Malaria Control in Africa
Dejan Zurovac, Ambrose O. Talisuna, Robert W. Snow Essay, published 21 Feb 2012

Summary Points
– Across many malaria-endemic areas in rural Africa, the communication gap between managers, health workers, and patients is a significant barrier to efficient malaria control.

– The rapid expansion of mobile network coverage and the widespread availability of basic handsets have the potential to substantively bridge the communication gap.

– Text messaging, as the least-expensive mobile phone function found on all handsets, could improve the delivery of health services and health outcomes.

– Six major areas of malaria control in which deficiencies are apparent and text messaging interventions could be beneficial are: (1) disease and treatment effectiveness surveillance, (2) monitoring of the availability of health commodities, (3) pharmacovigilance and post-marketing surveillance of the safety and quality of antimalarial drugs, (4) health worker adherence to guidelines, (5) patient adherence to medication regimens, and (6) post-treatment review.

– Text messages transmitting information from the periphery of the health systems to malaria control managers are in the first three malaria control areas: (1) disease and treatment effectiveness surveillance, (2) monitoring of the availability of health commodities, and (3) pharmacovigilance and post-marketing surveillance of the safety and quality of antimalarial medicines. Future projects in these three areas should demonstrate responses to data signals and comparative advantages with routine information systems.

– Text messages in the second three areas transmit information to health workers and patients to support the management of malaria patients by improving (4) health workers’ adherence to guidelines, (5) patient adherence to medicines, and (6) post-treatment review. Future priorities in these areas are cost-effectiveness evaluations, qualitative research, and studies measuring impact on the processes of care and health outcomes.

Urban outreach immunization in Patna, India

Tropical Medicine & International Health
March 2012  Volume 17, Issue 3  Pages 263–403

Child Health
Expanding and improving urban outreach immunization in Patna, India
Narottam Pradhan, Tove K. Ryman, Sherin Varkey, Alok Ranjan, Satish K. Gupta, Gopal Krishna, R. P. Swetanki and Randall Young
Article first published online: 14 DEC 2011 | DOI: 10.1111/j.1365-3156.2011.02916.x

Objectives  We conducted a case study of an urban immunization outreach strategy to determine the feasibility of the intervention and to measure administrative immunization coverage outcomes.

Methods  A multipronged strategy for improving immunization coverage in Urban Patna, India, was implemented for 1 year (2009/2010). The strategy was designed to increase immunization sites, shift human resources, plan logistics, improve community mobilization, provide supervision, strengthen data flow and implement special vaccination drives.

Results  Over 1 year, the coverage of all primary vaccines of the Universal Immunization Program improved by over 100%.

Conclusion  Coverage can be rapidly improved through outreach immunization in low socioeconomic areas if existing opportunities are carefully utilized.

Acceptability of coupling IPTi with EPI programs in infants

Tropical Medicine & International Health
March 2012  Volume 17, Issue 3  Pages 263–403

Acceptability of coupling Intermittent Preventive Treatment in infants with the Expanded Programme on Immunization in three francophone countries in Africa
Alexandra de Sousa, Leon P. Rabarijaona, Jean L. Ndiaye, Doudou Sow, Mouhamed Ndyiae, Jacques Hassan, Nilda Lambo, Paul Adovohekpe, Flavia Guidetti, Judith Recht and Alphonse Affo
Article first published online: 29 NOV 2011 | DOI: 10.1111/j.1365-3156.2011.02915.x

Objective  Intermittent preventive treatment in infants (IPTi) is a malaria control strategy currently recommended by WHO for implementation at scale in Africa, consisting of administration of sulphadoxine-pyrimethamine (SP) coupled with routine immunizations offered to children under 1 year. In this study, we analysed IPTi acceptability by communities and health staff.

Methods  Direct observation, in-depth interviews (IDIs) and focus group discussions (FGDs) were conducted in Benin, Madagascar and Senegal during IPTi pilot implementation. Villages were stratified by immunization coverage. Data were transcribed and analysed using NVivo7 software.

Results  Communities’ knowledge of malaria aetiology and diagnosis was good, although generally villagers did not seek treatment at health centres as their first choice. Perceptions and attitudes towards IPTi were very positive among communities and health workers. A misconception that SP was an antipyretic that prevents post-vaccinal fever contributed to IPTi’s acceptability. No refusals or negative rumours related to IPTi coupling with immunizations were identified, and IPTi did not negatively influence attitudes towards other malaria control strategies. Healthcare decisions about children, normatively made by the father, are starting to shift to educated and financially independent mothers.

Discussion  Intermittent preventive treatment in infants is well accepted by providers and communities, showing a synergic acceptability when coupled with routine immunizations. However, a misconception that SP alleviates fever should be addressed when scaling up implementation.