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1.  Air Cleaning Technologies 
Executive Summary
Objective
This health technology policy assessment will answer the following questions:
When should in-room air cleaners be used?
How effective are in-room air cleaners?
Are in-room air cleaners that use combined HEPA and UVGI air cleaning technology more effective than those that use HEPA filtration alone?
What is the Plasmacluster ion air purifier in the pandemic influenza preparation plan?
The experience of severe acute respiratory syndrome (SARS) locally, nationally, and internationally underscored the importance of administrative, environmental, and personal protective infection control measures in health care facilities. In the aftermath of the SARS crisis, there was a need for a clearer understanding of Ontario’s capacity to manage suspected or confirmed cases of airborne infectious diseases. In so doing, the Walker Commission thought that more attention should be paid to the potential use of new technologies such as in-room air cleaning units. It recommended that the Medical Advisory Secretariat of the Ontario Ministry of Health and Long-Term Care evaluate the appropriate use and effectiveness of such new technologies.
Accordingly, the Ontario Health Technology Advisory Committee asked the Medical Advisory Secretariat to review the literature on the effectiveness and utility of in-room air cleaners that use high-efficiency particle air (HEPA) filters and ultraviolet germicidal irradiation (UVGI) air cleaning technology.
Additionally, the Ontario Health Technology Advisory Committee prioritized a request from the ministry’s Emergency Management Unit to investigate the possible role of the Plasmacluster ion air purifier manufactured by Sharp Electronics Corporation, in the pandemic influenza preparation plan.
Clinical Need
Airborne transmission of infectious diseases depends in part on the concentration of breathable infectious pathogens (germs) in room air. Infection control is achieved by a combination of administrative, engineering, and personal protection methods. Engineering methods that are usually carried out by the building’s heating, ventilation, and air conditioning (HVAC) system function to prevent the spread of airborne infectious pathogens by diluting (dilution ventilation) and removing (exhaust ventilation) contaminated air from a room, controlling the direction of airflow and the air flow patterns in a building. However, general wear and tear over time may compromise the HVAC system’s effectiveness to maintain adequate indoor air quality. Likewise, economic issues may curtail the completion of necessary renovations to increase its effectiveness. Therefore, when exposure to airborne infectious pathogens is a risk, the use of an in-room air cleaner to reduce the concentration of airborne pathogens and prevent the spread of airborne infectious diseases has been proposed as an alternative to renovating a HVAC system.
Airborne transmission is the spread of infectious pathogens over large distances through the air. Infectious pathogens, which may include fungi, bacteria, and viruses, vary in size and can be dispersed into the air in drops of moisture after coughing or sneezing. Small drops of moisture carrying infectious pathogens are called droplet nuclei. Droplet nuclei are about 1 to 5μm in diameter. This small size in part allows them to remain suspended in the air for several hours and be carried by air currents over considerable distances. Large drops of moisture carrying infectious pathogens are called droplets. Droplets being larger than droplet nuclei, travel shorter distances (about 1 metre) before rapidly falling out of the air to the ground. Because droplet nuclei remain airborne for longer periods than do droplets, they are more amenable to engineering infection control methods than are droplets.
Droplet nuclei are responsible for the airborne transmission of infectious diseases such as tuberculosis, chicken pox (varicella), measles (rubeola), and dessiminated herpes zoster, whereas close contact is required for the direct transmission of infectious diseases transmitted by droplets, such as influenza (the flu) and SARS.
The Technology
In-room air cleaners are supplied as portable or fixed devices. Fixed devices can be attached to either a wall or ceiling and are preferred over portable units because they have a greater degree of reliability (if installed properly) for achieving adequate room air mixing and airflow patterns, which are important for optimal effectiveness.
Through a method of air recirculation, an in-room air cleaner can be used to increase room ventilation rates and if used to exhaust air out of the room it can create a negative-pressure room for airborne infection isolation (AII) when the building’s HVAC system cannot do so. A negative-pressure room is one where clean air flows into the room but contaminated air does not flow out of it. Contaminated room air is pulled into the in-room air cleaner and cleaned by passing through a series of filters, which remove the airborne infectious pathogens. The cleaned air is either recirculated into the room or exhausted outside the building. By filtering contaminated room air and then recirculating the cleaned air into the room, an in-room air cleaner can improve the room’s ventilation. By exhausting the filtered air to the outside the unit can create a negative-pressure room. There are many types of in-room air cleaners. They vary widely in the airflow rates through the unit, the type of air cleaning technology used, and the technical design.
Crucial to maximizing the efficiency of any in-room air cleaner is its strategic placement and set-up within a room, which should be done in consultation with ventilation engineers, infection control experts, and/or industrial hygienists. A poorly positioned air cleaner may disrupt airflow patterns within the room and through the air cleaner, thereby compromising its air cleaning efficiency.
The effectiveness of an in-room air cleaner to remove airborne pathogens from room air depends on several factors, including the airflow rate through the unit’s filter and the airflow patterns in the room. Tested under a variety of conditions, in-room air cleaners, including portable or ceiling mounted units with either a HEPA or a non-HEPA filter, portable units with UVGI lights only, or ceiling mounted units with combined HEPA filtration and UVGI lights, have been estimated to be between 30% and 90%, 99% and 12% and 80% effective, respectively. However, and although their effectiveness is variable, the United States Centers for Disease Control and Prevention has acknowledged in-room air cleaners as alternative technology for increasing room ventilation when this cannot be achieved by the building’s HVAC system with preference given to fixed recirculating systems over portable ones.
Importantly, the use of an in-room air cleaner does not preclude either the need for health care workers and visitors to use personal protective equipment (N95 mask or equivalent) when entering AII rooms or health care facilities from meeting current regulatory requirements for airflow rates (ventilation rates) in buildings and airflow differentials for effective negative-pressure rooms.
The Plasmacluster ion technology, developed in 2000, is an air purification technology. Its manufacturer, Sharp Electronics Corporation, says that it can disable airborne microorganisms through the generation of both positive and negative ions. (1) The functional unit is the hydroxyl, which is a molecule comprised of one oxygen molecule and one hydrogen atom.
Plasmacluster ion air purifier uses a multilayer filter system composed of a prefilter, a carbon filter, an antibacterial filter, and a HEPA filter, combined with an ion generator to purify the air. The ion generator uses an alternating plasma discharge to split water molecules into positively and negatively charged ions. When these ions are emitted into the air, they are surrounded by water molecules and form cluster ions which are attracted to airborne particles. The cluster ion surrounds the airborne particle, and the positive and negative ions react to form hydroxyls. These hydroxyls steal the airborne particle’s hydrogen atom, which creates a hole in the particle’s outer protein membrane, thereby rendering it inactive.
Because influenza is primarily acquired by large droplets and direct and indirect contact with an infectious person, any in-room air cleaner will have little benefit in controlling and preventing its spread. Therefore, there is no role for the Plasmacluster ion air purifier or any other in-room air cleaner in the control of the spread of influenza. Accordingly, for purposes of this review, the Medical Advisory Secretariat presents no further analysis of the Plasmacluster.
Review Strategy
The objective of the systematic review was to determine the effectiveness of in-room air cleaners with built in UVGI lights and HEPA filtration compared with those using HEPA filtration only.
The Medical Advisory Secretariat searched the databases of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, INAHATA (International Network of Agencies for Health Technology Assessment), Biosis Previews, Bacteriology Abstracts, Web of Science, Dissertation Abstracts, and NIOSHTIC 2.
A meta-analysis was conducted if adequate data was available from 2 or more studies and where statistical and clinical heterogeneity among studies was not an issue. Otherwise, a qualitative review was completed. The GRADE system was used to summarize the quality of the body of evidence comprised of 1 or more studies.
Summary of Findings
There were no existing health technology assessments on air cleaning technology located during the literature review. The literature search yielded 59 citations of which none were retained. One study was retrieved from a reference list of a guidance document from the United States Centers for Disease Control and Prevention, which evaluated an in-room air cleaner with combined UVGI lights and HEPA filtration under 2 conditions: UVGI lights on and UVGI lights off. Experiments were performed using different ventilation rates and using an aerosolized pathogen comprised of Mycobaterium parafortuitum, a surrogate for the bacterium that causes tuberculosis. Effectiveness was measured as equivalent air changes per hour (eACH). This single study formed the body of evidence for our systematic review research question.
Experimental Results
The eACH rate for the HEPA-UVGI in-room air cleaner was statistically significantly greater when the UV lights were on compared with when the UV lights were off. (P < .05). However, subsequent experiments could not attribute this to the UVGI. Consequently, the results are inconclusive and an estimate of effect (benefit) is uncertain.
The study was reviewed by a scientific expert and rated moderate for quality. Further analysis determined that there was some uncertainty in the directness of the outcome measure (eACH); thus, the GRADE level for the quality of the evidence was low indicating that an estimate of effect is very uncertain.
There is uncertainty in the benefits of using in-room air cleaners with combined UVGI lights and HEPA filtration over systems that use HEPA filtration alone. However, there are no known risks to using systems with combined UVGI and HEPA technology compared with those with HEPA alone. There is an increase in the burden of cost including capital costs (cost of the device), operating costs (electricity usage), and maintenance costs (cleaning and replacement of UVGI lights) to using an in-room air cleaner with combined UVGI and HEPA technology compared with those with HEPA alone. Given the uncertainty of the estimate of benefits, an in-room air cleaner with HEPA technology only may be an equally reasonable alternative to using one with combined UVGI and HEPA technology
Conclusions
In-room air cleaners may be used to protect health care staff from air borne infectious pathogens such as tuberculosis, chicken pox, measles, and dessiminated herpes zoster. In addition, and although in-room air cleaners are not effective at protecting staff and preventing the spread of droplet-transmitted diseases such as influenza and SARS, they may be deployed in situations with a novel/emerging infectious agent whose epidemiology is not yet defined and where airborne transmission is suspected.
It is preferable that in-room air cleaners be used with a fixed and permanent room placement when ventilation requirements must be improved and the HVAC system cannot be used. However, for acute (temporary) situations where a novel/emerging infectious agent presents whose epidemiology is not yet defined and where airborne transmission is suspected it may be prudent to use the in room air cleaner as a portable device until mode of transmission is confirmed. To maximize effectiveness, consultation with an environmental engineer and infection control expert should be undertaken before using an in-room air cleaner and protocols for maintenance and monitoring of these devices should be in place.
If properly installed and maintained, in room air cleaners with HEPA or combined HEPA and UVGI air cleaning technology are effective in removing airborne pathogens. However, there is only weak evidence available at this time regarding the benefit of using an in-room air cleaner with combined HEPA and UVGI air cleaner technology instead of those with HEPA filter technology only.
PMCID: PMC3382390  PMID: 23074468
2.  Cost-Effectiveness Comparison of Response Strategies to a Large-Scale Anthrax Attack on the Chicago Metropolitan Area: Impact of Timing and Surge Capacity 
Rapid public health response to a large-scale anthrax attack would reduce overall morbidity and mortality. However, there is uncertainty about the optimal cost-effective response strategy based on timing of intervention, public health resources, and critical care facilities. We conducted a decision analytic study to compare response strategies to a theoretical large-scale anthrax attack on the Chicago metropolitan area beginning either Day 2 or Day 5 after the attack. These strategies correspond to the policy options set forth by the Anthrax Modeling Working Group for population-wide responses to a large-scale anthrax attack: (1) postattack antibiotic prophylaxis, (2) postattack antibiotic prophylaxis and vaccination, (3) preattack vaccination with postattack antibiotic prophylaxis, and (4) preattack vaccination with postattack antibiotic prophylaxis and vaccination. Outcomes were measured in costs, lives saved, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). We estimated that postattack antibiotic prophylaxis of all 1,390,000 anthrax-exposed people beginning on Day 2 after attack would result in 205,835 infected victims, 35,049 fulminant victims, and 28,612 deaths. Only 6,437 (18.5%) of the fulminant victims could be saved with the existing critical care facilities in the Chicago metropolitan area. Mortality would increase to 69,136 if the response strategy began on Day 5. Including postattack vaccination with antibiotic prophylaxis of all exposed people reduces mortality and is cost-effective for both Day 2 (ICER=$182/QALY) and Day 5 (ICER=$1,088/QALY) response strategies. Increasing ICU bed availability significantly reduces mortality for all response strategies. We conclude that postattack antibiotic prophylaxis and vaccination of all exposed people is the optimal cost-effective response strategy for a large-scale anthrax attack. Our findings support the US government's plan to provide antibiotic prophylaxis and vaccination for all exposed people within 48 hours of the recognition of a large-scale anthrax attack. Future policies should consider expanding critical care capacity to allow for the rescue of more victims.
Rapid public health response to a large-scale anthrax attack would reduce overall morbidity and mortality, but what is the optimal cost-effective response strategy for timing of intervention, public health resources, and critical care facilities? Using a hypothetical large-scale anthrax attack on the Chicago metropolitan area, this study compared response strategies that would begin either 2 days or 5 days after the attack and would consist of administering prophylaxis and vaccine in various combinations. The findings support the government's plan to provide antibiotic prophylaxis and vaccination for all exposed people within 48 hours of the recognition of a large-scale anthrax attack.
doi:10.1089/bsp.2011.0105
PMCID: PMC3440066  PMID: 22845046
3.  Comparison of techniques to reduce residential lead dust on carpet and upholstery: the new jersey assessment of cleaning techniques trial. 
Environmental Health Perspectives  2002;110(12):1233-1237.
High-efficiency particulate air (HEPA) filtered vacuum cleaners are recommended by the U.S. Department of Housing and Urban Development for cleaning lead-contaminated house dust. We performed a randomized field study to determine whether a conventional (non-HEPA) vacuum cleaner could achieve cleaning results comparable with those of a HEPA vacuum cleaner. We compared the lead loading reductions of these two vacuum cleaners in a total of 127 New Jersey homes of lead-exposed children. We used wet towelettes and a vacuum sampler to collect lead dust from carpets and upholstery before and after vacuum cleaning. The vacuum sampling data showed that the HEPA and non-HEPA vacuum cleaners resulted in 54.7% (p = 0.006) and 36.4% (p = 0.020) reductions in lead loading, respectively, when used on soiled carpets, although the overall difference in lead loading reduction between the two vacuum cleaners was not statistically significant (p = 0.293). The wipe sampling data did not show any significant lead loading reduction for either of the vacuum cleaners, suggesting that both vacuum cleaners fail to clean the surfaces of carpet effectively, considering that wipe sampling media simulate surface contact. On upholstery, the wipe sampling data showed a significant reduction in lead loading for the non-HEPA vacuum cleaner (22.2%, p = 0.047). Even with the significant reduction, the postcleaning lead loadings on upholstery were similar to those on carpets. The similar lead loading results for carpets and upholstery indicate that soiled upholstery may be as important a source of childhood lead exposure as carpets.
PMCID: PMC1241111  PMID: 12460803
4.  Environmental Sampling for Spores of Bacillus anthracis 
Emerging Infectious Diseases  2002;8(10):1083-1087.
On November 11, 2001, following the bioterrorism-related anthrax attacks, the U.S. Postal Service collected samples at the Southern Connecticut Processing and Distribution Center; all samples were negative for Bacillus anthracis. After a patient in Connecticut died from inhalational anthrax on November 19, the center was sampled again on November 21 and 25 by using dry and wet swabs. All samples were again negative for B. anthracis. On November 28, guided by information from epidemiologic investigation, we sampled the site extensively with wet wipes and surface vacuum sock samples (using HEPA vacuum). Of 212 samples, 6 (3%) were positive, including one from a highly contaminated sorter. Subsequently B. anthracis was also detected in mail-sorting bins used for the patient’s carrier route. These results suggest cross-contaminated mail as a possible source of anthrax for the inhalational anthrax patient in Connecticut. In future such investigations, extensive sampling guided by epidemiologic data is imperative.
doi:10.3201/eid0810.020398
PMCID: PMC2730287  PMID: 12396920
Bacillus anthracis; anthrax; environmental sampling; postal facility; surface sampling; HEPA vacuum sock; swabs; wipes
5.  Anthrax vaccination strategies 
Molecular aspects of medicine  2009;30(6):490-502.
The biological attack conducted through the U.S. postal system in 2001 broadened the threat posed by anthrax from one pertinent mainly to soldiers on the battlefield to one understood to exist throughout our society. The expansion of the threatened population placed greater emphasis on the reexamination of how we vaccinate against Bacillus anthracis. The currently-licensed Anthrax Vaccine, Adsorbed (AVA) and Anthrax Vaccine, Precipitated (AVP) are capable of generating a protective immune response but are hampered by shortcomings that make their widespread use undesirable or infeasible. Efforts to gain U.S. Food and Drug Administration (FDA) approval for licensure of a second generation recombinant protective antigen (rPA)-based anthrax vaccine are ongoing. However, this vaccine's reliance on the generation of a humoral immune response against a single virulence factor has led a number of scientists to conclude that the vaccine is likely not the final solution to optimal anthrax vaccine design. Other vaccine approaches, which seek a more comprehensive immune response targeted at multiple components of the B. anthracis organism, are under active investigation. This review seeks to summarize work that has been done to build on the current PA-based vaccine methodology and to evaluate the search for future anthrax prophylaxis strategies.
doi:10.1016/j.mam.2009.08.006
PMCID: PMC2783700  PMID: 19729034
Bacillus anthracis; anthrax; vaccine
6.  Chemical or Biological Terrorist Attacks: An Analysis of the Preparedness of Hospitals for Managing Victims Affected by Chemical or Biological Weapons of Mass Destruction 
The possibility of a terrorist attack employing the use of chemical or biological weapons of mass destruction (WMD) on American soil is no longer an empty threat, it has become a reality. A WMD is defined as any weapon with the capacity to inflict death and destruction on such a massive scale that its very presence in the hands of hostile forces is a grievous threat. Events of the past few years including the bombing of the World Trade Center in 1993, the Murrah Federal Building in Oklahoma City in 1995 and the use of planes as guided missiles directed into the Pentagon and New York’s Twin Towers in 2001 (9/11) and the tragic incidents involving twenty-three people who were infected and five who died as a result of contact with anthrax-laced mail in the Fall of 2001, have well established that the United States can be attacked by both domestic and international terrorists without warning or provocation. In light of these actions, hospitals have been working vigorously to ensure that they would be “ready” in the event of another terrorist attack to provide appropriate medical care to victims. However, according to a recent United States General Accounting Office (GAO) nationwide survey, our nation’s hospitals still are not prepared to manage mass causalities resulting from chemical or biological WMD. Therefore, there is a clear need for information about current hospital preparedness in order to provide a foundation for systematic planning and broader discussions about relative cost, probable effectiveness, environmental impact and overall societal priorities. Hence, the aim of this research was to examine the current preparedness of hospitals in the State of Mississippi to manage victims of terrorist attacks involving chemical or biological WMD. All acute care hospitals in the State were selected for inclusion in this study. Both quantitative and qualitative methods were utilized for data collection and analysis. Six hypotheses were tested. Using a questionnaire survey, the availability of functional preparedness plans, specific preparedness education/training, decontamination facilities, surge capacity, pharmaceutical supplies, and laboratory diagnostic capabilities of hospitals were examined. The findings revealed that a majority (89.2%) of hospitals in the State of Mississippi have documented preparedness plans, provided specific preparedness education/training (89.2%), have dedicated facilities for decontamination (75.7%), and pharmaceutical plans and supplies (56.8%) for the treatment of victims in the event of a disaster involving chemical or biological WMD. However, over half (59.5%) of the hospitals could not increase surge capacity (supplies, equipment, staff, patient beds, etc.) and lack appropriate laboratory diagnostic services (91.9%) capable of analyzing and identifying WMD. In general, hospitals in the State of Mississippi, like a number of hospitals throughout the United States, are still not adequately prepared to manage victims of terrorist attacks involving chemical or biological WMD which consequently may result in the loss of hundreds or even thousands of lives. Therefore, hospitals continue to require substantial resources at the local, State, and national levels in order to be “truly” prepared.
PMCID: PMC3785681  PMID: 16823078
Hospital; Terrorism; Preparedness; Weapons of Mass Destruction
7.  Mold Occurring on the Air Cleaner High-Efficiency Particulate Air Filters Used in the Houses of Child Patients with Atopic Dermatitis 
Mycobiology  2014;42(3):286-290.
Fungi are the known sources of irritation associated with atopic diseases (e.g., asthma, allergic rhinoconjunctivitis, and atopic eczema). To quantitatively estimate their presence in the indoor environment of atopic dermatitis-inflicted child patient's houses (ADCPHs), the high-efficiency particulate air (HEPA) filters installed inside the air cleaners of three different ADCPHs were investigated for the presence of mold. The air cleaner HEPA filters obtained from the three different ADCPHs were coded as HEPA-A, -B, and -C, respectively, and tested for the presence of mold. The colony forming units (CFUs) corresponding to the HEPA-A, -B, and -C filters were estimated to be 6.51 × 102 ± 1.50 × 102 CFU/cm2, 8.72 × 102 ± 1.69 × 102 CFU/cm2, and 9.71 × 102 ± 1.35 × 102 CFU/cm2, respectively. Aspergillus, Penicillium, Alternaria, Cladosporium, Trichoderma, and other fungal groups were detected in the 2,494 isolates. The distribution of these fungal groups differed among the three filters. Cladosporium was the major fungal group in filters HEPA-A and -C, whereas Penicillium was the major fungal group in the filter HEPA-B. Nine fungal species, including some of the known allergenic species, were identified in these isolates. Cladosporium cladosporioides was the most common mold among all the three filters. This is the first report on the presence of fungi in the air cleaner HEPA filters from ADCPHs in Korea.
doi:10.5941/MYCO.2014.42.3.286
PMCID: PMC4206797  PMID: 25346608
Atopic dermatitis; Fungi; High-efficiency particulate air filters; Indoor air
8.  Public Acceptance and Willingness to Hepatitis A Vaccination in Children Aged 7-18 Years in Republic of Korea 
Journal of Korean Medical Science  2014;29(11):1528-1535.
Hepatitis A can cause serious illness among adolescents and adults with low vaccination coverage. Even though hepatitis A vaccine is one of the strong candidates for Korean national immunization program, adolescents aged older than 12 yr would not benefit. Our purpose was to assess the willingness and analyze the correlates of Korean mothers for hepatitis A (HepA) vaccination to develop strategies for HepA vaccination. A national telephone survey on 800 mothers with children aged 7-18 yr was conducted with random-digit dialing method. Sixty-two percent and 92% of the mothers reported that they were willing to HepA vaccination at current cost and at half of the current cost, respectively. However, at current cost, only 79% wished to vaccinate their child in an epidemic and 32% wished to vaccinate promptly. Having two or more children, not having future plans to send the child overseas, and low family income were significantly associated with not willing to HepA vaccination. Low perception of the susceptibility for hepatitis A and perception of the current cost as barrier increased the odds of unwillingness to vaccination at current cost and to prompt vaccination. The mothers' willingness to HepA vaccination for the children aged 7-18 yr in Korea was not very high at current cost and associated socioeconomic status and health-belief. Targeted intervention or strategies are needed to increase the HepA vaccination rate among children in Korea.
Graphical Abstract
doi:10.3346/jkms.2014.29.11.1528
PMCID: PMC4234921  PMID: 25408585
Hepatitis A; Vaccination; Willingness; Children; Adolescent
9.  Plant-Based Vaccine: Mice Immunized with Chloroplast-Derived Anthrax Protective Antigen Survive Anthrax Lethal Toxin Challenge  
Infection and Immunity  2005;73(12):8266-8274.
The currently available human vaccine for anthrax, derived from the culture supernatant of Bacillus anthracis, contains the protective antigen (PA) and traces of the lethal and edema factors, which may contribute to adverse side effects associated with this vaccine. Therefore, an effective expression system that can provide a clean, safe, and efficacious vaccine is required. In an effort to produce anthrax vaccine in large quantities and free of extraneous bacterial contaminants, PA was expressed in transgenic tobacco chloroplasts by inserting the pagA gene into the chloroplast genome. Chloroplast integration of the pagA gene was confirmed by PCR and Southern analysis. Mature leaves grown under continuous illumination contained PA as up to 14.2% of the total soluble protein. Cytotoxicity measurements in macrophage lysis assays showed that chloroplast-derived PA was equal in potency to PA produced in B. anthracis. Subcutaneous immunization of mice with partially purified chloroplast-derived or B. anthracis-derived PA with adjuvant yielded immunoglobulin G titers up to 1:320,000, and both groups of mice survived (100%) challenge with lethal doses of toxin. An average yield of about 150 mg of PA per plant should produce 360 million doses of a purified vaccine free of bacterial toxins edema factor and lethal factor from 1 acre of land. Such high expression levels without using fermenters and the immunoprotection offered by the chloroplast-derived PA should facilitate development of a cleaner and safer anthrax vaccine at a lower production cost. These results demonstrate the immunogenic and immunoprotective properties of plant-derived anthrax vaccine antigen.
doi:10.1128/IAI.73.12.8266-8274.2005
PMCID: PMC1307059  PMID: 16299323
10.  Further evaluation of alternative air-filtration systems for reducing the transmission of Porcine reproductive and respiratory syndrome virus by aerosol 
Abstract
The purpose of this study was to compare 4 methods for the reduction of aerosol transmission of Porcine reproductive and respiratory syndrome virus (PRRSV): high-efficiency particulate air (HEPA) filtration, 2×-low-cost filtration, bag filtration, and use of a filter tested against particles derived from dioctylphthalate (DOP). The HEPA-filtration system used a prefilter screen, a bag filter (Eurovent [EU] 8 rating), and a HEPA filter (EU13 rating). The low-cost-filtration system contained mosquito netting (prefilter), 2 fiberglass furnace filters, and 2 electrostatic furnace filters. Bag filtration involved the use of a filter rated EU8 and a minimum efficiency reporting value (MERV) of 14. The 95%-DOP, 0.3-μm-filtration system involved a pleat-in-pleat V-bank disposable filter with a 95% efficiency rating for particles 0.3 μm or greater in diameter and ratings of EU9 and MERV 15. No form of intervention was used in the control group. The experimental facilities consisted of 2 chambers connected by a 1.3-m-long duct containing the treatments. Recipient pigs, housed in chamber 2, were exposed to artificial aerosols created by a mechanically operated mister containing modified live PRRSV vaccine located in chamber 1. Aerosol transmission of PRRSV occurred in 0 of the 10 HEPA-filtration replicates, 2 of the 10 bag-filtration replicates, 4 of the 10 low-cost-filtration replicates, 0 of the 10 95%-DOP, 0.3-μm-filtration replicates, and all 10 of the control replicates. Using a similar approach, we further evaluated the HEPA- and 95%-DOP, 0.3-μm-filtration systems. Infection was not observed in any of the 76 HEPA-filtration replicates but was observed in 2 of the 76 95%-DOP, 0.3-μm replicates and 42 of the 50 control replicates. Although the difference between the 95%-DOP, 0.3-μm and control replicates was significant (P < 0.0005), so was the level of failure of the 95%-DOP, 0.3-μm system (P = 0.02). In conclusion, under the conditions of this study, some methods of air filtration were significantly better than others in reducing aerosol transmission of PRRSV, and HEPA filtration was the only system that completely prevented transmission.
PMCID: PMC1477932  PMID: 16850938
11.  Surface Sampling Methods for Bacillus anthracis Spore Contamination 
Emerging Infectious Diseases  2002;8(10):1145-1151.
During an investigation conducted December 17–20, 2001, we collected environmental samples from a U.S. postal facility in Washington, D.C., known to be extensively contaminated with Bacillus anthracis spores. Because methods for collecting and analyzing B. anthracis spores have not yet been validated, our objective was to compare the relative effectiveness of sampling methods used for collecting spores from contaminated surfaces. Comparison of wipe, wet and dry swab, and HEPA vacuum sock samples on nonporous surfaces indicated good agreement between results with HEPA vacuum and wipe samples. However, results from HEPA vacuum sock and wipe samples agreed poorly with the swab samples. Dry swabs failed to detect spores >75% of the time they were detected by wipe and HEPA vacuum samples. Wipe samples collected after HEPA vacuum samples and HEPA vacuum samples after wipe samples indicated that neither method completely removed spores from the sampled surfaces.
doi:10.3201/eid0810.020382
PMCID: PMC2730285  PMID: 12396930
Bacillus anthracis; anthrax; bacterial spores; surface sampling; HEPA vacuum sock; swabs; wipes; postal facility; bioterrorism
12.  Determination of serum IgG antibodies to Bacillus anthracis protective antigen in environmental sampling workers using a fluorescent covalent microsphere immunoassay 
Aims: To evaluate potential exposure to Bacillis anthracis (Ba) spores in sampling/decontamination workers in the aftermath of an anthrax terror attack.
Methods: Fifty six serum samples were obtained from workers involved in environmental sampling for Ba spores at the American Media, Inc. (AMI) building in Boca Raton, FL after the anthrax attack there in October 2001. Nineteen sera were drawn from individuals both pre-entry and several weeks after entrance into the building. Nine sera each were drawn from unique individuals at the pre-entry and follow up blood draws. Thirteen donor control sera were also evaluated. Individuals were surveyed for Ba exposure by measurement of serum Ba anti-protective antigen (PA) specific IgG antibodies using a newly developed fluorescent covalent microsphere immunoassay (FCMIA).
Results: Four sera gave positive anti-PA IgG results (defined as anti-PA IgG concentrations ⩾ the mean µg/ml anti-PA IgG from donor control sera (n = 13 plus 2 SD which were also inhibited ⩾ 85% when the serum was pre-adsorbed with PA). The positive sera were the pre-entry and follow up samples of two workers who had received their last dose of anthrax vaccine in 2000.
Conclusion: It appears that the sampling/decontamination workers of the present study either had insufficient exposure to Ba spores to cause the production of anti-PA IgG antibodies or they were exposed to anthrax spores without producing antibody. The FCMIA appears to be a fast, sensitive, accurate, and precise method for the measurement of anti-PA IgG antibodies.
doi:10.1136/oem.2003.008565
PMCID: PMC1740834  PMID: 15258278
13.  Evaluation of HEPA vacuum cleaning and dry steam cleaning in reducing levels of polycyclic aromatic hydrocarbons and house dust mite allergens in carpets 
Dry steam cleaning, which has gained recent attention as an effective method to reduce house dust mite (HDM) allergen concentration and loading in carpets, was evaluated in this study for its efficacy in lowering levels of polycyclic aromatic hydrocarbons (PAHs) as well as HDM allergens. Fifty urban homes with wail-to-wall carpets, mostly low-income and with known lead contamination, were studied in 2003 and 2004. Two carpet-cleaning interventions were compared: Repeated HEPA (High Efficiency Particulate Air filtered) vacuuming alone and repeated HEPA vacuuming supplemented with dry steam cleaning. Vacuum samples were collected to measure carpet loading of dust and contaminants immediately before and after cleaning. Paired comparisons were conducted to evaluate the effectiveness of the cleaning protocols in reducing the levels of PAHs and HDM allergens in carpets. The results indicated that both cleaning methods substantially reduced the loading of PAHs and HDM allergens as well as dust in carpets (p < 0.0001). The reductions in loading of dust (64.4%), PAHs (69.1%), and HDM allergens (85.5%), by dry steam cleaning plus repetitive HEPA vacuuming were larger than the reductions by regular HEPA vacuuming alone: dust (55.5%), PAHs (58.6%), and HDM allergens (80.8%), although the difference was statistically significant only for dust and PAHs. We conclude that intensive HEPA vacuum cleaning substantially reduced the loading of PAHs and HDM allergens in carpets in these urban homes and that dry steam cleaning added modestly to cleaning effectiveness.
doi:10.1039/b807821a
PMCID: PMC4035666  PMID: 19137159
14.  Comparison of home lead dust reduction techniques on hard surfaces: the New Jersey assessment of cleaning techniques trial. 
Environmental Health Perspectives  2002;110(9):889-893.
High efficiency particulate air filter (HEPA) vacuums, which collect particles > 0.3 micro m, and trisodium phosphate (TSP), a detergent claimed to selectively remove lead, have been included in the HUD Guidelines for the Evaluation and Control of Lead Based Paint Hazards in Housing without systematic validation of their effectiveness. At the time the study was initiated, both HEPA vacuums and TSP were relatively expensive, they were not readily found in urban retail centers, and there were environmental concerns about the use and disposal of high-phosphate detergents. A randomized, controlled trial was conducted in urban high-risk homes in northern New Jersey to determine whether a more readily available and less expensive low-phosphate, non-TSP detergent and non-HEPA vacuum could perform as well as TSP and a HEPA vacuum in a cleaning protocol. Homes were randomized to one of three cleaning methods: TSP/HEPA vacuum, TSP/non-HEPA vacuum, or non-TSP/non-HEPA vacuum. Change in log-transformed lead loading was used in mixed models to compare the efficacy of the three cleaning techniques separately for uncarpeted floors, window sills, and window troughs. After we adjusted for baseline lead loading, the non-HEPA vacuum produced larger reductions on hard floors [19%; 95% confidence interval (CI), 3-38%], but the HEPA vacuum produced larger reductions on window sills (22%; 95% CI, 11-32%) and larger reductions on window troughs (16%; 95% CI, -4 to 33%). The non-TSP produced larger reductions on window troughs (21%; 95% CI, -2 to 50%), but TSP produced larger reductions on hard floors (5%; 95% CI, -12 to 19%) and window sills (8%; 95% CI, -5 to 20%). TSP/HEPA produced larger reductions on window sills (28%; 95% CI, 18-37%) and larger reductions on window troughs (2%; 95% CI, -24 to 23%), whereas the non-TSP/non-HEPA method produced larger reductions on hard floors (13%; 95% CI, -5 to 34%). Because neither vacuum nor detergent produced consistent results across surface types, the use of low-phosphate detergents and non-HEPA vacuums in a temporary control measure is supported.
PMCID: PMC1240988  PMID: 12204823
15.  Optimizing the Dose of Pre-Pandemic Influenza Vaccines to Reduce the Infection Attack Rate 
PLoS Medicine  2007;4(6):e218.
Background
The recent spread of avian influenza in wild birds and poultry may be a precursor to the emergence of a 1918-like human pandemic. Therefore, stockpiles of human pre-pandemic vaccine (targeted at avian strains) are being considered. For many countries, the principal constraint for these vaccine stockpiles will be the total mass of antigen maintained. We tested the hypothesis that lower individual doses (i.e., less than the recommended dose for maximum protection) may provide substantial extra community-level benefits because they would permit wider vaccine coverage for a given total size of antigen stockpile.
Methods and Findings
We used a mathematical model to predict infection attack rates under different policies. The model incorporated both an individual's response to vaccination at different doses and the process of person-to-person transmission of pandemic influenza. We found that substantial reductions in the attack rate are likely if vaccines are given to more people at lower doses. These results are applicable to all three vaccine candidates for which data are available. As a guide to the magnitude of the effect, we simulated epidemics based on historical studies of immunogenicity. For example, for one of the vaccines for which data are available, the attack rate would drop from 67.6% to 58.7% if 160 out of the total US population of 300 million were given an optimal dose rather than 20 out of 300 million given the maximally protective dose (as promulgated in the US National Pandemic Preparedness Plan). Our results are conservative with respect to a number of alternative assumptions about the precise nature of vaccine protection. We also considered a model variant that includes a single high-risk subgroup representing children. For smaller stockpile sizes that allow vaccine to be offered only to the high-risk group at the optimal dose, the predicted benefits of using the homogenous model formed a lower bound in the presence of a risk group, even when the high-risk group was twice as infective and twice as susceptible.
Conclusions
In addition to individual-level protection (i.e., vaccine efficacy), the population-level implications of pre-pandemic vaccine programs should be considered when deciding on stockpile size and dose. Our results suggest that a lower vaccine dose may be justified in order to increase population coverage, thereby reducing the infection attack rate overall.
Steven Riley and colleagues examine the potential benefits of "stretching" a limited supply of vaccine and suggest that substantial reductions in the attack rate are possible if vaccines are given to more people at lower doses.
Editors' Summary
Background.
Every winter, millions of people catch influenza, a viral infection of the nose, throat, and airways. Most recover quickly, but the disease can be deadly. In the US, seasonal influenza outbreaks (epidemics) cause 36,000 excess deaths annually. And now there are fears that an avian (bird) influenza virus might trigger a human influenza pandemic—a global epidemic that could kill millions. Seasonal epidemics occur because flu viruses continually make small changes to their hemagglutinin and neuraminidase molecules, the viral proteins (antigens) that the immune system recognizes. Because of this “antigenic drift,” an immune system response (which can be induced by catching flu or by vaccination with disabled circulating influenza strains) that combats flu one year may provide only partial protection the next year. “Antigenic shift” (large changes in flu antigens) can cause pandemics because communities have no immunity to the changed virus.
Why Was This Study Done?
Although avian influenza virus, which contains a hemagglutinin type that differs from currently circulating human flu viruses, has caused a few cases of human influenza, it has not started a human pandemic yet because it cannot move easily between people. If it acquires this property, which will probably involve further small antigenic changes, it could kill millions of people before scientists can develop an effective vaccine against it. To provide some interim protection, many countries are preparing stockpiles of “pre-pandemic” vaccines targeted against the avian virus. The US, for example, plans to store enough pre-pandemic vaccine to provide maximum protection to 20 million people (including key health workers) out of its population of 300 million. But, given a limited stockpile of pre-pandemic vaccine, might giving more people a lower dose of vaccine, which might reduce the number of people susceptible to infection and induce herd immunity by preventing efficient transmission of the flu virus, be a better way to limit the spread of pandemic influenza? In this study, the researchers have used mathematical modeling to investigate this question.
What Did the Researchers Do and Find?
To predict the infection rates associated with different vaccination policies, the researchers developed a mathematical model that incorporates data on human immune responses induced with three experimental vaccines against the avian virus and historical data on the person–person transmission of previous pandemic influenza viruses. For all the vaccines, the model predicts that giving more people a low dose of the vaccine would limit the spread of influenza better than giving fewer people the high dose needed for full individual protection. For example, the researchers estimate that dividing the planned US stockpile of one experimental vaccine equally between 160 million people instead of giving it at the fully protective dose to 20 million people might avert about 27 million influenza cases in less than year. However, giving the maximally protective dose to the 9 million US health-care workers and using the remaining vaccine at a lower dose to optimize protection within the general population might avert only 14 million infections.
What Do These Findings Mean?
These findings suggest that, given a limited stockpile of pre-pandemic vaccine, increasing the population coverage of vaccination by using low doses of vaccine might reduce the overall influenza infection rate more effectively than vaccinating fewer people with fully protective doses of vaccine. However, because the researchers' model includes many assumptions, it can only give an indication of how different strategies might perform, not firm numbers for how many influenza cases each strategy is likely to avert. Before public-health officials use this or a similar model to help them decide the best way to use pre-pandemic vaccines to control a human influenza pandemic, they will need more information about the efficacy of these vaccines and about transmission rates of currently circulating viruses. They will also need to know whether pre-pandemic vaccines actually provide good protection against the pandemic virus, as assumed in this study, before they can recommend mass immunization with low doses of pre-pandemic vaccine, selective vaccination with high doses, or a mixed strategy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040218.
US Centers for Disease Control and Prevention provide information on influenza and influenza vaccination for patients and health professionals (in English, Spanish, Filipino, Chinese, and Vietnamese)
The World Health Organization has a fact sheet on influenza and on the global response to avian influenza (in English, Spanish, French, Russian, Arabic, and Chinese)
The MedlinePlus online encyclopedia devotes a page to flu (in English and Spanish)
The UK Health Protection Agency information on avian, pandemic, and seasonal influenza
The US National Institute of Allergy and Infectious Diseases has a comprehensive feature called “focus on the flu”
doi:10.1371/journal.pmed.0040218
PMCID: PMC1892041  PMID: 17579511
16.  Environmental Issues in Managing Asthma 
Respiratory care  2008;53(5):602-617.
Management of asthma requires attention to environmental exposures both indoors and outdoors. Americans spend most of their time indoors, where they have a greater ability to modify their environment. The indoor environment contains both pollutants (eg, particulate matter, nitrogen dioxide, secondhand smoke, and ozone) and allergens from furred pets, dust mites, cockroaches, rodents, and molds. Indoor particulate matter consists of particles generated from indoor sources such as cooking and cleaning activities, and particles that penetrate from the outdoors. Nitrogen dioxide sources include gas stoves, furnaces, and fireplaces. Indoor particulate matter and nitrogen dioxide are linked to asthma morbidity. The indoor ozone concentration is mainly influenced by the outdoor ozone concentration. The health effects of indoor ozone exposure have not been well studied. In contrast, there is substantial evidence of detrimental health effects from secondhand smoke. Guideline recommendations are not specific for optimizing indoor air quality. The 2007 National Asthma Education and Prevention Program asthma guidelines recommend eliminating indoor smoking and improving the ventilation. Though the guidelines state that there is insufficient evidence to recommend air cleaners, air cleaners and reducing activities that generate indoor pollutants may be sound practical approaches for improving the health of individuals with asthma. The guidelines are more specific about allergen avoidance; they recommend identifying allergens to which the individual is immunoglobin E sensitized and employing a multifaceted, comprehensive strategy to reduce exposure. Outdoor air pollutants that impact asthma include particulate matter, ozone, nitrogen dioxide, and sulfur dioxide, and guidelines recommend that individuals with asthma avoid exertion outdoors when these pollutants are elevated. Outdoor allergens include tree, grass, and weed pollens, which vary in concentration by season. Recommendations to reduce exposure include staying indoors, keeping windows and doors closed, using air conditioning and perhaps high-efficiency particulate arrestor (HEPA) air filters, and thorough daily washing to remove allergens from one’s person.
PMCID: PMC2396450  PMID: 18426614
asthma; pollutants; particulate matter; nitrogen dioxide; sulfur dioxide; secondhand smoke; ozone; allergens
17.  Bioterrorism in Canada: An economic assessment of prevention and postattack response 
The present paper calculates the human and economic consequences of a bioterrorist attack on Canadian soil using aerosolized Bacillus anthracis and Clostridium botulinum. The study assumed that 100,000 people in a Canadian suburban neighbourhood were exposed over a 2 h period to an infectious dose of one of the agents. Using an epidemic curve based on the epidemiology and management of anthrax and botulinum poisoning, the costs of intervention and treatment after an attack were compared with the costs of preparedness before a bioterrorist attack. The results show that an investment in planning and preparedness to manage the consequences of an attack can reduce morbidity, mortality and economic costs. The sooner that an intervention program is instituted, the more significant are the health and economic benefits. The greatest benefits were realized when postattack intervention was initiated before day 3 after the event. The economic impact of a bioterrorist attack in Canada could range from $6.4 billion/100,000 exposed to B anthracis to $8.6 billion/100,000 exposed in an attack using C botulinum. Without the benefit of an effective consequence management program, predicted deaths totalled 32,875 from anthrax and 30,000 from botulinum toxin. Rapid implementation of a postattack prophylaxis program that includes the stockpiling of antibiotics, vaccines and antitoxins; training of first responders in the diagnosis, handling and treatment of pathogens; and the general enhancement of Canada's response capability would reduce both human and economic losses.
PMCID: PMC2094836  PMID: 18159350
Actuarially fair premium; Anthrax; Bioterrorism; Botulinum toxin; Economic consequences
18.  Evidence of Local Persistence of Human Anthrax in the Country of Georgia Associated with Environmental and Anthropogenic Factors 
Background
Anthrax is a soil-borne disease caused by the bacterium Bacillus anthracis and is considered a neglected zoonosis. In the country of Georgia, recent reports have indicated an increase in the incidence of human anthrax. Identifying sub-national areas of increased risk may help direct appropriate public health control measures. The purpose of this study was to evaluate the spatial distribution of human anthrax and identify environmental/anthropogenic factors associated with persistent clusters.
Methods/Findings
A database of human cutaneous anthrax in Georgia during the period 2000–2009 was constructed using a geographic information system (GIS) with case data recorded to the community location. The spatial scan statistic was used to identify persistence of human cutaneous anthrax. Risk factors related to clusters of persistence were modeled using a multivariate logistic regression. Areas of persistence were identified in the southeastern part of the country. Results indicated that the persistence of human cutaneous anthrax showed a strong positive association with soil pH and urban areas.
Conclusions/Significance
Anthrax represents a persistent threat to public and veterinary health in Georgia. The findings here showed that the local level heterogeneity in the persistence of human cutaneous anthrax necessitates directed interventions to mitigate the disease. High risk areas identified in this study can be targeted for public health control measures such as farmer education and livestock vaccination campaigns.
Author Summary
Anthrax is a zoonotic bacterial disease that occurs nearly worldwide. Despite a large number of countries reporting endemic anthrax, persistence of the disease appears to be associated with specific ecological factors related to soil composition and climatic conditions. Human cases are most often associated with handling infected livestock or contaminated meat and most cases are in cutaneous form (skin infections). Following the collapse of the Soviet Union, the country of Georgia has undergone major restructuring in land management and livestock handling and anthrax remains a serious public health risk. Few studies have evaluated the local spatial patterns of human anthrax. Here we identify areas on the landscape where human cutaneous anthrax persisted over the last decade. Persistence was found to be associated with both anthropogenic and environmental factors including soil pH and livestock density. These findings aid in the establishment of spatial baseline estimates of the disease and allow public health officials to adopt targeted anthrax control strategies, such as livestock vaccination campaigns and farmer education.
doi:10.1371/journal.pntd.0002388
PMCID: PMC3764226  PMID: 24040426
19.  Live Attenuated Tularemia Vaccines: Recent Developments and Future Goals 
Vaccine  2013;31(35):3485-3491.
In the aftermath of the 2001 anthrax attacks in the U.S., numerous efforts were made to increase the level of preparedness against a biological attack both in the US and worldwide. As a result, there has been an increase in research interest in the development of vaccines and other countermeasures against a number of agents with the potential to be used as biological weapons. One such agent, Francisella tularensis, has been the subject of a surge in the level of research being performed, leading to a substantial increase in knowledge of the pathogenic mechanisms of the organism and the induced immune responses. This information has facilitated the development of multiple new Francisella vaccine candidates. Herein we review the latest live attenuated F. tularensis vaccine efforts. Historically, live attenuated vaccines have demonstrated the greatest degree of success in protection against tularemia and the greatest promise in recent efforts to develop of a fully protective vaccine. This review summarizes recent live attenuated Francisella vaccine candidates and the lessons learned from those studies, with the goal of collating known characteristics associated with successful attenuation, immunogenicity, and protection.
doi:10.1016/j.vaccine.2013.05.096
PMCID: PMC3766925  PMID: 23764535
Francisella tularensis; live attenuated vaccines; LVS; Schu S4
20.  Systemic but not mucosal immunity induced by AVA prevents inhalational anthrax 
Microbes and infection / Institut Pasteur  2007;9(12-13):1478-1483.
Improved vaccines and adjuvants are being developed to reduce the threat posed by a terrorist attack involving aerosolized anthrax spores. Nevertheless, uncertainty persists concerning the relative benefits of inducing mucosal vs systemic immunity to host survival following inhalational exposure to anthrax spores. This work examines the effect of delivering the licensed human vaccine (Anthrax Vaccine Adsorbed, AVA) combined with a CpG oligodeoxynucleotide (ODN) adjuvant intraperitoneally or intranasally to A/J mice. Results indicate that protection from inhalational anthrax correlates with the induction of a strong systemic rather than mucosal immune response, and demonstrate that protection is significantly improved and accelerated by the addition of CpG ODN.
doi:10.1016/j.micinf.2007.08.002
PMCID: PMC2117355  PMID: 17913545
Anthrax; vaccine; protection
21.  Assessment of Nanoparticle Exposure in Nanosilica Handling Process: Including Characteristics of Nanoparticles Leaking from a Vacuum Cleaner 
Industrial Health  2013;52(2):152-162.
Nanosilica is one of the most widely used nanomaterials across the world. However, their assessment data on the occupational exposure to nanoparticles is insufficient. The present study performed an exposure monitoring in workplace environments where synthetic powders are prepared using fumed nanosilica. Furthermore, after it was observed during exposure monitoring that nanoparticles were emitted through leakage in a vacuum cleaner (even with a HEPA-filter installed in it), the properties of the leaked nanoparticles were also investigated. Workers were exposed to high-concentration nanosilica emitted into the air while pouring it into a container or transferring the container. The use of a vacuum cleaner with a leak (caused by an inadequate sealing) was found to be the origin of nanosilica dispersion in the indoor air. While the particle size of the nanosilica that emitted into the air (during the handling of nanosilica by a worker) was mostly over 100 nm or several microns (µm) due to the coagulation of particles, the size of nanosilica that leaked out of vacuum cleaner was almost similar to the primary size (mode diameter 11.5 nm). Analysis of area samples resulted in 20% (60% in terms of peak concentration) less than the analysis of the personals sample.
doi:10.2486/indhealth.2013-0087
PMCID: PMC4202753  PMID: 24366536
Exposure assessment; Nanomaterials; Silica nanoparticle; Aerosol characteristic; Vacuum cleaner leakage
22.  Expression of Bacillus anthracis protective antigen in transgenic chloroplasts of tobacco, a non-food/feed crop 
Vaccine  2004;22(31-32):4374-4384.
The Centers for Disease Control (CDC) lists Bacillus anthracis as a category A agent and estimates the cost of an anthrax attack to exceed US$ 26 billion per 100,000 exposed individuals. Concerns regarding anthrax vaccine purity, a requirement for multiple injections, and a limited supply of the protective antigen (PA), underscore the urgent need for an improved vaccine. Therefore, the 83 kDa immunogenic Bacillus anthracis protective antigen was expressed in transgenic tobacco chloroplasts. The PA gene (pag) was cloned into a chloroplast vector along with the psbA regulatory signals to enhance translation. Chloroplast integration of the transgenes was confirmed by PCR and Southern blot analyses. Crude plant extracts contained up to 2.5 mg full length PA/g of fresh leaf tissue and this showed exceptional stability for several months in stored leaves or crude extracts. Maximum levels of expression were observed in mature leaves under continuous illumination. Co-expression of the ORF2 chaperonin from Bacillus thuringiensis did not increase PA accumulation or induce folding into cuboidal crystals in transgenic chloroplasts. Trypsin, chymotrypsin and furin proteolytic cleavage sites present in PA were protected in transgenic chloroplasts because only full length PA 83 was observed without any degradation products. Both CHAPS and SDS detergents extracted PA with equal efficiency and PA was observed in the soluble fraction. Chloroplast-derived PA was functionally active in lysing mouse macrophages when combined with lethal factor (LF). Crude leaf extracts contained up to 25 μg functional PA/ml. With an average yield of 172 mg of PA per plant using an experimental transgenic cultivar grown in a greenhouse, 400 million doses of vaccine (free of contaminants) could be produced per acre, a yield that could be further enhanced 18-fold using a commercial cultivar in the field.
doi:10.1016/j.vaccine.2004.01.069
PMCID: PMC3481842  PMID: 15474731
Bioterrorism; GM crops; Anthrax vaccine
23.  Immunization of Mice with Lactobacillus casei Expressing a Beta-Intimin Fragment Reduces Intestinal Colonization by Citrobacter rodentium ▿ † 
Clinical and Vaccine Immunology : CVI  2011;18(11):1823-1833.
Enteropathogenic Escherichia coli (EPEC) is a common cause of diarrhea in children from developing countries. Intimate adhesion of the bacteria to intestinal cells occurs via binding of the adhesin intimin to the TIR receptor exposed on cell surfaces. Here, Lactobacillus casei expressing a fragment of β-intimin (L. casei-Intcv) was tested as mucosal vaccines in mice against intestinal colonization with the murine pathogen Citrobacter rodentium. Oral or sublingual immunization of C57BL/6 mice with L. casei-Intcv induced anti-Intcv IgA in feces but no IgG in sera. Conversely, anti-Intcv IgG was induced in the sera of mice after sublingual immunization with purified Intcv. All vaccines were able to decrease C. rodentium recovery from feces. However, this reduction was more evident and sustained over time in mice immunized with L. casei-Intcv by the sublingual route. These mice also displayed an increase in interleukin 6 (IL-6) and gamma interferon (IFN-γ) secretion by spleen cells 10 days after infection. Additionally, oral or sublingual immunization of C3H/HePas mice, which are highly susceptible to C. rodentium infection, with L. casei-Intcv induced anti-Intcv antibodies and significantly increased survival after challenge. Immunohistological analysis of colon sections revealed that C. rodentium was located in deep fractions of the tissue from C3H/HePas mice immunized with L. casei whereas superficial staining was observed in colon sections from mice immunized with L. casei-Intcv. The results indicate that vaccines composed of L. casei expressing intimin may represent a promising approach and that the C3H/HePas infection model with C. rodentium can be used to evaluate potential vaccines against EPEC.
doi:10.1128/CVI.05262-11
PMCID: PMC3209022  PMID: 21900533
24.  Frequency of Adverse Events after Vaccination with Different Vaccinia Strains 
PLoS Medicine  2006;3(8):e272.
Background
Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH) strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus.
Methods and Findings
We analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect that showed decreasing incidences of adverse events over several decades. To estimate death rates, we then restricted our analysis to more-recent studies. We estimated that vaccination with the NYCBH strain leads to an average of 1.4 deaths per million vaccinations (95% credible interval, 0–6) and that vaccination with Lister vaccine leads to an average of 8.4 deaths per million vaccinations (95% credible interval, 0–31). We combined age-dependent estimates of the frequency of death after vaccination and revaccination with demographic data to obtain estimates of the expected number of deaths in present societies due to vaccination with the NYCBH and Lister vaccinia strains.
Conclusions
Previous analyses of smallpox vaccination policies, which rely on the commonly assumed value of one death per million vaccinations, may give serious underestimates of the number of deaths resulting from vaccination. Moreover, because there are large, strain-dependent differences in the frequency of adverse events due to smallpox vaccination, it is difficult to extrapolate from predictions for the NYCBH-derived vaccines (stockpiled in countries such as the US) to predictions for the Lister-derived vaccines (stockpiled in countries such as Germany). In planning for an effective response to a possible smallpox outbreak, public-health decision makers should reconsider their strategies of when to opt for ring vaccination and when to opt for mass vaccination.
Analysis of historical data for adverse events suggests that the commonly assumed number of one death per million vaccinations is inaccurate. Large differences between different vaccinia strains used should be taken into account when mass vaccinations are considered.
Editors' Summary
Background.
For thousands of years, smallpox was one of the world's most-feared diseases. This contagious disease, caused by the variola virus, historically killed about 30 percent of the people it infected. Over the centuries, it probably killed more people than all other infectious diseases combined, but it was also the first disease to be prevented by vaccination. In 1796, the English physician Edward Jenner rubbed pus from the spots of a milkmaid with cowpox into scratches on a young boy's arm; according to folklore, people who caught cowpox, a related but mild disease of cows, were protected against smallpox. Six weeks later, after a mild bout of cowpox, when the boy was challenged with pus from a smallpox patient, he did not develop smallpox. This vaccination procedure was later refined so that people were inoculated with pure preparations of live vaccinia virus, which is closely related to the smallpox and cowpox viruses, and by 1979 a global vaccination campaign had totally eradicated the disease.
Why Was This Study Done?
Smallpox vaccination has some adverse effects. In particular, vaccinia virus occasionally infects the brain. This so-called post-vaccination encephalitis can cause permanent brain damage and, it has been estimated, kills one vaccinee in every million. Consequently, as smallpox became rarer, the dangers of vaccination began to outweigh its benefits. Routine smallpox vaccination stopped in the US in 1972, and in 1980 the World Health Organization recommended that all countries stop vaccination. Now, however, there are fears that smallpox may be used for bioterrorism. If this did happen, exposed individuals and their contacts, possibly even whole populations, would have to be vaccinated as quickly as possible (very few people now have strong immunity to smallpox). Many countries have stockpiles of smallpox vaccines for this eventuality, but these contain different vaccinia virus strains. In this study, the researchers examined historical data to discover whether these strains differ in their potential to cause encephalitis and death. This information should help public-health officials plan their vaccination strategies in response to a bioterrorism attack with smallpox.
What Did the Researchers Do and Find?
The researchers collected data from published studies on smallpox vaccination and adverse events from several countries from the late 1950s onwards. They then used these data to extrapolate how often the different vaccinia strains might cause encephalitis and death if they were used today in vaccination programs. They estimate that vaccinating with the New York City Board of Health (NYCBH) strain, which is stockpiled in the US, might cause 2.9 cases of post-vaccination encephalitis and 1.4 deaths per million vaccinated individuals. In contrast, the Lister strain, which is stockpiled in many European countries, might cause 26.2 cases of post-vaccination encephalitis and 2.5 deaths per million vaccinees. For both strains, vaccination of children younger than 1 year old would cause the highest death rate, and individuals being re-vaccinated would be less likely to die than those being vaccinated for the first time. Finally, the researchers use their figures to estimate that about ten people would die if mass vaccination with the NYCBH strain were used in the Netherlands (population 16 million), whereas 55 people would die if the Lister strain were used.
What Do These Findings Mean?
The data used in this study are of variable quality, so the figures calculated by the researchers are only estimates. For instance, given the scatter of the original data, mass vaccination in the Netherlands with the Lister strain might cause anywhere between seven and nearly 200 deaths. However, the study clearly suggests that more serious adverse events would occur after vaccination with the Lister strain than after vaccination with the NYCBH strain. It also indicates that even in the US, where the NYCBH vaccine strain is stockpiled, previous analyses of the effects of vaccination in response to a bioterrorist attack have probably underestimated how many people might die from post-vaccination encephalitis. Public-health decision makers should incorporate these new estimates into their planning for a smallpox outbreak. These increased estimates of adverse events after vaccination might, for example, make mass vaccination with the Lister strain of vaccinia virus less acceptable. Instead, public-health officials might decide to rely on vaccination of only the people directly exposed to released smallpox virus and their close contacts (ring vaccination) to contain a smallpox outbreak.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030272.
World Health Organization, information on smallpox and preparedness in the event of a smallpox outbreak
MedlinePlus encyclopedia entry on smallpox
US National Institute of Allergy and Infectious Diseases, patient fact sheet on smallpox
US Centers for Disease Control and Prevention, information for patients and professionals on smallpox
Wikipedia page on smallpox (note that Wikipedia is a free online encyclopedia that anyone can edit)
Wellcome Library MedHist, links to information on the history of smallpox vaccination
doi:10.1371/journal.pmed.0030272
PMCID: PMC1551910  PMID: 16933957
25.  Changing Patterns of Human Anthrax in Azerbaijan during the Post-Soviet and Preemptive Livestock Vaccination Eras 
We assessed spatial and temporal changes in the occurrence of human anthrax in Azerbaijan during 1984 through 2010. Data on livestock outbreaks, vaccination efforts, and human anthrax incidence during Soviet governance, post-Soviet governance, preemptive livestock vaccination were analyzed. To evaluate changes in the spatio-temporal distribution of anthrax, we used a combination of spatial analysis, cluster detection, and weighted least squares segmented regression. Results indicated an annual percent change in incidence of +11.95% from 1984 to 1995 followed by declining rate of −35.24% after the initiation of livestock vaccination in 1996. Our findings also revealed geographic variation in the spatial distribution of reporting; cases were primarily concentrated in the west early in the study period and shifted eastward as time progressed. Over twenty years after the dissolution of the Soviet Union, the distribution of human anthrax in Azerbaijan has undergone marked changes. Despite decreases in the incidence of human anthrax, continued control measures in livestock are needed to mitigate its occurrence. The shifting patterns of human anthrax highlight the need for an integrated “One Health” approach that takes into account the changing geographic distribution of the disease.
Author Summary
Zoonotic diseases, such as anthrax, represent a threat to public and veterinary health in many developing parts of the world. Control of anthrax is dependent upon several factors, including proper management of outbreaks and livestock vaccination. Following the dissolution of the Soviet Union, resources for disease management in Azerbaijan were dramatically diminished leading to increases in zoonotic diseases. In this study, our objective was to analyze human anthrax incidence during Soviet governance, post-Soviet governance, and after the implementation of a preemptive livestock vaccination campaign to identify potential changes in the occurrence of the disease. We applied spatial and temporal statistical approaches in a geographic information system to describe changes. Our findings provide evidence of a changing incidence and a shift in the geographic patterns of human anthrax. These findings highlight the importance of proper livestock disease management to mitigate human disease and the need for dynamic surveillance that takes into account changes in the distribution of disease.
doi:10.1371/journal.pntd.0002985
PMCID: PMC4102439  PMID: 25032701

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