Optimizing tactics for use of the U.S. antiviral strategic national stockpile for pandemic influenza

In 2009, public health agencies across the globe worked to mitigate the impact of the swine-origin influenza A (pH1N1) virus. These efforts included intensified surveillance, social distancing, hygiene measures, and the targeted use of antiviral medications to prevent infection (prophylaxis). In addition, aggressive antiviral treatment was recommended for certain patient subgroups to reduce the severity and duration of symptoms. To assist States and other localities meet these needs, the U.S. Government distributed a quarter of the antiviral medications in the Strategic National Stockpile within weeks of the pandemic's start. However, there are no quantitative models guiding the geo-temporal distribution of the remainder of the Stockpile in relation to pandemic spread or severity. We present a tactical optimization model for distributing this stockpile for treatment of infected cases during the early stages of a pandemic like 2009 pH1N1, prior to the wide availability of a strain-specific vaccine. Our optimization method efficiently searches large sets of intervention strategies applied to a stochastic network model of pandemic influenza transmission within and among U.S. cities. The resulting optimized strategies depend on the transmissability of the virus and postulated rates of antiviral uptake and wastage (through misallocation or loss). Our results suggest that an aggressive community-based antiviral treatment strategy involving early, widespread, pro-rata distribution of antivirals to States can contribute to slowing the transmission of mildly transmissible strains, like pH1N1. For more highly transmissible strains, outcomes of antiviral use are more heavily impacted by choice of distribution intervals, quantities per shipment, and timing of shipments in relation to pandemic spread. This study supports previous modeling results suggesting that appropriate antiviral treatment may be an effective mitigation strategy during the early stages of future influenza pandemics, increasing the need for systematic efforts to optimize distribution strategies and provide tactical guidance for public health policy-makers.     

Control of adenovirus acute respiratory disease in U.S. Army trainees.

Although limited almost exclusively to military trainees, acute respiratory disease (ARD) caused by adenovirus types 4 and 7 had been the leading cause of hospitalization in U.S. Army personnel. This decrease which resembles influenza in clinical manifestations led to hospitalization of as many as 50% of military trainees in midwinter and imposed a heavy burden on military hospitals and training programs. In studies undertaken from 1965 to 1970, live adenovirus type 4 and subsequently type 7 vaccines were found to be safe and immunogenic and to confer protection against type specific adenovirus ARD. For the past 5 yr. military trainees have been immunized with both adenovirus vaccines during periods of expected adenovirus disease. Since 1966, use of adenovirus vaccines has been monitored through the adenovirus surveillance program which yields weekly data on incidence and etiology of ARD in basic combat trainees. Since 1973, stable adenovirus vaccines have resulted in excellent control of adenovirus ARD. Potential problems with this immunization program are discussed.     

Application of recombinant hemagglutinin proteins as alternative antigen standards for pandemic influenza vaccines

Objectives

The single radial immunodiffusion (SRID) assay, used to quantify hemagglutinin (HA) in influenza vaccines, requires reference reagents; however, because centralized production of reference reagents may slow the emergency deployment of vaccines, alternatives are needed.

Results

We investigated the production of HA proteins using recombinant DNA technology, rather than a traditional egg-based production process. The HA proteins were then used in an SRID assay as a reference antigen. We found that HA can be quantified in both egg-based and cell-based influenza vaccines when recombinant HAs (rHAs) are used as the reference antigen. Furthermore, we confirmed that rHAs obtained from strains with pandemic potential, such as H5N1, H7N3, H7N9, and H9N2 strains, can be utilized in the SRID assay. The rHA production process takes just one month, in contrast to the traditional process that takes three to four months.

Conclusions

The use of rHAs may reduce the time required to produce reference reagents and facilitate timely introduction of vaccines during emergencies.

     

Progress in the development of pandemic influenza vaccines and their production technologies

This article analyzes the current situation in the field of construction and production of pandemic influenza vaccines. The main task of protecting the population against influenza pandemics requires state-of-the-art approaches to the construction of influenza vaccines to be based on reassortment and genetic engineering techniques, including the analysis of primary structures of influenza viral genes, synthesis and cloning of the main viral genes, reverse genetics techniques, and banks of plasmids bearing basic viral genes. Reassortant technologies are now giving way to new approaches for objective reasons. The state-of-the-art technologies provide safety not only at the laboratories where vaccine viruses are constructed but also make the production process wholly safe. We are using the following approaches to the development of industrial production: use of nanoparticles and nanoemulsions as functional adjuvants, construction of totally-safe strains for live attenuated influenza vaccines with deletions of molecular determinants of pathogenicity, application of protein and chemical chaperones to provide self-assembly of haemagglutinin molecules of the H1N1v-2009 virus, and impregnation of whole-virion preparations with nanoparticles to enhance antigenicity.     

Southeastern U.S.A. continental shelf respiratory rates revisited

Respiratory rates on the U. S. southeastern continental shelf have been estimated several times by different investigators, most recently by Jiang et al. (Biogeochemistry 98:101–113, 2010) who report lower mean rates than were found in earlier work and attribute the differences to analytical error in all methods used in earlier studies. The differences are, instead, attributable to the differences in the geographical scope of the studies. The lower estimates of regional organic carbon flux of Jiang et al. (Biogeochemistry 98:101–113, 2010) are a consequence of their extrapolation of data from a small portion of the shelf to the entire South Atlantic Bight. This comment examines the methodologies used as well as the variability of respiratory rates in this region over space and time.     

Live enteroviral vaccines for the emergency nonspecific prevention of mass respiratory diseases during fall-winter epidemics of influenza and acute respiratory diseases]

The results of the 3-year controlled trials of a new method of nonspecific urgent prophylaxis of influenza and acute respiratory diseases (ADR) by immunization of healthy adults with standard live enterovirus oral vaccines, introduced in 2-3 administrations at intervals of 7-10 days, at the initial stages of autumn and winter epidemics are presented. Observations, carried out in three republics, covered more than 150,000 persons immunized with enterovirus interferonogenic vaccines. A considerable decrease in morbidity rate among the vaccinees was achieved (on the average, by 3.2 times) in comparison to that among nonimmunized subjects. The method of nonspecific prophylaxis with live enterovirus interferonogenic vaccines is recommended during outbreaks of diseases induced simultaneously by several causative agents of influenza and ARD, as well as by pathogenic enterovirus strains.     

Inter-annual patterns in macroinvertebrate communities of wilderness streams in Idaho, U.S.A.

This study examined the inter-annual variation in macroinvertebrate assemblages in six wilderness streams in central Idaho over a 6-year period (1990–1995). Benthic macroinvertebrates and associated environmental correlates were sampled during baseflow each summer. Little environmental change, as assessed using coefficients of variation (CVs) for substrate size and embeddedness, width, depth and periphyton standing crops, occurred in the streams over the period of study. There was also little temporal change in macroinvertebrate assemblages based on the relative abundance of the 10 most abundant taxa, all shredder taxa and all plecopteran taxa. CVs for individual taxa were substantially greater than those of most community measures, with rare taxa contributing 30–50% of the variation for any one stream. Frequency distributions for taxa CVs excluding rare taxa were more normally distributed. Differences in assemblage structure among streams were attributed to stream size (shift in shredder assemblages) and temperature (shift in plecopteran taxa). These data indicate a long-term (multi-year) persistence in the macroinvertebrate composition of these pristine streams, thus supporting the premise that such streams are excellent references for use in long-term biomonitoring programs.     

Distinguishing characteristics between pandemic 2009-2010 influenza A (H1N1) and other viruses in patients hospitalized with respiratory illness

Background

Differences in clinical presentation and outcomes among patients infected with pandemic 2009 influenza A H1N1 (pH1N1) compared to other respiratory viruses have not been fully elucidated.

Methodology/Principal Findings

A retrospective study was performed of all hospitalized patients at the peak of the pH1N1 season in whom a single respiratory virus was detected by a molecular assay targeting 18 viruses/subtypes (RVP, Luminex xTAG). Fifty-two percent (615/1192) of patients from October, 2009 to December, 2009 had a single respiratory virus (291 pH1N1; 207 rhinovirus; 45 RSV A/B; 37 parainfluenza; 27 adenovirus; 6 coronavirus; and 2 metapneumovirus). No seasonal influenza A or B was detected. Individuals with pH1N1, compared to other viruses, were more likely to present with fever (92% & 70%), cough (92% & 86%), sore throat (32% & 16%), nausea (31% & 8%), vomiting (39% & 30%), abdominal pain (14% & 7%), and a lower white blood count (8,500/L & 13,600/L, all p-values<0.05). In patients with cough and gastrointestinal complaints, the presence of subjective fever/chills independently raised the likelihood of pH1N1 (OR 10). Fifty-five percent (336/615) of our cohort received antibacterial agents, 63% (385/615) received oseltamivir, and 41% (252/615) received steroids. The mortality rate of our cohort was 1% (7/615) and was higher in individuals with pH1N1 compared to other viruses (2.1% & 0.3%, respectively; p = 0.04).

Conclusions/Significance

During the peak pandemic 2009–2010 influenza season in Rhode Island, nearly half of patients admitted with influenza-like symptoms had respiratory viruses other than influenza A. A high proportion of patients were treated with antibiotics and pH1N1 infection had higher mortality compared to other respiratory viruses.     

The use of Twitter to track levels of disease activity and public concern in the U.S. during the influenza A H1N1 pandemic

Twitter is a free social networking and micro-blogging service that enables its millions of users to send and read each other's "tweets," or short, 140-character messages. The service has more than 190 million registered users and processes about 55 million tweets per day. Useful information about news and geopolitical events lies embedded in the Twitter stream, which embodies, in the aggregate, Twitter users' perspectives and reactions to current events. By virtue of sheer volume, content embedded in the Twitter stream may be useful for tracking or even forecasting behavior if it can be extracted in an efficient manner. In this study, we examine the use of information embedded in the Twitter stream to (1) track rapidly-evolving public sentiment with respect to H1N1 or swine flu, and (2) track and measure actual disease activity. We also show that Twitter can be used as a measure of public interest or concern about health-related events. Our results show that estimates of influenza-like illness derived from Twitter chatter accurately track reported disease levels.     

Effects of forest fire on headwater stream macroinvertebrate communities in eastern Washington,U.S.A.

1. Recent increases in fire frequency in North America have focused interest on potential effects on adjacent ecosystems, including streams. Headwaters could be particularly affected because of their high connectivity to riparian and downstream aquatic ecosystems through aquatic invertebrate drift and emergence. 2. Headwater streams from replicated burned and control catchments were sampled in 2 years following an intense forest fire in northeastern Washington (U.S.A.). We compared differences in benthic, drift and emergent macroinvertebrate density, biomass and community composition between five burned and five unburned catchments (14–135 ha). 3. There were significantly higher macroinvertebrate densities in burned than control sites for all sample types. Macroinvertebrate biomass was greater at burned sites only from emergence samples; in benthic and drift samples there was no significant difference between burn and control sites. 4. For all sample types, diversity was lower in the burned catchments, and the macroinvertebrate community was dominated by chironomid midges. 5. Compared to the effects of fire in less disturbed ecosystems, this study illustrated that forest fire in a managed forest may have greater effects on headwater macroinvertebrate communities, influencing prey flow to adjacent terrestrial and downstream aquatic habitats for at least the first 2 years post‐fire.     

A clinical diagnostic model for predicting influenza among young adult military personnel with febrile respiratory illness in Singapore

Introduction

Influenza infections present with wide-ranging clinical features. We aim tocompare the differences in presentation between influenza and non-influenzacases among those with febrile respiratory illness (FRI) to determinepredictors of influenza infection.

Methods

Personnel with FRI (defined as fever≥37.5°C, with cough or sorethroat) were recruited from the sentinel surveillance system in theSingapore military. Nasal washes were collected, and tested using theResplex II and additional PCR assays for etiological determination.Interviewer-administered questionnaires collected information on patientdemographics and clinical features. Univariate comparison of the variousparameters was conducted, with statistically significant parameters enteredinto a multivariate logistic regression model. The final multivariate modelfor influenza versus non-influenza cases was used to build a predictiveprobability clinical diagnostic model.

Results

821 out of 2858 subjects recruited from 11 May 2009 to 25 Jun 2010 hadinfluenza, of which 434 (52.9%) had 2009 influenza A (H1N1), 58(7.1%) seasonal influenza A (H3N2) and 269 (32.8%) influenzaB. Influenza-positive cases were significantly more likely to present withrunning nose, chills and rigors, ocular symptoms and higher temperature, andless likely with sore throat, photophobia, injected pharynx, andnausea/vomiting. Our clinical diagnostic model had a sensitivity of65% (95% CI: 58%, 72%), specificity of69% (95% CI: 62%, 75%), and overall accuracy of68% (95% CI: 64%, 71%), performing significantlybetter than conventional influenza-like illness (ILI) criteria.

Conclusions

Use of a clinical diagnostic model may help predict influenza better than theconventional ILI definition among young adults with FRI.     

Meta-analysis of the immunogenicity and tolerability of pandemic influenza A 2009 (H1N1) vaccines

Background

Although the 2009 (H1N1) influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation.

Methods

We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis.

Results

Eighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects). After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (> = 70%) in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses < = 6 µg (even with as little as 1.875 µg of hemagglutinin antigen) was not significantly lower than that achieved after higher doses. Finally, the rate of serious vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of 22826 vaccinated subjects). However, mild to moderate adverse reactions were more (and very) frequent for oil-in-water adjuvanted vaccines.

Conclusions

Several one-dose formulations might be valid for future vaccines, but 2 doses may be needed for children, especially if a low-dose non-adjuvanted vaccine is used. Given that 15 RCTs were sponsored by vaccine manufacturers, future trials sponsored by non-industry agencies and comparing vaccines using different types of adjuvants are needed.     

Compensatory mechanisms of central U.S. hardwood forest communities in a changing environment

Although it is known that forest productivity is highly correlated with canopy leaf area, the influence of environmental gradients within a forest on leaf area-productivity relationships has not been well-documented, particularly for mixed-species forests. The present study was conducted to define the mechanisms by which Central Hardwood forest communities respond to changes in environment. Ecological Land Type Phases (ELTPs) of the Central Hardwood region, delineated by soils, topography, and indicator vegetation, provided a framework to examine the impacts of environmental gradients on leaf area-productivity relationships at a landscape level. Three ELTPs- (1) Quercus prinus / Carex picta-Vaccinium, Dry slope, (2) Quercus alba-Acer saccharum / Parthenocissus, Dry-Mesic Slope, and (3) Fagus-Acer saccharum / Arisaema, Mesic Slope- were selected and stratified into three slope positions viz. the upper edge of the community, the middle or center of the community on the slope, and the lower edge of the community. Circular plots of 0.02 ha in size were established for sampling. Standing stock (basal area, volume, and biomass), annual production, leaf area index, and growth efficiency were determined for each slope position and examined to determine the mechanisms and trends for community change across slope positions. Among the three communities studied, dry slopes compensated for drier conditions through both a shift in species composition and reduced annual production. Dry-mesic slopes exhibited adaptation only through changing species composition whereas mesic slopes compensated for drier conditions primarily through reduction in annual production. These results indicate that mixed-species forest communities adjust to environmental gradients through several mechanisms and that the relative importance of these mechanisms changes with community type.     

Forest communities of the northern whitefish range, rocky mountains, Montana, U.S.A.

The montane and subalpine forests of a mountain range in northwestern Montana were investigated using phytosociological and numerical methods. Twelve associations and two subassociations were identified, of which eight are described here for the first time. The forest vegetation of valleys and lower slopes is strongly affected by repeated fire and is placed in the new orderCalamagrostio-Pseudotsugetalia glaucae, which includes temperate, low elevation forests in inland regions of northwestern North America. These forests bear only weak resemblance to forests traditionally assigned to the classVaccinio-Piceetea, and occupy the habitats filled by broad-leaved forests elsewhere at temperate latitudes. Montane and subalpine forest vegetation is moister and has longer snow duration and a shorter growing season. Upper montane vegetation more closely resembles that of other temperate montane forests of the classVaccinio-Piceetea.